interleukin-8 and Reperfusion-Injury

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; 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Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

The goal of this study was to investigate whether hemoglobin-based oxygen carrier (HBOC) attenuated ischemia/reperfusion (I/R)-induced kidney injury. Male SD rats were randomly divided into a sham group, I/R group, and HBOC group (injection of 0.1 gHb/kg PolyPHb). The ischemia was induced by bilateral renal pedicle cross-clamping for 45min. Then the clamp was released to allow 24h reperfusion. Without increasing blood pressure, PolyPHb reduced the blood urea nitrogen and creatinine in plasma and attenuated the tumor necrosis factor-α and interleukin-8 in kidney tissue. Therefore, our findings suggest that PolyPHb could reduce kidney injury after I/R injury, and this effect was probably associated with the depressed inflammatory response.

Topics: Animals; Blood Substitutes; Female; Hemoglobins; Humans; Interleukin-8; Kidney; Male; Models, Animal; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

Topics: Animals; Hepatitis; Humans; Interleukin-8; Ischemia; Liver; Neutrophils; Reperfusion Injury

Neutrophil recruitment is one of the hallmarks of acute inflammation. A potent neutrophil chemotactic and activating factor, interleukin-8 (IL-8), has been demonstrated to be elevated in body fluids in various human diseases and experimental animal models. Recent investigations on animal disease models using blocking antibodies to IL-8 have revealed the essential involvement of IL-8 in acute inflammation. We previously reported that the administration of a neutralizing antibody against IL-8 prevented the neutrophil infiltration and neutrophil-mediated tissue injury in several animal studies. In addition, we have recently demonstrated that anti-IL-8 treatment is also effective in prevention of two models that are very relevant to clinical situations: cerebral reperfusion injury and endotoxemia-induced acute respiratory distress syndrome-like lung injury. These results further support the hypothesis that IL-8 has a pivotal role and is a novel target for therapeutic intervention in neutrophil-mediated injury.

Topics: Animals; Brain; Brain Diseases; Humans; Interleukin-8; Reperfusion Injury; Respiratory Distress Syndrome

Neutrophil infiltration into inflammatory sites is one of the hallmarks of acute inflammation. Locally produced chemotactic factors are presumed to mediate the sequence of events leading to the infiltration at inflammatory sites. Interleukin-8 (IL-8), a novel leukocyte chemotactic activating cytokine (chemokine), is produced by various types of cells upon stimulation with inflammatory stimuli and exerts a variety of functions on leukocytes, particularly, neutrophils in vitro. However, no definitive evidence has been presented on its role in recruiting and activating neutrophils in the lesions of various types of inflammatory reactions. We administered a highly specific neutralizing antibody against IL-8 in several types of acute inflammatory reactions, including lipopolysaccharide (LPS)-induced dermatitis, LPS/IL-1-induced arthritis, lung reperfusion injury, and acute immune complex-type glomerulonephritis. Anti-IL-8 treatment prevented neutrophil-dependent tissue damage as well as neutrophil infiltration in these conditions. These results suggest that IL-8 plays a causative role in acute inflammation by recruiting and activating neutrophils.

Topics: Animals; Antibodies; Antigen-Antibody Complex; Arthritis; Cross Reactions; Dermatitis; Glomerulonephritis; Inflammation; Inflammation Mediators; Interleukin-1; Interleukin-8; Lipopolysaccharides; Lung Diseases; Neutrophil Activation; Neutrophils; Rabbits; Reperfusion Injury

Topics: Arteriosclerosis; Arthritis, Rheumatoid; Chemokine CCL2; Chemotactic Factors; Humans; Interleukin-8; Lung Diseases; Neutrophils; Reperfusion Injury

To compare the effect between nebulized and intravenous administration of Shenmai Injection () on pulmonary gas exchange function of patients following tourniquet-induced lower limb ischemia-reperfusion.. Thirty-eight patients scheduled for lower extremity surgery were randomized into three groups using the closed envelop method: Shenmai Injection was administered 30 min before tourniquet inflflation by nebulization [0.6 mL/kg in 10 mL normal saline (NS)] in the nebulization group or by intravenous drip (0.6 mL/kg dissolved in 250 mL of 10% glucose) in the intravenous drip group, and equal volume of NS was given intravenously in the NS group; 15 in each group. Arterial blood gases were analyzed, serum levels of malonaldehyde (MDA) and interleukine-6 (IL-6) and interleukine-8 (IL-8) were determined using the method of thiobarbituric acid reaction and enzyme-linked immuno sorbent assay respectively just before tourniquet inflflation (T0), and at 0.5 h (T1), 2 h (T2), 6 h (T3) after tourniquet deflflation.. Compared with baselines at T0, MDA levels signifificantly increased at T2, T3 in the NS group and at T3 in the nebulization group, and IL-6 and IL-8 levels were signifificantly increased at T2, T3 in NS, the intravenous drip and the nebulization groups (P <0.05). Arterial pressure of oxygen (PaO. Intravenous administration of Shenmai Injection provided a better protective effect than nebulization in mitigating pulmonary gas exchange dysfunction in patients following tourniquet-induced limb ischemia-reperfusion.

Topics: Adult; Blood Gas Analysis; Drug Administration Routes; Drug Combinations; Drugs, Chinese Herbal; Female; Humans; Injections; Interleukin-6; Interleukin-8; Male; Malondialdehyde; Pulmonary Gas Exchange; Reperfusion Injury; Tourniquets

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

To investigate the effects of dexmedetomidine preconditioning attenuating remote lung injury of lower limb ischemia-reperfusion.. Sixty patients form Central Hospital of Cangzhou scheduled for lower limb operation with tourniquet from January 2014 to June 2014. Lumbar plexus combined with sciatic nerve block was performed guided by a nerve stimulator in both groups. All patients were randomly assigned to two groups, conventional general anesthesia group (R group, n = 30) and dexmedetomidine preconditioning group (Pre-Dex group, n = 30). In the group Pre-Dex, a dexmedetomidine intravenous infusion was started at a dose of 0.125 ml/kg (4 µg/ml) for 10 minutes before using tourniquet, whereas group R received an equivalent volume of normal saline. Blood samples were taken in femoral vein for 4 ml. Monocytes TLR4 expression and interleukin-6(IL-6), interleukin-8(IL-8), tumor necrosis factor-α(TNF-α) level were determinated 15 minute before tourniquet inflation(T(1)), 15 minute (T(2)), 2 h(T(3)), 6 h(T(4))and 24 h(T(5)) after tourniquet release. Artery blood gas analysis, respiratory index and oxygenation index were measured by drawing off femoral artery for 2 ml.. Compare with T(1), RI in group R was higher at T(4) and OI was lower at T(3-5) (P < 0.01), and there were no significant differences in group Pre-Dex at T(2)-T(5) about RI and OI (P > 0.05); IL-8,IL-6 level at T(3)-T(5) and TNF-α level at T(2)-T(5) in group R were significantly higher. IL-8,IL-6 level at T(3)-T(4) and TNF-α level at T(2)-T(4) in group Pre-Dex were higher. Monocytes TLR4 expression was higher in group R at T(3)-T(4) (P < 0.05). Compare with group R, RI in group Pre-Dex was lower and OI was higher at T(4) (P < 0.05); IL-8, IL-6 level at T(3)-T(5) and TNF-α level at T(2)-T(4) in group Pre-Dex was significantly lower (P < 0.05). Monocytes TLR4 expression was lower in group Pre-Dex at T(3)-T(5) (P < 0.05). IL-6, IL-8 level had positive correlation with TLR4 and RI ((r = 0.673, 0.647, 0.521, 0.457, P < 0.01 ), but had negative correlation with OI in group R (r = -0.613, -0.578, P < 0.01).. Dexmedetomidine preconditioning attenuate remote lung injury of lower limb ischemia-reperfusion, and the mechanism may be related to down-regulation of monocytes TLR4 expression and degradation of IL-6, IL-8 and TNF-α level.

Topics: Dexmedetomidine; Humans; Interleukin-6; Interleukin-8; Lower Extremity; Lung Injury; Reperfusion Injury; Tourniquets; Tumor Necrosis Factor-alpha

Hypothermic machine perfusion (HMP) has shown significant benefits in renal transplantation but is still in its infancy in liver transplantation. Potential benefits include diminished preservation injury and improved early graft function.. We analyzed liver tissue and effluent collected during our Phase 1 trial of liver HMP. Liver allografts underwent HMP for 4-7 h using dual centrifugal perfusion with Vasosol solution at 4-8°C were transplanted and compared with cold stored (CS) transplant controls. Histology, reverse transcription-polymerase chain reaction (RT-PCR), and immunohistochemistry on liver biopsies compared histology and expression of early proinflammatory cytokines, IL-8 and TNF-α, and intracellular adhesion molecule-1 (ICAM-1). Gel electrophoresis was used to evaluate effluent protein content representing residual metabolism.. We saw no differences between HMP and CS in early histologic findings after reperfusion. RT-PCR of reperfusion biopsy samples in the CS group showed high expression of proinflammatory cytokines and ICAM-1. This up-regulation was significantly attenuated by HMP (ICAM-1; P = 0.0152) (IL-8; P = 0.0014) (TNF-α; P = 0.0284). This was confirmed with immunohistochemistry. Albumin was identified in the perfusate throughout HMP.. HMP significantly reduced proinflammatory cytokine expression compared with CS controls. Further studies of human liver HMP with detailed molecular investigations are now warranted to elucidate benefits of HMP in liver transplantation.

Topics: Adult; Aged; Biomarkers; Biopsy; Humans; Hypothermia, Induced; Intercellular Adhesion Molecule-1; Interleukin-8; Liver; Liver Transplantation; Middle Aged; Organ Preservation; Organ Preservation Solutions; Reperfusion Injury; Transplantation, Homologous; Tumor Necrosis Factor-alpha

Tourniquet has been considered as a recognized cause of lower limb ischemia-reperfusion injury in the orthopedic field. This study investigates pulmonary function after tourniquet deflation and the protective effect of Shenmai injection (SMI), a traditional Chinese medicine.. Twenty-eight patients undergoing lower extremity surgery were randomized into a control group (group C) and a SMI group (group S), 14 patients in each group. Blood gas and circulating indicators (malondialdehyde, interleukin [IL]-6, and IL-8) were measured immediately before tourniquet inflation and at 0.5 hour, 2 hours, 6 hours, and 24 hours after tourniquet deflation.. Plasma levels of malondialdehyde, IL-6, and IL-8 in group C were significantly increased over baselines from 2 hours to 24 hours after tourniquet deflation and the levels reached their peaks at 6 hours after tourniquet deflation, when arterial partial pressures of oxygen and arterial-alveolar oxygen tension ratio were decreased, whereas alveolar-arterial oxygen difference was increased significantly. Both the changes in blood gas variables and plasma mediators were attenuated in group S.. Pulmonary gas exchange is impaired after lower limb ischemia-reperfusion induced by clinical tourniquet application. Pretreatment with SMI, a traditional Chinese medicine, attenuates lipid peroxidation and systemic inflammatory response and mitigates pulmonary dysfunction.

Topics: Adult; Blood Gas Analysis; Blood Pressure; Double-Blind Method; Drug Combinations; Drugs, Chinese Herbal; Female; Heart Rate; Humans; Interleukin-6; Interleukin-8; Leg; Male; Malondialdehyde; Reperfusion Injury; Tourniquets

Acute lung injury is a recognized complication of lower limb ischemia-reperfusion that has been demonstrated experimentally and in the clinical setting of aortic surgery. The application of a tourniquet can cause lower limb ischemia-reperfusion in orthopedic surgery. We studied the effect of unilateral thigh tourniquet-induced lower limb ischemia-reperfusion on pulmonary function, and the role of ischemic preconditioning in attenuating pulmonary dysfunction.. Thirty ASA I or II patients scheduled for lower extremity surgery were randomized into 2 groups: a limb ischemia-reperfusion group with tourniquet application (ischemia-reperfusion group, n = 15) and an ischemia preconditioning group (preconditioning group, n = 15), in which patients received 3 cycles of 5 minutes of ischemia, alternating with 5 minutes of reperfusion before extended use of the tourniquet. Blood gas, plasma malondialdehyde, and serum interleukin-6 (IL-6), IL-8, and IL-10 levels were measured just before tourniquet inflation, 1 hour after inflation and 2 hours, 6 hours, and 24 hours after tourniquet deflation. Arterial-alveolar oxygen tension ratio, alveolar-arterial oxygen tension difference, and respiratory index also were calculated.. In comparison with the baseline values, arterial Po(2) and arterial-alveolar oxygen tension ratio were decreased, while alveolar-arterial oxygen tension difference and respiratory index were increased significantly 6 hours after tourniquet deflation in both groups (P < 0.01). However, these changes were less significant in the ischemic preconditioning group than those in the lower limb ischemia-reperfusion group (P < 0.01). Similarly, the increases in the malondialdehyde, IL-6, and IL-8 from 2 hours to 24 hours after release of the tourniquet in the lower limb ischemia-reperfusion group were attenuated by ischemic preconditioning.. Pulmonary gas exchange is impaired after lower limb ischemia-reperfusion associated with the clinical use of a tourniquet for lower limb surgery. Ischemic preconditioning preceding tourniquet-induced ischemia attenuates lipid peroxidation and systemic inflammatory response and mitigates pulmonary dysfunction.

Topics: Acute Lung Injury; Adult; Biomarkers; Carbon Dioxide; Chi-Square Distribution; Female; Humans; Inflammation Mediators; Interleukin-10; Interleukin-6; Interleukin-8; Ischemic Preconditioning; Lipid Peroxidation; Lung; Male; Malondialdehyde; Middle Aged; Orthopedic Procedures; Oxygen; Prospective Studies; Pulmonary Gas Exchange; Regional Blood Flow; Reperfusion Injury; Thigh; Time Factors; Tourniquets; Treatment Outcome

The prophylactic administration of inhaled nitric oxide (NO) during reperfusion after lung transplantation has been shown to reduce neutrophil-induced injury in animal models. There remain questions regarding efficacy in the clinical setting and concerns regarding increased free radical injury. We sought to assess the efficacy of NO in reducing neutrophil infiltration and associated injury if administered from the very onset of reperfusion in clinical lung transplantation.. Twenty bilateral sequential lung transplant recipients were randomized to receive 20-ppm inhaled NO (NO group) or a standard anesthetic gas mixture (control group) from the onset of ventilation. Bronchoalveolar lavage was performed immediately prior to implantation and after 30 minutes of reperfusion and analyzed for inflammatory cytokine levels and free radical surrogates. Primary graft dysfunction (PGD) scoring was performed prospectively for 72 hours post-transplant.. The prophylactic administration of NO during the first 30 minutes of reperfusion had no statistically significant effect on the development of Grade II to III PGD (5 of 10 in NO group and 7 of 10 in control group, p = 0.36) or gas exchange (area under the curve: 429 +/- 296 vs 336 +/- 306; p = 0.64) in the NO and control groups, respectively. Pulmonary neutrophil sequestration, as measured by the transpulmonary arteriovenous neutrophil difference, was not influenced by the administration of NO. Prophylactic NO did not significantly alter the concentration of interleukin-8, myeloperoxidase or nitrotyrosine during transplantation.. This study could not demonstrate a significant effect of inhaled NO during the first 30 minutes of reperfusion in the prevention of neutrophil injury and primary graft dysfunction after lung transplantation.

Topics: Administration, Inhalation; Adult; Bronchoalveolar Lavage Fluid; Female; Free Radical Scavengers; Free Radicals; Graft Rejection; Humans; Interleukin-8; Lung; Lung Transplantation; Male; Middle Aged; Neutrophils; Nitric Oxide; Peroxidase; Reperfusion Injury; Tyrosine

Temporary vascular clampage (Pringle maneuver) during liver surgery can cause ischemia-reperfusion injury. In this process, activation of polymorphonuclear leukocytes (PMNLs) might play a major role. Thus, we investigated the effects of hepatic ischemic preconditioning on PMNL functions.. Prospective randomized study. Patients who underwent partial liver resection were randomly assigned to 3 groups: group 1 without Pringle maneuver; group 2 with Pringle maneuver, and group 3 with ischemic preconditioning using 10 minutes of ischemia and 10 minutes of reperfusion prior to Pringle maneuver for resection.. University hospital, Munich, Germany.. Seventy-five patients underwent hepatic surgery mostly owing to metastasis.. Perioperative factors for PMNL activation, inflammation, and postoperative hepatocellular integrity.. Ischemia-reperfusion of the human liver (mean +/- SD time to perform the Pringle maneuver, 35.5 +/- 2.6 minutes) caused (1) a decrease in the number of circulating PMNLs, (2) their intrahepatic sequestration, (3) their systemic activation, and (4) a significant correlation between the degree of their postischemic activation and the postoperative rise in liver enzyme serum levels. In parallel, cytokines with proinflammatory and chemotactic properties were released reaching the highest values when stimulation of PMNLs was most pronounced. When ischemic preconditioning preceded the Pringle maneuver, activation of PMNLs and cytokine plasma levels was reduced as evidenced by the attenuation of superoxide anion production, beta(2)-integrin up-regulation, and interleukin 8 serum concentrations, followed by a significant reduction in serum alanine aminotransferase levels on the first and second postoperative days.. These results demonstrate in humans that ischemic preconditioning reduces activation of PMNLs elicited by the Pringle maneuver. The down-regulation of potentially cytotoxic functions of PMNLs might be one of yet unknown important pathways that altogether mediate protection by ischemic preconditioning.

Topics: CD18 Antigens; Female; Hepatectomy; Humans; Interleukin-8; Ischemic Preconditioning; Liver Neoplasms; Male; Middle Aged; Neutrophil Activation; Neutrophils; Peroxidase; Prospective Studies; Reperfusion Injury

Nicorandil (NCR), a KATP channel opener, has been reported to preserve microvascular integrity in patients with reperfused myocardial infarction. We tested the hypothesis that NCR suppresses myocardial ischemia and reperfusion injury via the attenuation of cytokine production. Forty patients who underwent coronary artery bypass graft surgery were studied. The patients were randomly divided into two groups, i.e., the patients with NCR (4-6 mg/h; N group, n = 20) or without NCR (C group, n = 20). Cardiac surgery was performed under anesthesia using fentanyl and propofol. Blood were sampled at the time of induction of anesthesia, pre-cardiopulmonary bypass, 60 min after aortic occlusion, and 60, 120, and 180 min after declamping the aorta. The activation of NF-kappaB, expression of adhesion molecules, and cytokine production were evaluated in blood samples from the control volunteers by flow cytometric analysis with or without lipopolysaccharide (LPS) stimulation in vitro. Serum IL-6 and IL-8 levels in both groups increased 60 min after declamping the aorta compared with the preoperative value (P < 0.001); the increases of these parameters in N group were lower than those in C group (P < 0.05). Serum creatine kinase with muscle and brain subunits and troponin-T levels increased 60 min after declamping the aorta in two groups (P < 0,001), but the increases of both parameters in N group were lower than those in C group (P < 0.05). NF-kappaB activation, CD11b/CD18 expression, and the production of TNF-alpha, IL-8, and IL-6 in monocytes and granulocytes were inhibited by NCR in vitro. NCR suppressed the increase of inflammatory cytokines such as IL-6 and IL-8 levels, and reduced myocardial reperfusion injury. The inhibition on NF-kappaB activation, adhesion molecule expression, and cytokine production may be one of the important mechanisms of myocardial protection of NCR.

Topics: Antihypertensive Agents; Aorta; Brain; CD18 Antigens; Cell Adhesion; Coronary Artery Bypass; Creatine Kinase; Cytokines; Flow Cytometry; Granulocytes; Hemodynamics; Humans; Interleukin-6; Interleukin-8; Lipopolysaccharides; Monocytes; Muscles; Myocardium; NF-kappa B; Nicorandil; Potassium Channels; Reperfusion Injury; Time Factors; Troponin T

We investigated the immunoinflammatory profile of patients successfully resuscitated after cardiac arrest, representing a model of whole-body ischemia/reperfusion syndrome.. Plasma cytokine, endotoxin, and ex vivo cytokine production in whole-blood assays was assessed in 61, 35, and 11 patients, respectively. On admission, high levels of plasma interleukin (IL)-6, IL-8, IL-10, and soluble tumor necrosis factor (TNF) receptor type II could discriminate between survivors and nonsurvivors. Among nonsurvivors, the initial need for a vasopressor agent was associated with higher levels of IL-1 receptor antagonist, IL-10, and IL-6 on day 1. Plasma endotoxin was detected in 46% of the analyzed patients within the 2 first days. Endotoxin-induced TNF and IL-6 productions were dramatically impaired in these patients compared with healthy control subjects, whereas an unaltered production was observed with heat-killed Staphylococcus aureus. In contrast, IL-1 receptor antagonist productions were enhanced in these patients compared with healthy control subjects. The productions of T-cell-derived IL-10 and interferon-gamma were also impaired in these patients. Finally, using in vitro plasma exchange between healthy control subjects and patients, we demonstrated that the endotoxin-dependent hyporeactivity was an intrinsic property of patients' leukocytes and that an immunosuppressive activity was also present in their plasma.. Altogether, the high levels of circulating cytokines, the presence of endotoxin in plasma, and the dysregulated production of cytokines found in these patients recall the immunological profile found in patients with sepsis.

Topics: Aged; Antigens, CD; Cardiopulmonary Resuscitation; Cytokines; Endotoxins; Female; Glasgow Coma Scale; Heart Arrest; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-10; Interleukin-6; Interleukin-8; Leukocytes; Male; Middle Aged; Plasma; Predictive Value of Tests; Prospective Studies; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type II; Reference Values; Reperfusion Injury; Sialoglycoproteins; Survival Rate; Systemic Inflammatory Response Syndrome; Treatment Outcome

Cardiopulmonary bypass (CPB) causes inflammatory reactions and abnormal responses of vascular resistance. Theoretically, the difference in the blood temperature during CPB may influence the degree of CPB-induced inflammatory reactions.. To elucidate the effect of the perfusate temperature during CPB, serum levels of inflammatory cytokines, neutrophil elastase, complements, and vasoactive substances were measured in 18 patients undergoing elective coronary artery bypass grafting under tepid temperature (34 degrees C) and moderate hypothermia (28 degrees C). Respiratory index and systemic vascular resistance index during and after CPB and intubation time after postoperative course were also analyzed.. The patterns of the change in interleukin-8 and neutrophil elastase were significantly different between the two groups. The tepid group showed an earlier decrease in interleukin-8 and neutrophil elastase levels as compared with the hypothermic group. The prostaglandin E2 level just after CPB was significantly higher in the tepid group than in the hypothermic group. Systemic vascular resistance index and respiratory index and intubation time were significantly lower in the tepid group than in the hypothermic group.. These results demonstrated that tepid CPB affected the inflammatory cytokine release and neutrophil activation compared with hypothermic CPB, resulting in the attenuation of respiratory dysfunction. This may suggest a beneficial effect of tepid temperature in CPB with possible attenuation of the postperfusion syndrome.

Topics: Bradykinin; Cardiopulmonary Bypass; Dinoprostone; Hemodynamics; Humans; Inflammation Mediators; Interleukin-8; Leukocyte Elastase; Neutrophil Activation; Perfusion; Reperfusion Injury; Temperature; Vascular Resistance

Reperfusion after cerebral ischemia causes brain injury. Total saponins of Panax notoginseng (PNS) have potential roles in protecting against cerebral ischemia-reperfusion injury. However, whether PNS regulates astrocytes on oxygen-glucose deprivation/reperfusion (OGD/R) injury in rat brain microvascular endothelial cells (BMECs) and its mechanism still need further clarification.. Rat C6 glial cells were treated with PNS at different doses. Cell models were established by exposing C6 glial cells and BMECs to OGD/R. Cell viability was assessed, and levels of nitrite concentration, inflammatory factors (iNOS, IL-1β, IL-6, IL-8, TNF-α), and oxidative stress-related factors (MDA, SOD, GSH-Px, T-AOC) were subsequently measured through CCK8, Grice analysis, Western blot, and ELISA, respectively. The co-cultured C6 and endothelial cells were treated with PNS for 24 hours before model establishment. Then transendothelial electrical resistance (TEER), lactate dehydrogenase (LDH) activity, brain-derived neurotrophic factor (BDNF) content, and mRNA and protein levels and positive rates of tight junction proteins [Claudin-5, Occludin, ZO-1] were measured by a cell resistance meter, corresponding kits, ELISA, RT-qPCR, Western blot, and immunohistochemistry, respectively.. PNS had no cytotoxicity. PNS reduced iNOS, IL-1β, IL-6, IL-8, and TNF-α levels in astrocytes, promoted T-AOC level and SOD and GSH-Px activities, and inhibited MDA levels, thus inhibiting oxidative stress in astrocytes. In addition, PNS alleviated OGD/R injury, reduced Na-Flu permeability, and enhanced TEER, LDH activity, BDNF content, and levels of tight junction proteins Claudin-5, Occludin, ZO-1 in the culture system of astrocytes and rat BMECs after OGD/R.. PNS repressed astrocyte inflammation and attenuated OGD/R injury in rat BMECs.

Topics: Animals; Astrocytes; Brain; Brain-Derived Neurotrophic Factor; Claudin-5; Endothelial Cells; Glucose; Interleukin-6; Interleukin-8; Occludin; Oxygen; Panax notoginseng; Rats; Reperfusion Injury; Saponins; Signal Transduction; Superoxide Dismutase; Tumor Necrosis Factor-alpha

To analyze the clinical observation of salvianolic acid combined with panax notoginseng saponins combined with basic nursing intervention on cerebral ischemia-reperfusion injury in rats and its effects on the expression of apoptosis-related proteins Bcl-2, Bax and caspase-3.. A total of 72 male Wistar rats were randomly divided into sham, ischemia/reperfusion (I/R), edaravone (Eda), salvianolic acid (SA), panax notoginseng saponins (PNS), and SA+PNS group. After administration for 5 days, the neurological function, cerebral infarction volume, brain index, and brain water content of rats were observed. ELISA kit assay was applied to measure the levels of IL-1. SA, PNS and they combined with basic nursing have protective effects on cerebral I/R injury, and the combination with basic nursing has better effects than that used alone. The mechanism may be to regulate the expression of downstream apoptotic proteins by inhibiting the TLR4/NF-

Topics: Alkenes; Animals; bcl-2-Associated X Protein; Caspase 3; Female; Humans; Infarction; Interleukin-6; Interleukin-8; Male; NF-kappa B; Panax notoginseng; Polyphenols; Rats; Rats, Wistar; Reperfusion Injury; Saponins; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Water

Ischemia-reperfusion (IR) injury is induced by an interrupted blood flow and succeeding blood restoration, which is common in the operation of liver transplantation. Serious IR injury is a major reason leading to transplant failure. Hepatic IR is featured by excessive inflammatory response, oxidative stress, and apoptosis. Sinomenine (SIN) is derived from the herb Sinomeniumacutum and shows properties of anti-inflammation and antiapoptosis in multiple IR-induced organ injuries. However, the effect of SIN in hepatic IR has not been investigated.. This study aims to investigate impacts of SIN on hepatic IR and the involved signaling pathway. An in vivo rat model of syngeneic orthotopic liver transplantation was constructed to induce the hepatic IR injury.. Results showed that SIN pretreatment provided a significant prevention against IR-induced hepatic injury as manifested by the downregulated activities of serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, the alleviatedoxidative stress as shown by increased activities of serum superoxide dismutase and glutathione peroxidase, and decreased serum level of malondialdehyde, the suppressed inflammatory responses as shown by downregulated serum tumor necrosis factor-α, interleukin (IL)-6, IL-8 levels, and upregulated IL-10 level, as well as attenuated apoptosis as shown by decreased protein expression of cleaved caspase-3 and -9. In line with these results, SIN pretreatment also alleviatedthe hepatic histopathological changes in IR rats and induced Nrf-2/HO-1 activation. The use of brusatol, a selective inhibitor for Nrf-2, effectively reversed SIN-induced above effects.. Altogether, our results demonstrate that SIN might be a useful therapeutic drug for preventing hepatic IR-induced injury during clinical liver transplantation.

Topics: Alanine; Alanine Transaminase; Animals; Aspartate Aminotransferases; Caspase 3; Glutathione Peroxidase; Interleukin-10; Interleukin-8; Lactate Dehydrogenases; Liver Diseases; Malondialdehyde; Morphinans; Rats; Reperfusion Injury; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Ginkgo biloba, a natural biflavonoid isolated from Ginkgo biloba leaves, is reported to have strong anti-inflammatory and immunosuppressive properties. The aim of this study is to investigate the potential anti-inflammatory mechanisms of ginkgo flavonoids on cerebral ischemia/reperfusion (I/R) injury. Inflammatory-associated cytokines in cerebral ischemic hemispheres were determined by immunohistochemical staining, Western blot and enzyme-like immunosorbent assay (ELISA). Our results indicated that treatment with Ginkgetin significantly restored rat brain I/R-induced neurological deficit scores. Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in Ginkgetin treatment group (100 mg/kg) also significantly reduced. The expression inflammation-related protein prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and interleukin-8 (IL-8) was also decreased in Ginkgetin treatment group. However, the expression of interleukin-10 (IL-10) was remarkably increased. Thus, this study demonstrates that Ginkgetin protects neurons from I/R-induced rat injury by down-regulating pro-inflammatory cytokines and blocking the TLR4/NF-κB pathway.

Topics: Animals; Anti-Inflammatory Agents; Biflavonoids; Brain Ischemia; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Drug Administration Schedule; Gene Expression Regulation; Ginkgo biloba; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Neuroprotective Agents; NF-kappa B; Nitric Oxide Synthase Type II; Plant Extracts; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

In this study, we examined whether the IL-8 content of urine sampled on day 1 and day 14 after renal transplantation is a marker of early and long-term renal function. Moreover, we assessed whether its concentration is positively correlated with the matrix metalloproteinase-9 (MMP-9) content of urine sampled on day 1 and day 30 and 12 months after renal transplantation. Our analysis covered 87 patients who underwent a kidney transplant. The patients were observed for an average of 30 months (12-60 months). The IL-8 concentration determined on day 1 was significantly negatively correlated with creatinine clearance early after renal transplantation (on days 1, 7, 14 and 30), as well as during long-term observations. IL-8 concentration in urine sampled on day 1 and day 14 was higher in patients demonstrating DGF than in those without DGF. No relationship was found between IL-8 content and cold ischaemia time. MMP-9 activity determined on day 1 and month 3 after renal transplantation was positively correlated with the IL-8 content determined in urine sampled on day 1, Rs = +0.32, p < .05 and Rs = +0.31, p < .05, respectively. The results of this study suggest that a high IL-8 content in urine sampled on day 1 after renal transplantation is an unfavourable marker of early and long-term (years-long) graft function. A high IL-8 content in urine sampled on day 1 after renal transplantation was positively correlated with the activity of metalloproteinase-9 in urine. This proves that both of these chemokines cooperate in ischaemia-reperfusion injuries in transplanted kidneys.

Topics: Adult; Aged; Aged, 80 and over; Allografts; Biomarkers; Biopsy; Cold Ischemia; Creatinine; Delayed Graft Function; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Interleukin-8; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Matrix Metalloproteinase 9; Middle Aged; Reperfusion Injury; Young Adult

Topics: Acupuncture Points; Adult; Blood Gas Analysis; Chemokine CCL2; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged; Reperfusion Injury; Transcutaneous Electric Nerve Stimulation; Tumor Necrosis Factor-alpha

The present study was to investigate the effects of infusing remifentanil-poly-caprolactone(REM-PCL)through the abdominal aorta on spinal cord ischemia reperfusion injury(SCIRI).The model of SCIRI was created by clamping the infrarenal aortic in thirty-six New Zealand white rabbits,which were randomly divided into sham group(group S),control group(group C),and REM-PCL group(group R)with 12 rabbits in each one.The spinal cord microcirculatory blood flow(SCMBF)and blood flow rate(BFR)were monitored before ischemia,15 min,30min,60 min and 120 min after reperfusion,respectively.Neurologic Function was evaluated before ischemia,6h,12hand24 hafter reperfusion.The concentration of serum neuron-specific enolase(NSE),interleukin-lβ(IL-lβ)and interleukin-8(IL-8)were monitored before ischemia,45 min after ischemia,30 min,60min,6h,12 hand 24hafter reperfusion.The abnormal rate of motor neuron of spinal cord tissues and the level of superoxide dismutase(SOD),reactive oxygen species(ROS),glutathione peroxidase(GSH-PX),malondialdehyde(MDA),total anti-oxidation capacity(T-AOC)and mitochondrial swelling degree(MSD)in neural mitochondria were determined before ischemia,45 min after clamping,60 min and 120 min after reperfusion.As a result,the neural mitochondrial SOD,GSH-PX and T-AOC decreased while ROS,MDA,MSD,IL-lβ,IL-8and NSE distinctly increased after clamping of the abdominal aorta as compared to the value before ischemia in group C(P<0.01).Neurologic function scores recovered more rapidly in group R than those in group C during reperfusion(P<0.01).The neural mitochondrial SOD,GSH-PX and T-AOC were distinctly higher while ROS,MDA,MSD,IL-lβ,IL-8and NSE were distinctly lower in group R than those in group C(P<0.01).The abnormal rate of motor neuron was significantly higher in group C during reperfusion than that in group R(P<0.01).It has been shown that the intra-aortic REM-PCL infusion can alleviate SCIRI by inhibiting inflammatory response and improving mitochondrial anti-oxidation capacity.

Topics: Animals; Antioxidants; Aorta, Abdominal; Caproates; Glutathione Peroxidase; Interleukin-1beta; Interleukin-8; Lactones; Malondialdehyde; Microcirculation; Motor Neurons; Phosphopyruvate Hydratase; Piperidines; Rabbits; Reactive Oxygen Species; Remifentanil; Reperfusion Injury; Spinal Cord; Spinal Cord Ischemia; Superoxide Dismutase

Biglycan, a ubiquitous proteoglycan, acts as a danger signal when released from the extracellular matrix. As such, biglycan triggers the synthesis and maturation of interleukin-1β (IL-1β) in a Toll-like receptor (TLR) 2-, TLR4-, and reactive oxygen species (ROS)-dependent manner. Here, we discovered that biglycan autonomously regulates the balance in IL-1β production in vitro and in vivo by modulating expression, activity and stability of NADPH oxidase (NOX) 1, 2 and 4 enzymes via different TLR pathways. In primary murine macrophages, biglycan triggered NOX1/4-mediated ROS generation, thereby enhancing IL-1β expression. Surprisingly, biglycan inhibited IL-1β due to enhancement of NOX2 synthesis and activation, by selectively interacting with TLR4. Synthesis of NOX2 was mediated by adaptor molecule Toll/IL-1R domain-containing adaptor inducing IFN-β (TRIF). Via myeloid differentiation primary response protein (MyD88) as well as Rac1 activation and Erk phosphorylation, biglycan triggered translocation of the cytosolic NOX2 subunit p47(phox) to the plasma membrane, an obligatory step for NOX2 activation. In contrast, by engaging TLR2, soluble biglycan stimulated the expression of heat shock protein (HSP) 70, which bound to NOX2, and consequently impaired the inhibitory function of NOX2 on IL-1β expression. Notably, a genetic background lacking biglycan reduced HSP70 expression, rescued the enhanced renal IL-1β production and improved kidney function of Nox2(-/y) mice in a model of renal ischemia reperfusion injury. Here, we provide a novel mechanism where the danger molecule biglycan influences NOX2 synthesis and activation via different TLR pathways, thereby regulating inflammation severity. Thus, selective inhibition of biglycan-TLR2 or biglycan-TLR4 signaling could be a novel therapeutic approach in ROS-mediated inflammatory diseases.

Topics: Animals; Biglycan; Cells, Cultured; Interleukin-8; Kidney; Macrophages; Membrane Glycoproteins; Mice; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; NADPH Oxidase 2; NADPH Oxidase 4; NADPH Oxidases; Reperfusion Injury; Signal Transduction; Toll-Like Receptors

Renal transplantation can often be complicated due to delayed graft function, which is a direct sequel of ischaemia reperfusion injury. The adverse outcome of delayed graft function is not only short term but the long-term function of the graft is also affected. Therefore, it is important to understand the mechanisms of ischaemia reperfusion injury. Reactive oxygen species are the key mediators in ischaemia reperfusion injury causing direct cell damage which also initiate inflammation by inducing chemokines. The presence of inflammation is a marker of severe delayed graft function. However, the effect of oxidative stress on the expression of key chemokines has not been fully established yet. Therefore, the aim of this study was to measure the oxidative stress response and the secretion of chemokines in a cell culture model that mimics the effects of ischaemia reperfusion injury in immortalised human renal proximal tubular epithelial cells, HK-2. Cells were treated with varying concentrations of hydrogen peroxide and markers of oxidative stress response and chemokine release were measured. Exposure to hydrogen peroxide induced a significant increase in the activity of the antioxidant enzyme glutathione peroxidase and the levels of the chemokines Interleukin-8 (IL-8; CXCL8) and MCP-1 (CCL2). A dose related increase of chemokine secretion was also observed. The cytokine Interleukin-1β (IL-1β) at 1 ng/ml significantly potentiated the expression of both IL-8 (CXCL8) and MCP-1 (CCL2) which showed synergistic response in the presence of hydrogen peroxide. Pre-incubation of the cells with the anti-oxidant N-acetyl cysteine (NAC) strongly suppressed the induction of both IL-8 and MCP-1 when stimulated with hydrogen peroxide and IL-1β. This study demonstrates the potential of anti-oxidants like N-acetyl cysteine in ameliorating the effects of ischaemia reperfusion injury thus suggesting a new therapeutic approach in renal transplantation. These findings can have potential implications for clinical use to prevent ischaemia reperfusion injury in renal transplantation.

Topics: Acetylcysteine; Cell Culture Techniques; Cell Line; Chemokine CCL2; Humans; Interleukin-1beta; Interleukin-8; Kidney Transplantation; Oxidative Stress; Reperfusion Injury

Argon has recently come into scientific focus as a neuroprotective agent. The underlying neuroprotective mechanism remains unknown although toll-like receptors were recently suggested to play an important role. We hypothesized that TLR-associated downstream transcription factors are responsible for argon's effects, leading to anti-apoptotic and anti-inflammatory properties. Apoptosis was induced in human neuroblastoma cells. Immediately afterwards, argon treatment (75 Vol% for 2 h) was initiated. Cells were analyzed, measuring mitochondrial membrane potential, reactive-oxygen-species, annexin-V/propidium iodide staining, transcription factor phosphorylation and binding activity as well as protein and mRNA expression of interleukins. Argon's in vivo effects were analyzed by quantification of retinal ganglion cell density, mRNA expression, serum cytokine analysis and immunohistochemistry after retinal ischemia reperfusion injury (IRI) in rats. Argon diminished rotenone-induced kappa-light-chain-enhancer' of activated B-cells (NF-κB) and signal transducer and activator of transcription 3 (STAT3) but not STAT5 or cAMP-response element-binding protein (CREB) phosphorylation and DNA-binding activity. Argon treatment attenuated apoptosis by preservation of mitochondrial membrane potential and decline in reactive oxygen species (ROS) generation. NF-κB and STAT3 inhibition, as well as TLR2 and TLR4 inhibition reversed argon's effects on IL-8 mRNA expression. Argon attenuated rotenone-induced IL-8 protein and mRNA expression in vitro. Inhibition of TLR2 and 4 attenuated argon's protective effect in vivo reducing IRI driven retinal IL-8 expression. IL-8 expression was found in the retina in co-localization with Müller cells and retinal ganglion cells. Argon mediates its neuroprotective effects by TLR-mediated regulation of transcription factors NF-κB and STAT3, thus decreasing interleukin-8 expression in vitro and in vivo. These findings may open up new opportunities to effectively treat cerebral ischemia and reperfusion injury through the inhalation of argon. Argon exerts its protective effects in vitro and in vivo via toll-like receptors TLR2 and TLR4 signaling, followed by alteration of downstream enzymes. In conclusion, argon mediates its beneficial effects by suppression of STAT3 and NF-κB phosphorylation and subsequent suppression of interleukin IL-8 protein expression. These novel findings may open up opportunities for argon as a therapeutic agent, particular

Topics: Animals; Apoptosis; Argon; Female; Humans; Interleukin-8; Male; Membrane Potential, Mitochondrial; Neuroblastoma; Neuroprotective Agents; NF-kappa B; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; Retinal Diseases; Signal Transduction; STAT3 Transcription Factor; Toll-Like Receptor 2; Toll-Like Receptor 4

Cerebral ischemic-reperfusion injury as an inflammatory and microcirculation dysfunction pathological condition negatively affects the clinical outcome of stroke patients. The novel inflammatory procoagulant protein fgl2 has been reported to play a role in some inflammatory and coagulation dysregulation diseases. This study aimed to examine the relationship between fgl2 expression and infarct size in an acute cerebral ischemic-reperfusion rat model. We studied fgl2 mRNA and protein expressions in cerebral tissue and peripheral macrophages, and the expressions of several inflammatory factors (TNF-α, IL-1β, MCP-1, and IL-8) in serum samples from rats with acute cerebral ischemic-reperfusion injury. Fiber microthrombosis in situ contributed to the microvascular thrombosis in acute cerebral ischemic-reperfusion injury, and fgl2 expression tended to strongly correlate with cerebral infarct size. The expression levels of the other inflammatory factors significantly increased but weakly correlated with cerebral infarct size. These findings support the potential of fgl2 level as a novel biomarker of acute cerebral ischemic-reperfusion injury.

Topics: Animals; Biomarkers; Chemokine CCL2; Cytokines; Fibrinogen; Gene Expression Regulation; Inflammation; Interleukin-1beta; Interleukin-8; Macrophages; Male; Microcirculation; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptor, Fibroblast Growth Factor, Type 3; Reperfusion Injury; RNA, Messenger; Thrombosis; Tumor Necrosis Factor-alpha

Sodium butyrate (NaB) is a dietary microbial fermentation product of fiber and serves as an important neuromodulator in the central nervous system. In this study, we further investigated that NaB attenuated cerebral ischemia/reperfusion (I/R) injury in vivo and its possible mechanisms. NaB (5, 10 mg/kg) was administered intragastrically 3 h after the onset of reperfusion in bilateral common carotid artery occlusion (BCCAO) mice. After 24 h of reperfusion, neurological deficits scores were estimated. Morphological examination was performed by electron microscopy and hematoxylin-eosin (H&E) staining. The levels of oxidative stress and inflammatory cytokines were assessed. Apoptotic neurons were measured by TUNEL; apoptosis-related protein caspase-3, Bcl-2, Bax, the phosphorylation Akt (p-Akt), and BDNF were assayed by western blot and immunohistochemistry. The results showed that 10 mg/kg NaB treatment significantly ameliorated neurological deficit and histopathology changes in cerebral I/R injury. Moreover, 10 mg/kg NaB treatment markedly restored the levels of MDA, SOD, IL-1β, TNF-α, and IL-8. 10 mg/kg NaB treatment also remarkably inhibited the apoptosis, decreasing the levels of caspase-3 and Bax and increasing the levels of Bcl-2, p-Akt, and BDNF. This study suggested that NaB exerts neuroprotective effects on cerebral I/R injury by antioxidant, anti-inflammatory, and antiapoptotic properties and BDNF-PI3K/Akt pathway is involved in antiapoptotic effect.

Topics: Animals; Apoptosis; Brain Ischemia; Butyric Acid; Caspase 3; Cerebrovascular Disorders; Humans; Interleukin-8; Mice; Neuroprotective Agents; Oxidative Stress; Proto-Oncogene Proteins c-akt; Reperfusion Injury; Signal Transduction; Tumor Necrosis Factor-alpha

Ex vivo lung perfusion (EVLP) has been used not only for graft evaluation but also for graft reconditioning prior to lung transplantation. Inflammatory cells such as neutrophils may cause additional graft injury during EVLP. Neutrophil elastase inhibitors protect lungs against neutrophil-induced lung injury, such as acute respiratory distress syndrome. This study aimed to investigate the effect of a neutrophil elastase inhibitor during EVLP.. EVLP was performed for 4 h in bilateral pig lungs that had previously experienced warm ischemia for 2 h with or without a neutrophil elastase inhibitor (treated and control groups, respectively; n = 6). Following EVLP, the left lung was transplanted into a recipient pig, and this was followed by observation for 4 h. Pulmonary functions were observed both during EVLP and during the early post-transplant stage.. During EVLP, decreases in neutrophil elastase levels (P < 0.001), the wet-dry weight ratio (P < 0.05), and pulmonary vascular resistance (P < 0.01) and increases in the PaO2/FiO2 ratio (P < 0.01) and pulmonary compliance (P < 0.05) were observed in the treated group. After transplantation, decreased pulmonary vascular resistance (P < 0.05) was observed in the treated group.. A neutrophil elastase inhibitor attenuated the inflammatory response during EVLP and may decrease the incidence of lung reperfusion injury after transplantation.

Topics: Animals; Cytokines; Enzyme-Linked Immunosorbent Assay; Interleukin-6; Interleukin-8; Lung; Lung Compliance; Lung Injury; Lung Transplantation; Protease Inhibitors; Proteinase Inhibitory Proteins, Secretory; Reperfusion Injury; Swine; Tumor Necrosis Factor-alpha; Vascular Resistance; Warm Ischemia

To investigate the protective effects of oxymatrine (OMT) on lung ischemia reperfusion injury (LIRI) in rabbits, models of LIRI in rabbit were used. Thirty-two rabbits were randomly divided into four groups: control group (n = 8), ischemia reperfusion group (I/R group, n = 8), OMTl group (n = 8), OMT2 group (n = 8). Lung tissue samples were collected at 40, 80, 120 min time-points after lung ischemia reperfusion. TNF-α, 1I-8, IL-10, apoptosis index (AI), and index of quantitative assessment of histologic lung injury (IQA) were measured in each group. TNF-α and IL-8 in I/R group were significantly higher than those of the control group and OMT2 group (P < 0.01), but in OMT2 group they were significantly lower than those of OMTl group (P < 0.05). IL-10 in OMT2 group and OMTl group was significantly higher than that of I/R group (P < 0.01). But in OMTl group it was significantly lower than that of OMT2 group (P < 0.05). AI in I/R group was significantly higher than that of OMT2 group and the control group at 80 min after lung ischemia reperfusion (P < 0.01). IQA in OMTl group and OMT2 group was significantly lower than that of the I/R group (P < 0.01). Oxymatrine can protect against LIRI in rabbits by upregulating levels of IL-10 and downregulating levels of TNF-α and IL-8, inhibiting the alveolar cells apoptosis and inflammatory response, and attenuating the acute LIRI.

Topics: Alkaloids; Animals; Apoptosis; Interleukin-10; Interleukin-8; Lung; Quinolizines; Rabbits; Reperfusion Injury; Tumor Necrosis Factor-alpha

Mast cell (MC) degranulation has been implicated in small intestinal ischemia reperfusion (IIR) injury, therein, inhibiting overproduction of histamine released from activated MC may provide promising strategies against IIR-mediated liver injuries. The aim of the present study was to explore whether anti-histamine treatment contribute to attenuating IIR-mediated liver injury. Adult SD rats were randomized into sham-operated group (S group), sole IIR group (IIR group), and IIR treated with Ketotifen, a histamine antagonist (IIR+K group), Cromolyn Sodium, a MC stabilizer (IIR+C group), and Compound 48/80, a MC degranulator (IIR+CP group), respectively. IIR was induced by superior mesenteric artery occlusion for 75 min followed by 4 h of reperfusion. The agents were intravenously administrated 5 min before reperfusion to induce different levels of histamine. Subsequently, serum concentrations of ALT, AST and histamine; levels of LDH,TNF-α, IL-8 and MDA as well as SOD activities in the liver were assessed. Histopathologic changes were also evaluated. IIR resulted in severe liver injury as demonstrated by significant increases in injury scores, with concomitant significant increases in serum ALT, AST and histamine levels, as well as LDH, TNF-α, IL-8, and MDA levels in the liver, accompanied by reduction in SOD activities (all P < 0.05, IIR vs. S). Treatments by Ketotifen and Cromolyn Sodium similarly markedly alleviated IIR-mediated liver injury as confirmed by significant reduction of the above biomedical changes whereas Compound 48/80 further aggravated IIR-mediated liver injury by dramatically enhancing the above biomedical changes. Data of our study suggest that anti-histamine treatments may provide promising benefits in alleviating liver injury triggered by IIR.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Cell Degranulation; Histamine; Histamine H1 Antagonists; Interleukin-8; Intestine, Small; Ketotifen; Liver; Liver Diseases; Mast Cells; p-Methoxy-N-methylphenethylamine; Rats, Sprague-Dawley; Reperfusion Injury; Treatment Outcome; Tumor Necrosis Factor-alpha

In traditional Chinese medicine, Ligusticum wallichii (Chuan Xiong) and its bioactive ingredient, tetramethylpyrazine (TMP), have been used to treat cardiovascular diseases and to relieve various neurological symptoms, such as those associated with ischemic injury. In the present study, we investigated whether ultrasound (US) exposure could enhance the protective effect of TMP against cerebral ischemia/reperfusion (I/R) injury. Glutamate-induced toxicity to pheochromocytoma (PC12) cells was used to model I/R injury. TMP was paired with US to examine whether this combination could alleviate glutamate-induced cytotoxicity. The administration of TMP effectively protected cells against glutamate-induced apoptosis, which could be further enhanced by US-mediated sonoporation. The anti-apoptotic effect of TMP was associated with the inhibition of oxidative stress and a change in the levels of apoptosis-related proteins, Bcl-2 and Bax. Furthermore, TMP reduced the expression of proinflammatory cytokines such as TNF-α and IL-8, which likely also contributes to its cytoprotective effects. Taken together, our findings suggest that ultrasound-enhanced TMP treatment might be a promising therapeutic strategy for ischemic stroke. Further study is required to optimize ultrasound treatment parameters.

Topics: Animals; bcl-2-Associated X Protein; Brain Ischemia; Glutamic Acid; High-Energy Shock Waves; Interleukin-8; Ligusticum; Medicine, Chinese Traditional; Microscopy, Electron, Scanning; PC12 Cells; Proto-Oncogene Proteins c-bcl-2; Pyrazines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Vasodilator Agents

Donor preconditioning by fenoldopam is demonstrated to improve graft function in recipients. Involvement of hypoxia-inducible factor-1alpha (HIF-1α) and heme oxygenase-1 (HO-1) in renoprotection after fenoldopam pretreatment was investigated.. Donor Sprague-Dawley (SD) rats were intravenously treated with fenoldopam (5 μg/kg · min), Sch23390 (10 μg/kg · min), or fenoldopam + Sch23390 for 1 hour. Kidneys experiencing 24 hours of cold preservation were transplanted into syngeneic SD recipients. Ten days after transplantion, serum concentrations of creatinine (sCR), blood urea nitrogen (BUN), interleukin (IL)-8, and tumor necrosis factor (TNF)-α in recipient were determined. Grafts were procured for histopathological examination, apoptosis analysis, and measurements of malondialdehyde and total superoxide dismutase activities; meanwhile, both protein level and mRNA level of HIF-1α and HO-1 were assessed.. Fenoldopam preconditioning significantly decreased the serum concentrations of sCR, BUN, IL-8, and TNF-α in recipients. Low apoptosis rate and reduced oxidative stress were found in these grafts. Increased HIF-1α activation and HO-1 expression were observed in fenoldopam pretreatment group. Sch23390 partly inhibited the effects of fenoldopam in the combination group.. Donor preconditioning by fenoldopam exerts renoprotection in grafts, at least in part, through HIF-1α activation and HO-1 expression. This provides a preference for further studies.

Topics: Animals; Apoptosis; Benzazepines; Blood Urea Nitrogen; Cold Ischemia; Creatinine; Cytoprotection; Disease Models, Animal; Fenoldopam; Heme Oxygenase (Decyclizing); Hypoxia-Inducible Factor 1, alpha Subunit; Infusions, Intravenous; Interleukin-8; Kidney; Kidney Transplantation; Male; Malondialdehyde; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger; Superoxide Dismutase; Time Factors; Tumor Necrosis Factor-alpha

Capsaicin-sensitive C fibers (CapsCF) are abundantly distributed in the respiratory tract. Inflammation is one of the main contributors to lung ischemia-reperfusion (IR) injury. This study was designed to investigate the role of CapsCF in lung IR-induced inflammatory response.. Thirty-two male rabbits were randomized into four groups as follows: sham group (S), IR group (IR), large dose of capsaicin plus sham group (CS), and large dose of capsaicin plus IR group (CIR). The CS and CIR groups were pretreated with capsaicin (100 mg/kg) to induce functional ablation of CapsCF. The IR and CIR groups were subjected to 1 h lung ischemia and 3 h reperfusion. Thereafter, blood and lung tissue samples were obtained for blood gas and biochemical analyses. Levels of substance P and calcitonin gene-related peptide (CGRP), lung wet-to-dry weight ratio, and histopathologic changes as well as neutrophil counts in bronchoalveolar lavage fluids were also assessed.. Capsaicin pretreatment in the CIR group resulted in increased lung wet-to-dry ratio, neutrophil counts in bronchoalveolar lavage fluids, and lung pathologic lesions, along with higher levels of plasma tumor necrosis factor α and interleukin 8 and lower level of interleukin 10 (P < 0.05 versus IR), although capsaicin did not alter the above variables in the CS group (P > 0.05 versus S). Lung tissue CGRP was elevated more than 2-fold in the IR group (P < 0.05 versus S), but it did not significantly change in the CIR group.. Denervation of CapsCF aggravated lung IR-induced inflammation, probably by depleting the CGRP content of CapsCF. CapsCF may protect against lung IR-induced inflammation and injury.

Topics: Animals; Bronchoalveolar Lavage Fluid; Capsaicin; Cell Count; Disease Models, Animal; Dose-Response Relationship, Drug; Interleukin-8; Male; Nerve Fibers, Unmyelinated; Neutrophils; Pneumonia; Rabbits; Reperfusion Injury; Sympathectomy, Chemical; Tumor Necrosis Factor-alpha

Previous studies have shown that complement activation is required for intestinal ischemia-reperfusion (IIR)-induced tissue damage. Cobra venom factor (CVF), a structural and functional homolog to the activated form of C3 (the central component of the complement system), can cause exhaustive activation of the alternative pathway and deplete the complement components.. This study aims to investigate the effect of CVF pretreatment on acute lung injury induced by IIR in rats.. Lung injury was induced by clamping superior mesenteric artery (SMA) for 60 min followed by 4 h of reperfusion. CVF was given via the tail vein 24 h before the operation.. Histological results as well as lung edema determination and permeability assay showed the severe damages were induced in the lungs of rats in the IIR group, accompanying with the increases in the levels of pulmonary malondialdehyde (MDA), myeloperoxidase (MPO) activity, intercellular adhesion molecule-1 (ICAM-1), interleukin (IL)-8. Remarkably, CVF pretreatment significantly attenuated the morphological lung injury, lung edema and lung permeability, reduced the increase of the levels of MDA, MPO, ICAM-1 and IL-8 induced by IIR. In addition, the severe damage of intestinal and elevation of plasma diamine oxidase activity in the IIR rats were significantly alleviated by CVF pretreatment.. CVF pretreatment could significantly reduce the acute lung injury induced by IIR. The mechanism might include, at least in part, the inhibition of oxidant generation, infiltration of neutrophils, ICAM-1 expression and IL-8 release. CVF might be an efficient reagent for preventing the IIR injuries in clinical condition.

Topics: Acute Lung Injury; Animals; Complement Inactivating Agents; Elapid Venoms; Intercellular Adhesion Molecule-1; Interleukin-8; Intestine, Small; Male; Mesenteric Arteries; Neutrophil Infiltration; Oxidants; Rats; Rats, Sprague-Dawley; Reperfusion Injury

To investigate the protective effect of low-dose ketamine against intestinal ischemia reperfusion injury following pneumoperitoneum with carbon dioxide in rats.. Thirty healthy male adult SD rats (body weight 280-320 g) were randomized into sham-operated group, model group and ketamine group and subjected to pneumoperitoneum for 120 min with carbon dioxide (not in sham-operated group). The rats in ketamine group received an intraperitoneal injection of 10 mg/kg ketamine 10 min before pneumoperitoneum, and those in the other two groups received saline injection. Fifteen minutes after pneumoperitoneum or sham operation, the small intestines were sampled to detect the content of malondialdehyde (MDA) and fore pathological testing. ELISA was used to detect the serum levels of I-FABP, TNF-α IL-6 and IL-8.. Pneumoperitoneum caused a significant increase in intestinal MDA content (P<0.05), which was lowered by ketamine pretreatment (P<0.05). Serum I-FABP, TNF-α, IL-6 and IL-8 levels all significantly increased following pneumoperitoneum (P<0.05) and were obviously lowered by ketamine pretreatment (P<0.05). Pneumoperitoneum also caused obvious pathologies in intestinal mucosa, which were ameliorated by ketamine pretreatment.. Low-dose ketamine preconditioning can reduce the inflammatory reaction and lessen oxidative damage in the intestinal mucosa following pneumoperitoneum in rats.

Topics: Animals; Carbon Dioxide; Dose-Response Relationship, Drug; Fatty Acid-Binding Proteins; Interleukin-6; Interleukin-8; Intestine, Small; Ketamine; Male; Malondialdehyde; Pneumoperitoneum; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

Safflower yellow (SY) is the safflower extract and is the one of traditional Chinese medicine. The aim of the present work was to investigate the effect of SY on spinal cord ischemia reperfusion injury (SCIRI) in rabbits. The models of spinal cord ischemia reperfusion (SI/R) were constructed, and the degree of the post-ischemic injury was assessed by means of the neurological deficit scores and plasma levels of lipid peroxidation reactioin and neuronal morphologic changes. SCIRI remarkably affected the functional activities of the hind limbs and activated lipid peroxidation reaction. SY could attenuate apoptosis and SCIRI by enhancing Bcl-2 expression and inhibiting Bax and caspase-3 activation.

Topics: Animals; Anterior Horn Cells; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cell Shape; Chalcone; Hindlimb; In Situ Nick-End Labeling; Interleukin-8; Male; Malondialdehyde; Phytotherapy; Rabbits; Reperfusion Injury; Spinal Cord Ischemia; Superoxide Dismutase; Time Factors; Vital Signs

After ischemic stroke, early thrombolytic therapy to reestablish tissue perfusion improves outcome but triggers a cascade of deleterious cellular and molecular events. Using a collaborative approach, our groups examined the effects of guanosine (Guo) in response to ischemic reperfusion injury in vitro and in vivo. In a transient middle cerebral artery occlusion (MCAO) in rats, Guo significantly reduced infarct volume in a dose-dependent manner when given systemically either immediately before or 30 min, but not 60 min, after the onset of the 5.5-hr reperfusion period. In a separate experiment, Guo significantly reduced infarct volume after 24 hr of reperfusion when administered 5 min before reperfusion. Western blot analysis did not reveal any significant changes either in endoplasmic reticulum (ER) stress proteins (GRP 78 and 94) or HSP 70 or in levels of m-calpain. In vitro oxygen and glucose deprivation (OGD) significantly increased production of both reactive oxygen species (ROS) and interleukin-8 (IL-8) in the primary astrocytes. Guo did not alter ROS or IL-8 production when given to the astrocytes before OGD. However, Guo when added to the cells prior to or 30 min after reperfusion significantly reduced IL-8 release but not ROS formation. Our study revealed a dose- and time-dependent protective effect of Guo on reperfusion injury in vitro and vivo. The mechanisms by which Guo exerts its effect are independent of unfolded proteins in ER or the level of intracellular calcium or ROS formation. However, the effect may be induced, at least partially, by inhibiting IL-8, a marker of reperfusion-triggered proinflammatory events.

Topics: Analysis of Variance; Animals; Animals, Newborn; Astrocytes; Brain Infarction; Cells, Cultured; Gene Expression Regulation; Glucose; Guanosine; Heat-Shock Proteins; Hypoxia; Infarction, Middle Cerebral Artery; Interleukin-8; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion; Reperfusion Injury; Time Factors

The process of brain death induces acute lung injury in donors and aggravates ischemia-reperfusion injury (IRI) in grafts. Hydrogen, a new anti-oxidant, attenuates IRI in several organ transplant models. We examined whether 2% inhaled hydrogen would show favorable effects on lung grafts from brain-dead donor rats.. Brain-dead donor rats inhaled mixed gases with either 50% oxygen and 50% nitrogen or mixed gases with 2% hydrogen, 50% oxygen and 48% nitrogen for 2 hours. The recipients inhaled the same gas as the donors and were euthanized 2 hours after lung transplantation.. Hydrogen improved PaO(2)/FIO(2) and PVO(2)/FIO(2) from the arterial and pulmonary venous blood in recipients and decreased the lung injury score in grafts from brain-dead donors. Hydrogen decreased the amount of IL-8 and TNF-α in serum, inhibited the activity of malondialdehyde and myeloperoxidase, and increased the activity of superoxide dismutase in the lung grafts from brain-dead donors. Furthermore, hydrogen decreased the apoptotic index of the cells and inhibited the protein expression of intercellular adhesion molecule-1 and caspase-3 in lung grafts from brain-dead donors.. Hydrogen can exert protective effects on lung grafts from brain-dead donors through anti-inflammatory, anti-oxidant and anti-apoptotic mechanisms.

Topics: Acute Lung Injury; Animals; Antioxidants; Apoptosis; Brain Death; Caspase 1; Hydrogen; In Situ Nick-End Labeling; Intercellular Adhesion Molecule-1; Interleukin-8; Lung Transplantation; Male; Rats; Rats, Wistar; Reperfusion Injury; Tissue Donors; Tumor Necrosis Factor-alpha

DF 2156A is a new dual inhibitor of IL-8 receptors CXCR1 and CXCR2 with an optimal pharmacokinetic profile. We characterized its binding mode, molecular mechanism of action and selectivity, and evaluated its therapeutic potential.. The binding mode, molecular mechanism of action and selectivity were investigated using chemotaxis of L1.2 transfectants and human leucocytes, in addition to radioligand and [(35) S]-GTPγS binding approaches. The therapeutic potential of DF 2156A was evaluated in acute (liver ischaemia and reperfusion) and chronic (sponge-induced angiogenesis) experimental models of inflammation.. A network of polar interactions stabilized by a direct ionic bond between DF 2156A and Lys(99) on CXCR1 and the non-conserved residue Asp(293) on CXCR2 are the key determinants of DF 2156A binding. DF 2156A acted as a non-competitive allosteric inhibitor blocking the signal transduction leading to chemotaxis without altering the binding affinity of natural ligands. DF 2156A effectively and selectively inhibited CXCR1/CXCR2-mediated chemotaxis of L1.2 transfectants and leucocytes. In a murine model of sponge-induced angiogenesis, DF 2156A reduced leucocyte influx, TNF-α production and neovessel formation. In vitro, DF 2156A prevented proliferation, migration and capillary-like organization of HUVECs in response to human IL-8. In a rat model of liver ischaemia and reperfusion (I/R) injury, DF 2156A decreased PMN and monocyte-macrophage infiltration and associated hepatocellular injury.. DF 2156A is a non-competitive allosteric inhibitor of both IL-8 receptors CXCR1 and CXCR2. It prevented experimental angiogenesis and hepatic I/R injury in vivo and, therefore, has therapeutic potential for acute and chronic inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Cell Membrane; Cell Proliferation; Chemotaxis, Leukocyte; Disease Models, Animal; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-8; Leukocytes; Liver; Male; Mice; Mice, Inbred C57BL; Models, Molecular; Mutagenesis, Site-Directed; Neovascularization, Pathologic; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Reperfusion Injury; Skin; Sulfonamides

Mast cell has been demonstrated to be involved in the small intestinal ischemia-reperfusion (IIR) injury, however, the precise role of tryptase released from mast cell on acute lung injury(ALI) induced by IIR remains to be elucidated, our study aimed to observe the roles of tryptase on ALI triggered by IIR and its underlying mechanism. Adult SD rats were randomized into sham-operated group, sole IIR group in which rats were subjected to 75 min superior mesenteric artery occlusion followed by 4 h reperfusion, or IIR being respectively treated with cromolyn sodium, protamine, and compound 48/80. The above agents were, respectively, administrated intravenously 5 min before reperfusion. At the end of experiment, lung tissue was obtained for assays for protein expressions of tryptase and mast cell protease 7 (MCP7) and protease-activated receptor 2 (PAR-2). Pulmonary mast cell number and levels of IL-8 were quantified. Lung histologic injury scores and lung water content were measured. IIR resulted in lung injury evidenced as significant increases in lung histological scores and lung water contents, accompanied with concomitant increases of expressions of tryptase and MCP7, and elevations in PAR-2 expressions and IL-8 levels in lungs. Stabilizing mast cell with cromolyn sodium and inhibiting tryptase with protamine significantly reduced IIR-mediated ALI and the above biochemical changes while activating mast cell with compound 48/80 further aggravated IIR-mediated ALI and the increases of above parameters. Tryptase released from mast cells mediates ALI induced by intestinal ischemia-reperfusion by activating PAR-2 to produce IL-8.

Topics: Acute Lung Injury; Animals; Cromolyn Sodium; Interleukin-8; Intestine, Small; Lung; Mast Cells; Mesenteric Artery, Superior; p-Methoxy-N-methylphenethylamine; Protamines; Rats; Receptor, PAR-2; Reperfusion Injury; Tryptases

Hydrogen gas, an antioxidant agent, was found to protect against cerebral and myocardial ischemia-reperfusion (I/R) injury. In the present study, we investigated the effect of hydrogen-rich saline (HRS) on the I/R-induced lung injury.. Left lung of male New Zealand White rabbits rendered normothermic ischemia for 60 min and reperfused for up to 240 min. Treated animals received intraperitoneal injection of 5 mL/kg HRS or the same volume of normal saline 10 min before the start of reperfusion. Blood and lung tissue samples were obtained for blood gas and biochemical analyses. The tissues obtained from lower lobe of left lung were used for histologic examination.. After 240 min of reperfusion, intraperitoneal administration of HRS increased PaO2/FiO2 ratio and superoxide dismutase activities, and decreased malondialdehyde contents, proinflammatory cytokines expression, and myeloperoxidase activities, along with reduced wet/dry ratio and histologic injury scores (P < 0.05 versus I/R group).. These results suggest that intraperitoneal administration of HRS before reperfusion protects the lung from I/R injury. The protective effect seems to be closely related to regulating oxidative damage and antioxidant enzyme activities and neutrophil infiltration.

Topics: Animals; Hydrogen; Interleukin-8; Lung; Male; Oxidative Stress; Pulmonary Edema; Pulmonary Gas Exchange; Rabbits; Reperfusion Injury; Sodium Chloride; Tumor Necrosis Factor-alpha

Small intestinal ischemia-reperfusion (IIR) injury may lead to severe local and remote tissue injury, especially acute lung injury (ALI). Mast cell activation plays an important role in IIR injury. It is unknown whether IIR mediates lung injury via mast cell activation.. Adult SD rats were randomized into sham operated group (S), sole IIR group (IIR) in which rats were subjected to 75 min of superior mesenteric artery occlusion followed by 4h reperfusion, or IIR being respectively treated with the mast cell stabilizer Cromolyn Sodium (IIR+CS group), with the tryptase antagonist Protamine (IIR+P group), with the histamine receptor antagonist Ketotifen (IIR+K group), or with the mast cell degranulator Compound 48/80 (IIR+CP group). The above agents were, respectively, administrated intravenously 5 min before reperfusion. At the end of experiment, lung tissue was obtained for histologic assessment and assays for protein expressions of tryptase and mast cell protease 7(MCP7). Pulmonary mast cell number and levels of histamine, TNF-α and IL-8 were quantified.. IIR resulted in lung injury evidenced as significant increases in lung histological scores (P<0.05 IIR vs. S), accompanied with concomitant increases of mast cell counts and elevations in TNF-α and IL-8 concentrations and reductions in histamine levels (all P<0.05 IIR vs. S). IIR also increased lung tissue tryptase and MCP7 protein expressions (all P<0.05, IIR vs. S). Cromolyn Sodium, Ketotifen and Protamine significantly reduced whilst Compound 48/80 aggravated IIR mediated ALI and the above biochemical changes (P<0.05).. Mast cells activation play a critical role in IIR mediated ALI.

Topics: Acute Lung Injury; Animals; Cromolyn Sodium; Histamine H1 Antagonists; Interleukin-8; Intestine, Small; Ketotifen; Male; Mast Cells; Mesenteric Artery, Superior; Protamines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

Despite its presumed effectiveness and clinical use, the physiology of selective visceral perfusion combined with distal aortic perfusion during open thoracoabdominal aortic surgery has not been characterized. Thus, the aim of this study was to establish a translatable model of thoracic aortic-clamping to assess the effect of selective visceral perfusion with added distal aortic perfusion on local intestinal macrohemodynamics and microhemodynamics, intestinal histopathology, and markers of inflammation and intestinal damage.. A thoracolaparotomy was performed in 15 pigs, and the aorta was exposed, including the origins of celiac trunk and superior mesenteric artery. The animals were divided into three cohorts: control (I), thoracic aortic cross-clamping (II), and thoracic aortic cross-clamping with selective visceral perfusion plus distal aortic perfusion using extracorporeal circulation (III). Macrocirculatory and microcirculatory blood flow was assessed by transit time ultrasound volume flow measurements and fluorescent microspheres. Intestinal ischemia-reperfusion injury was determined by the analysis of perioperative intestinal fatty acid-binding protein (IFABP) and interleukin-8 (IL-8) levels and correlated with histopathologic changes.. Severe intestinal tissue injury and an inflammatory response were observed in cohort II compared with cohort III for IL-8 (38.2 vs 3.56 pg/mL; P = .04). The procedure in cohort III resulted in a flow and pressure-associated intestinal hypoperfusion compared with cohort I in the superior mesenteric artery (mean blood pressure, 24.1 ± 10.4 vs 67.2 ± 7.4 mm Hg; P < .0001; mean flow rates: 353.3 ± 133.8 vs 961.7 ± 310.8 mL/min; P < .0001). This was paralleled in cohort III vs cohort I by a significant mucosal injury (IFABP, 713 ± 307.1 vs 170 ± 115.4 pg/mL; P = .014) despite a profound recruitment of intestinal microcirculation (338% ± 206.7% vs 135% ± 123.7%; P = .05).. This study reports a novel large-animal model of thoracic aortic cross-clamping that allows the study of visceral perfusion strategies. However, we demonstrated with IL-8 and IFABP measurements that thoracoabdominal aortic aneurysm surgery with selective visceral perfusion and distal aortic perfusion is superior to the clamp-and-sew technique, even though small intestinal tissue damage cannot be completely avoided by selective visceral perfusion and distal aortic perfusion. In any case, this model seems to be a platform to evaluate and optimize measures for gut wall protection.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Blood Flow Velocity; Constriction; Extracorporeal Circulation; Fatty Acid-Binding Proteins; Female; Hemodynamics; Interleukin-8; Intestines; Models, Animal; Regional Blood Flow; Reperfusion Injury; Swine; Vascular Surgical Procedures; Viscera

Ex vivo lung perfusion (EVLP) is a promising modality for the evaluation and treatment of marginal donor lungs. The optimal timing of EVLP initiation and the potential for rehabilitation of donor lungs with extended warm ischemic times is unknown. The present study compared the efficacy of different treatment strategies for uncontrolled non-heart-beating donor lungs.. Mature swine underwent hypoxic arrest, followed by 60 minutes of no-touch warm ischemia. The lungs were harvested and flushed with 4°C Perfadex. Three groups (n = 5/group) were stratified according to the preservation method: cold static preservation (CSP; 4 hours of 4°C storage), immediate EVLP (I-EVLP: 4 hours EVLP at 37°C), and delayed EVLP (D-EVLP; 4 hours of CSP followed by 4 hours of EVLP). The EVLP groups were perfused with Steen solution supplemented with heparin, methylprednisolone, cefazolin, and an adenosine 2A receptor agonist. The lungs then underwent allotransplantation and 4 hours of recipient reperfusion before allograft assessment for resultant ischemia-reperfusion injury.. The donor blood oxygenation (partial pressure of oxygen/fraction of inspired oxygen ratio) before death was not different between the groups. The oxygenation after transplantation was significantly greater in the D-EVLP group than in the I-EVLP or CSP groups. The mean airway pressure, pulmonary artery pressure, and expression of interleukin-8, interleukin-1β, and tumor necrosis factor-α were all significantly reduced in the D-EVLP group. Post-transplant oxygenation exceeded the acceptable clinical levels only in the D-EVLP group.. Uncontrolled non-heart-beating donor lungs with extended warm ischemia can be reconditioned for successful transplantation. The combination of CSP and EVLP in the D-EVLP group was necessary to obtain optimal post-transplant function. This finding, if confirmed clinically, will allow expanded use of nonheart-beating donor lungs.

Topics: Animals; Arterial Pressure; Citrates; Cold Ischemia; Cold Temperature; Disease Models, Animal; Female; Heart Arrest; Inflammation Mediators; Interleukin-1beta; Interleukin-8; Lung; Lung Transplantation; Male; Organ Preservation Solutions; Perfusion; Pulmonary Artery; Pulmonary Gas Exchange; Reperfusion Injury; Respiratory Function Tests; Sus scrofa; Time Factors; Tissue Donors; Tumor Necrosis Factor-alpha; Warm Ischemia

To investigate the impact of a traditional Chinese medicinal compound known as Fufang Shenhua Tablet (SHP) on the expression of Toll-like receptors (TLRs) during renal ischemia-reperfusion injury (IRI)-induced acute kidney injury (AKI) in rats.. A total of 28 Wistar rats were randomly divided into five groups: (1) pseudo-operation control group, (2) ischemia-reperfusion model group, (3) Astragaloside group, (4) high-dose SHP group, and (5) low-dose SHP group. There were four rats in the pseudo-operation group and six rats in each of the other groups. The accepted ischemia-reperfusion model was established after a 7-day gavage intervention, and pathological changes and renal function were observed, using an enzyme-linked immunosorbent assay (ELISA) to detect interleukin 8 (IL-8) and interferon gamma (IFN-γ) levels, as well as immunohistochemical staining to detect altered levels of TLR2 and TLR4 expression in renal tissue.. After 24 h, renal pathological damage and the expression levels of serum creatinine (Scr), IL-8, IFN-γ, TLR2, and TLR4 were significantly higher in the model group as compared with the pseudo-operation group (P<0.05). In addition, at 24 h the above indicators decreased significantly in the Astragaloside group, high-dose SHP group and low-dose SHP group as compared with the ischemia-reperfusion model group (P< 0.05). TLR2 and TLR4 expression levels were significantly reduced in the SHP treatment and Astragaloside group as compared with the pseudo-operation group (P<0.05). Further, the high-dose SHP group showed significantly less renal damage score and decreased levels of TLR expression than those of low-dose SHP group and Astragaloside group (all P<0.05).. SHP can alleviate the renal structural and functional damage caused by IRI-induced AKI in rats by reducing the damage of renal pathology, which may reduce inflammatory cytokine levels by downregulating the expression of TLRs in renal tissue in a dose-dependent manner.

Topics: Acute Kidney Injury; Animals; Drugs, Chinese Herbal; Enzyme-Linked Immunosorbent Assay; Immunohistochemistry; Interferon-gamma; Interleukin-8; Kidney Tubules; Male; Rats; Rats, Wistar; Reperfusion Injury; Tablets; Toll-Like Receptor 2; Toll-Like Receptor 4

Ischemia-reperfusion (I/R) injury is one of the main factors affecting the function and structure of small bowel transplantation (SBT), by generation of proinflammatory mediators such as reactive oxygen species, reactive nitrogen species, cytokines, and endotoxin. Experimental data have demonstrated that N-acetylcysteine (NAC) attenuates intestinal I/R injury. The objective of this study was to determine the effect of NAC preconditioning on the SBT-I/R induced inflammatory cascade, with particular focus on TNF, IL-8, hyaluronic acid, and NO.. Fifteen domestic pigs were used as donors. Fifteen recipient animals were randomly assigned into two groups. Group 1: SBTx (n=7) served as controls and Group 2: SBTx (n=8) served as the experimental group (NAC administration).. NAC administration at a continuous 4 h intravenous bolus dose of 200 mg/kg of body weight, starting before initiation of bowel transplantation, resulted in statistically significant (P<0.05) higher plasma levels of NO, and lower plasma levels of hyaluronic acid, TNF-α, IL-8, and LDH compared with those of the control group, at the 360 min time point.. NAC confers a protective role in small bowel transplantation associated, partly, with NO generation and hyaluronic acid, TNF-α and IL-8 amelioration.

Topics: Acetylcysteine; Animals; Free Radical Scavengers; Hyaluronic Acid; Interleukin-8; Intestine, Small; Ischemic Preconditioning; Nitric Oxide; Random Allocation; Reperfusion Injury; Swine; Tumor Necrosis Factor-alpha

Experimental studies have shown protective effect by the non-essential amino acid glycine to liver ischemia-reperfusion (I/R) injury but the mechanism of action is unknown.. A rabbit model of hepatic lobar I/R was used. Three groups of animals (n=6) were studied: Sham group (laparotomy alone), ischemia reperfusion (I/R) group (1 h of liver lobar ischemia and 6 h of reperfusion), and a glycine I/R group (intravenous glycine 5 mg/kg prior to the I/R protocol). Systemic and hepatic hemodynamics, degree of liver injury (bile flow, transaminases), hepatic microcirculation, mitochondrial activity (redox state of cytochrome oxidase), bile composition and cytokines (tumor necrosis factor-α and interleukin-8) were measured during the experiment.. Glycine administration increased portal blood flow, bile production, hepatic microcirculation and maintained cytochrome oxidase activity as compared with the I/R group during reperfusion. Glycine also reduced bile lactate surge and stimulated acetoacetate release in bile during reperfusion versus the I/R group. Cytokine levels (tumor necrosis factor-α, interleukin-8) and hepatocellular injury (aspartate aminotransferase and alanine aminotransferase) were significantly reduced by glycine administration.. Intravenous glycine administration reduces liver warm I/R injury by reducing the systemic inflammatory response, and maintaining cellular energy production.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Bile; Disease Models, Animal; Electron Transport Complex IV; Energy Metabolism; Glycine; Hemodynamics; Infusions, Intravenous; Interleukin-8; Liver; Liver Circulation; Microcirculation; Mitochondria, Liver; Oxidation-Reduction; Rabbits; Reperfusion Injury; Time Factors; Tumor Necrosis Factor-alpha; Warm Ischemia

Systemic inflammatory response following ischemia-reperfusion injury (IRI) to a specific organ may cause injuries in multiple remote organs. The emergence of ischemic postconditioning (IPO) provides a potential method for experimentally and clinically attenuating various types of organ postischemic injuries. We have shown that IPO can attenuate lung IRI by up-regulating the protein expression of heme oxygenase-1(HO-1). This study tested the hypothesis that IPO attenuates systemic inflammatory responses following lung IRI by activating HO-1.. Anaesthetized and mechanically ventilated adult Sprague-Dawley rats were randomly assigned to one of the following groups (n = 8 each): the sham-operated control group, the ischemia-reperfusion (IR) group (40 min of left-lung ischemia and 120 min of reperfusion), the IPO group (three successive cycles of 30-s reperfusion per 30-s occlusion before restoring full perfusion), and the zinc protoporphyrin IX (ZnP) plus IPO group (ZnP, an inhibitor of HO-1, was injected intraperitoneally at 20 mg/kg 24 h prior to the experiment, and the rest of the procedures were similar to that of the IPO group). Lung injury was assessed by arterial blood gas analysis, wet-to-dry lung weight ratio and tissue histologic and biochemical changes. The lung tissue and plasma levels of lipid peroxidation were determined by measuring the contents of malondialdehyde (MDA) production. Protein expression of HO-1 was determined by Western blotting. Pulmonary neutrophil was counted. Lung tissue myeloperoxidase (MPO) activity as well as plasma levels of proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukines 6 and 8 (IL-6, IL-8) were determined by spectrophotography.. Lung ischemia-reperfusion led to severe lung pathologic morphologic changes and increased pulmonary MDA production, neutrophil count, and MPO activity and reduced arterial oxygen partial pressure (all P < 0.05 IR versus sham), accompanied with a compensatory increase in HO-1 protein and activity. Plasma levels of TNF-α, IL-6, and IL-8 were increased in the IR group (all P < 0.05 versus sham). IPO attenuated or prevented all the above changes, except that it further increased lung HO-1 activity. Treatment with ZnP abolished all the protective effects of postconditioning.. Postconditioning attenuated pulmonary neutrophil accumulation and activation and lung IRI and reduced systemic inflammatory responses by activating HO-1.

Topics: Animals; Blood Gas Analysis; Cytokines; Female; Heme Oxygenase (Decyclizing); Interleukin-6; Interleukin-8; Ischemic Preconditioning; Lung; Male; Neutrophils; Organ Size; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

The aim of the study was to investigate the effect of Ginkgo biloba extract 50 (GBE50), a well-known natural antioxidant, against immunity and antioxidant enzyme activities in ischemia reperfusion (IR) rats. Rats were then divided into six groups fed for 15 days with the same diet: three groups (IV, V, VI) were treated by different doses of GBE50 suspension [20, 40, or 60 mg/kg body weight by oral gavage every day at a fixed time (10.00 a.m.)] (equal to 5, 10 and 20 times, respectively, the maximum recommended human dose), and three groups (I, II, III) were untreated. At the end of the experiment, rats' hearts were subjected to 30 min of ischemia followed by 90 min of reperfusion. Results showed that IR significantly enhanced heart rate, S-T height, myocardium (myeloperoxidase) MPO activity and blood interleukin-8 (IL-8), tumor necrosis factor Alpha (TNF-a), interleukin-1β (IL-1β) levels, blood aspartate transaminase (AST), lactate dehydrogenase (LDH), and creatinine kinase (CK) activities, reduced myocardium sodium-potassium adenosine triphosphatase (Na(+)-K(+)-ATPase), calcium-magnesium adenosine triphosphatase (Ca(2+)-Mg(2+)-ATPase) activities and antioxidant enzyme activities in IR group (III) compared to sham control group (II). Pretreatment of GBE50 markedly significantly reduced heart rate, S-T height, myocardium MPO activity and blood IL-8, TNF-a, IL-1β levels, blood AST, LDH, and CK activities, enhanced myocardium Na(+)-K(+)-ATPase, Ca(2+)-Mg(2+)-ATPase activities and antioxidant enzyme activities in IR group (II) compared to IR group (III). The results suggested that the GBE50 may reduce the oxidative stress in the reperfused myocardium, and increased immunity and antioxidant activities in IR rats.

Topics: Adenosine Triphosphatases; Animals; Antioxidants; Aspartate Aminotransferases; Creatine Kinase; Ginkgo biloba; Heart Rate; Humans; Immunity; Interleukin-1beta; Interleukin-8; L-Lactate Dehydrogenase; Male; Peroxidase; Plant Extracts; Rats; Rats, Wistar; Reperfusion Injury; Tumor Necrosis Factor-alpha

Sterile inflammation resulting from cell death is due to the release of cell contents normally inactive and sequestered within the cell; fragments of cell membranes from dying cells also contribute to sterile inflammation. Endothelial cells undergoing stress-induced apoptosis release membrane microparticles, which become vehicles for proinflammatory signals. Here, we show that stress-activated endothelial cells release two distinct populations of particles: One population consists of membrane microparticles (<1 μm, annexin V positive without DNA and no histones) and another larger (1-3 μm) apoptotic body-like particles containing nuclear fragments and histones, representing apoptotic bodies. Contrary to present concepts, endothelial microparticles do not contain IL-1α and do not induce neutrophilic chemokines in vitro. In contrast, the large apoptotic bodies contain the full-length IL-1α precursor and the processed mature form. In vitro, these apoptotic bodies induce monocyte chemotactic protein-1 and IL-8 chemokine secretion in an IL-1α-dependent but IL-1β-independent fashion. Injection of these apoptotic bodies into the peritoneal cavity of mice induces elevated serum neutrophil-inducing chemokines, which was prevented by cotreatment with the IL-1 receptor antagonist. Consistently, injection of these large apoptotic bodies into the peritoneal cavity induced a neutrophilic infiltration that was prevented by IL-1 blockade. Although apoptosis is ordinarily considered noninflammatory, these data demonstrate that nonphagocytosed endothelial apoptotic bodies are inflammatory, providing a vehicle for IL-1α and, therefore, constitute a unique mechanism for sterile inflammation.

Topics: Animals; Apoptosis; Autoimmunity; Cell-Derived Microparticles; Chemokine CCL2; Endothelial Cells; Histones; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1alpha; Interleukin-8; Lupus Erythematosus, Systemic; Male; Mice; Mice, Inbred C57BL; Reperfusion Injury

This study aimed to analyze changes in nuclear factor-kappa B (NF-kappaB), inflammation factors, and macrophages in pulmonary tissue under deep hypothermia circulatory arrest (DHCA) at different time points, which can be used to infer the role of early macrophage activation and NF-kappaB activity in pulmonary injury. The possible pathogenic mechanisms of DHCA-induced pulmonary injury were investigated in this study to provide an experimental basis for clinical lung protective strategies. Piglets (n = 12) were randomly divided into 2 groups, with 6 piglets in each group. The control group had ambient temperature cardiopulmonary bypass (CPB), and the experimental group had DHCA. Both groups had conventional CPB with 30 min of parallel circulation. Changes in NF-kappaB and inflammatory factors were examined in each group at 6 different time points. At 0.5 h after ischemia-reperfusion, NF-kappaB expression in the nucleus of pulmonary tissue reached its peak, and brown-stained nuclei were mainly polymorphonuclear antibodies. At 1 h after ischemia-reperfusion, plasma tumor-necrosis factor (TNF)-alpha in the experimental group was significantly increased compared with that before reperfusion (P < 0.05). The plasma levels of interleukin (IL)-8 and IL-6 in the experimental group were significantly increased at 1.5 h after ischemia-reperfusion compared with the levels before reperfusion (P < 0.05). Early activation of NF-kappaB under DHCA might play an important role in DHCA-induced pulmonary injury.

Topics: Animals; Circulatory Arrest, Deep Hypothermia Induced; Humans; Immunohistochemistry; Interleukin-6; Interleukin-8; Lung Injury; Macrophage Activation; NF-kappa B; Random Allocation; Reperfusion Injury; Swine; Tumor Necrosis Factor-alpha

Toll-like receptors (TLRs) are an evolutionarily conserved family of cell membrane receptors that are part of the innate immunity system playing an important role as a first response to tissue injury. TLR2 and TLR4 are constitutively expressed on renal epithelium, and their expression is enhanced following renal ischemia/reperfusion (I/R) injury. Genetic deletion of either TLR2 or TLR4 protects from renal I/R injury. However, it is not known whether deletion of both combined protects the kidney more than a deletion of either one alone. Therefore, we performed renal I/R injury in mice lacking TLR2, TLR4, and TLR2/4, respectively. Our results demonstrate that there are no significant differences regarding protection from renal I/R injury in TLR2/4((-/-)) compared with either TLR2((-/-)) or TLR4((-/-)) gene-targeted mice as determined by histological evaluation and renal functional parameters. Furthermore, there was no difference in the number of apoptotic tubular cells and in nuclear translocation of nuclear factor kappa-B (NF-kappaB) between the TLR-gene-targeted groups. In parallel, in vitro experiments did not demonstrate an additional effect of the double genetic deletion compared with the single gene deletion with respect to tumor necrosis factor (TNF)-alpha and interleukin (IL)-8 production in hypoxic isolated proximal tubular epithelial cells of the respective animals. In conclusion, a double genetic deletion of TLR2 and TLR4 confers a similar protection following renal I/R injury compared with single deletions of TLR2 and TLR4.

Topics: Animals; Apoptosis; Cells, Cultured; Disease Models, Animal; Immunity, Innate; Interleukin-8; Kidney; Kidney Diseases; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; Reperfusion Injury; Toll-Like Receptor 2; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Human intestinal ischemia-reperfusion (IR) is a frequent phenomenon carrying high morbidity and mortality. Although intestinal IR-induced inflammation has been studied extensively in animal models, human intestinal IR induced inflammatory responses remain to be characterized. Using a newly developed human intestinal IR model, we show that human small intestinal ischemia results in massive leakage of intracellular components from ischemically damaged cells, as indicated by increased arteriovenous concentration differences of intestinal fatty acid binding protein and soluble cytokeratin 18. IR-induced intestinal barrier integrity loss resulted in free exposure of the gut basal membrane (collagen IV staining) to intraluminal contents, which was accompanied by increased arteriovenous concentration differences of endotoxin. Western blot for complement activation product C3c and immunohistochemistry for activated C3 revealed complement activation after IR. In addition, intestinal IR resulted in enhanced tissue mRNA expression of IL-6, IL-8, and TNF-alpha, which was accompanied by IL-6 and IL-8 release into the circulation. Expression of intercellular adhesion molecule-1 was markedly increased during reperfusion, facilitating influx of neutrophils into IR-damaged villus tips. In conclusion, this study for the first time shows the sequelae of human intestinal IR-induced inflammation, which is characterized by complement activation, production and release of cytokines into the circulation, endothelial activation, and neutrophil influx into IR-damaged tissue.

Topics: Aged; Aged, 80 and over; Complement C3c; Female; Humans; Immunohistochemistry; Inflammation; Interleukin-6; Interleukin-8; Intestine, Small; Male; Middle Aged; Reperfusion Injury; Tissue Culture Techniques; Tumor Necrosis Factor-alpha

Today, there is no continuous monitoring of the bronchial epithelial lining fluid. This study used microdialysis as a method of continuous monitoring of early lung cytokine response secondary to intestinal ischemia-reperfusion in pigs. The authors aimed to examine bronchial microdialysis for continuous monitoring of IL-1β, TNF-α, IL-8, and fluorescein isothiocyanate Dextran 4,000 Da (FD-4). The superior mesenteric artery was cross-clamped for 120 min followed by 240 min of reperfusion (ischemia group, n = 8). Four sham-operated pigs served as controls. The pigs were anesthetized and normoventilated (peak inspiratory pressure, <20 cm H2O; positive end-expiratory pressure, 7 cm H2O). Samples from bronchial and luminal intestinal and arterial microdialysis catheters (flow-rate of 1 μL/min) were collected during reperfusion in 60-min fractions. Samples were analyzed for TNF-α, IL-1β, IL-8, and FD-4. Data are presented as median (interquartile range). A lung biopsy was collected at the end of the experiment. During reperfusion, there was an increase in bronchial concentrations of both IL-8 (3.70 [1.47-8.93] ng/mL per h vs. controls, 0.61 [0.47-0.91] ng/mL per h; P < 0.001) and IL-1β (0.32 [0.05-0.56] ng/mL per h vs. controls, 0.07 [0.04-0.10] ng/mL per h; P = 0.008). In the intestinal lumen, IL-8 was increased in the ischemia group (6.33 [3.13-9.23] ng/mL per h vs. controls, 0.89 [0.21-1.86] ng/mL per h; P < 0.001). The FD-4 did not differ between groups. Pulmonary vascular resistance and pulmonary shunt increased versus controls. During reperfusion, PaO2/FiO2 ratio decreased in the ischemia group. Histology was normal in both groups. Bronchial microdialysis detects altered levels of cytokines in the epithelial lining fluid and can be used for continuous monitoring of the immediate local lung cytokine response secondary to intestinal ischemia-reperfusion.

Topics: Acute Lung Injury; Animals; Body Fluids; Bronchi; Constriction; Cytokines; Epithelial Cells; Hemodynamics; Interleukin-1beta; Interleukin-8; Intestines; Ischemia; Mesenteric Artery, Superior; Microdialysis; Reperfusion Injury; Sus scrofa; Swine; Time Factors; Tumor Necrosis Factor-alpha

Ischemia-reperfusion (I/R) injury may influence graft function after transplantation. Erythropoietin (EPO) attenuates I/R injury in various animal organs such as intestine, brain, and kidney.. To evaluate the effects of pretreatment with recombinant human EPO (rhEPO) on I/R-induced heart injury.. A rat model of I/R injury was established by ligating the left descending coronary artery for 30 minutes, followed by reperfusion for 4 hours. Fifty Sprague-Dawley rats were divided into 5 groups: sham operation; I/R; I/R+rhEPO, 100 U/kg; I/R+rhEPO, 1000 U/kg; and I/R+rhEPO, 5000 U/kg. Electrocardiograms were assessed continuously to note arrhythmia caused by reperfusion. Serum concentrations of interleukin (IL)-6 and IL-8, and tumor necrosis factor-alpha were measured at 2 and 4 hours after reperfusion.. The rhEPO-treated animals exhibited dosage-dependent significant reduction in the incidence of ventricular arrhythmia caused by reperfusion, and markedly decreased serum concentrations of IL-6, IL-8, and tumor necrosis factor-alpha (P < .05) compared with the I/R group (P < .05).. The rhEPO attenuates myocardial I/R injury in rats, at least in part related to inhibition of the system inflammatory response.

Topics: Animals; Erythropoietin; Humans; Inflammation; Interleukin-6; Interleukin-8; Myocardial Ischemia; Myocardial Reperfusion Injury; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reperfusion Injury; Tumor Necrosis Factor-alpha

To study the effects of limb ischemia preconditioning on pulmonary free radicals and cytokine levels during lung ischemia-reperfusion injury in rabbits.. Eighteen healthy rabbits were randomly divided into three groups: control group (group C, n = 6), ischemia/reperfusion group (group I/R, n = 6), limb ischemia preconditioning group (group L, n = 6). At the end of experiments, the wet to dry-weight ratio (W/D), activities of superoxide dismutase (SOD) and myeloperoxidase (MPO), levels of malondialdehyde (MDA) and the contents of cytokines (TNF-α, IL-6, IL-8 and IL-10) were determined in lung tissues. Protein levels of bronchoalveolar lavage fluid and serum were measured to calculate the lung permeability index. Pathologic changes of lung tissues were also observed.. Compared to the group I/R, the lung tissue W/D ratio, MPO activity, lung permeability index, MDA and the cytokines (TNF-α, IL-6 and IL-8) levels were significantly decreased in group L (P < 0.05), while the SOD activity (P < 0.05) and IL-10 contents were significantly increased (P < 0.01). There was no statistical difference in the changes of the above parameters between group L and group C (P > 0.05). The morphologic damages were significantly reduced in group L than that in group I/R.. Limb ischemia preconditioning has protective effect against lung ischemia-reperfusion injury, which may at least in part through inhibiting the release of oxygen-derived free radicals and pro-inflammatory cytokines (TNF-α, IL-6, IL-8) and increasing the production of anti-inflammatory cytokine IL-10.

Topics: Animals; Disease Models, Animal; Extremities; Female; Interleukin-10; Interleukin-6; Interleukin-8; Ischemic Preconditioning; Lung; Male; Rabbits; Random Allocation; Reactive Oxygen Species; Reperfusion Injury; Tumor Necrosis Factor-alpha

The present study aims to explore whether Mg infusion has a preventive effect on ischemia-reperfusion injury in rats. A total of 20 Sprague-Dawley-type adult male rats were used. In group 1 (control), 0.9% isotonic solution was administered. In group 2 (experiment), magnesium sulfate (0.5 mg per 100 g) was administered. Ischemia was induced for 15 min for the two groups. Magnesium (Mg), interleukin 8 (IL-8), and malondialdehyde levels were analyzed in blood, while edema, neutrophil infiltration, eosinophilia, loss of striation, and nucleolization were evaluated in histopathological examination. Mg levels in the experiment group were higher than those in the control group after ischemia-reperfusion (p < 0.05). In the control group, postischemia and postreperfusion IL-8 values were higher than preoperative values (p < 0.05). As for eosinophilia and loss of striation values, these were higher in the experiment group after ischemia-reperfusion than the values in the control group (p < 0.05). Histopathologically, Mg infusion cannot prevent the tissue injury triggered in ischemia-reperfusion periods. Eosinophilia can be one of the major and earliest markers of ischemia-reperfusion injury.

Topics: Animals; Edema; Eosinophilia; Interleukin-8; Magnesium; Magnesium Sulfate; Male; Malondialdehyde; Models, Statistical; Muscle, Skeletal; Muscle, Striated; Neutrophil Infiltration; Rats; Rats, Sprague-Dawley; Reperfusion Injury

We sought to evaluate the association between ischemic times, cytokines-interleukin (IL)-6, IL-1b, tumor necrosis factor-alpha, sIL-2r, IL-8, and IL-10-and alterations in gaseous exchange.. This prospective study of 42 orthotopic liver transplantation (OLT) recipients examined ischemic times and respiratory variables measured as alterations in intrapulmonary shunt and in the Po(2)/Fio(2) ratio. Centrifuged blood samples were frozen at -80 degrees C for storage. The Inmulite-One system (Euro/Dpc, Gwynedd, UK) was used to determine the concentration of cytokines. For statistical analysis, we used the Pearson correlation coefficient.. The average cold ischemic time was 478 minutes (range, 35-929) and warm ischemic time was 69.58 minutes (range, 20-180). The warm ischemic time affected the degree of shunt at the end of the operation (P < .027) and the levels of IL-10 (P < .018) and IL-6 (P < .000). The final degree of shunting and IL-10 (P < .044) showed a correlation. The cold ischemic time affected IL-1 (P < .046) and IL-8 levels (P < .023). The reperfusion syndrome was correlated with the final levels of IL-10 (P < .064) and of IL-8 (P < .066).. Warm and cold ischemic times affect the final cytokine levels and the degree of intrapulmonary shunt.

Topics: Cytokines; Humans; Inflammation; Interleukin-1; Interleukin-10; Interleukin-6; Interleukin-8; Ischemia; Liver Circulation; Liver Transplantation; Oxygen; Oxygen Consumption; Partial Pressure; Portal Vein; Reperfusion; Reperfusion Injury

We evaluated the degree of inflammatory response after ischemia/reperfusion injury by an extracorporeal normothermic autologous hemoperfusion of porcine livers.. Livers explanted from 7 pigs were perfused extracorporeally at 39 degrees C with autologous blood. Serum samples were obtained hourly until 6 hours from the beginning of reperfusion and assayed for 9 different cytokines.. Significant elevations in interleukin 6 (IL-6) and IL-8 were noted following reperfusion (P < .001), with both demonstrating an increase which followed a sigmoid curve; other cytokines that were assessed showed no significant change.. The ex vivo model excludes the liver from the influence of external systemic factors such as hormones, the autonomic nervous system, and other regulatory molecules produced elsewhere in the body, allowing the response to the ischemia/reperfusion injury to be studied in isolation and in considerable detail. Although this study examined a relatively short period, the increases in only IL-6 and IL-8 suggested that these are important molecules in the early phase after reperfusion.

Topics: Animals; Cytokines; Disease Models, Animal; Female; Interleukin-6; Interleukin-8; Liver; Reperfusion Injury; Swine

Cold ischemia/reperfusion injury of the hepatic graft has been attributed to the release of various inflammatory cytokines. Specific inhibition of these cytokines may improve viability of the hepatic graft upon reperfusion. Herein we have assessed the efficacy of cis element decoy against nuclear factor-kappaB binding site delivery to the hepatic tissue in a rodent liver transplantation model. At 8 hours after reperfusion of the liver, significant reduction was noted in the livers treated with decoy in the release of cytosolic enzymes from the hepatocytes and in serum tumor necrosis factor alpha (P < .05). The neutrophilic infiltration into the hepatic grafts was significantly suppressed in the livers treated with decoy oligodeoxynucleotides (ODNs). Decoy ODNs against nuclear factor-kappaB binding site delivery improved the viability of the hepatic graft against cold ischemia/reperfusion injury in the rodent liver transplantation model.

Topics: Alanine Transaminase; Animals; Cytokines; Inflammation; Interleukin-8; L-Lactate Dehydrogenase; Liposomes; Liver Circulation; Liver Transplantation; Male; Neutrophils; NF-kappa B; Oligodeoxyribonucleotides; Rats; Rats, Inbred BN; Reperfusion Injury; Sendai virus; Tumor Necrosis Factor-alpha

The objective of this research is to investigate the influence of rhBMP-2 on the renal tissue of rat with renal ischemia reperfusion injury. In this program the ischemia reperfusion rat model was established and Wistar rats were divided into six groups: sham operation group (S group), renal ischemia reperfusion injury group (R group), rhBMP-2 treatment group (B1, B2, B3 and B4 group). In the rhBMP treatment groups, rhBMP-2 was intravenously administered with different doses before reperfusion. The contents of TNF-alpha, IL-6, IL-8, MDA and SOD in kidney tissue were observed. At the same time, renal function (blood creatine (Scr) and urea nitrogen (BUN)) were measured. As a result, compared with renal ischemia reperfusion group, administration of rhBMP-2 significantly reduced the content of IL-6 and IL-8 (P < 0.05) and ameliorated renal dysfunction cellular damages (P < 0.05). Higher dose of rhBMP-2 may reduce the content of TNF-alpha (P < 0.05) in kidney tissue. rhBMP-2 also increased activity of SOD and reduced the level of MDA, BUN and Scr. So, we can draw a conclusion that rhBMP-2 treatment attenuates renal ischemia reperfusion injury through inhibition of pro-inflammatory cytokines production and anti-oxidation activity.

Topics: Adrenal Cortex; Animals; Blood Urea Nitrogen; Bone Morphogenetic Protein 2; Creatine; Interleukin-6; Interleukin-8; Kidney; Male; Malondialdehyde; Random Allocation; Rats; Rats, Wistar; Recombinant Proteins; Reperfusion Injury; Superoxide Dismutase; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Recruitment of various stem and progenitor cells is crucial for the regeneration of an injured organ. Levels of uric acid, one of the prototypical "alarm signals," surge after ischemia-reperfusion injury. Exogenous uric acid rapidly mobilizes endothelial progenitor cells and hematopoietic stem cells and protects the kidney from ischemia. The relatively fast responses to uric acid suggest that preformed second messengers may be released from a storage pool. Here, it is reported that monosodium urate (MSU) results in exocytosis of Weibel-Palade bodies in vitro and in vivo, leading to the release of IL-8, von Willebrand factor, and angiopoietin 2 in the culture medium or circulation. Confocal and immunoelectron microscopy confirmed depletion of von Willebrand factor in MSU-treated aortic endothelial cells. Angiopoietin 2 alone induced exocytosis of Weibel-Palade bodies, mobilized hematopoietic stem cells and depleted splenic endothelial progenitor cells, partially reproducing the actions of MSU. In addition, pretreatment with angiopoietin 2 protected the kidneys from an ischemic insult, suggesting that the previously reported renoprotection conferred by MSU likely results from exocytosis of Weibel-Palade bodies. Furthermore, experiments with toll-like receptor 4 (TLR-4)-and TLR-2-deficient mice demonstrated that uric acid-induced exocytosis of Weibel-Palade bodies is mediated by TLR-4 and that uric acid-induced release of IL-8 requires both TLR-2 and TLR-4. In summary, these results suggest that exocytosis of Weibel-Palade bodies links postischemic repair with inflammation and mobilization of stem cells.

Topics: Angiopoietin-2; Cells, Cultured; Exocytosis; Hematopoietic Stem Cells; Humans; Interleukin-8; Ischemia; Reperfusion Injury; Stem Cells; Toll-Like Receptor 2; Toll-Like Receptor 4; Uric Acid; von Willebrand Factor; Weibel-Palade Bodies

Ischemia-reperfusion injury is a leading cause of acute renal failure and a major determinant in the outcome of kidney transplantation. Here we explored systemic gene therapy with a modified adenovirus expressing Interleukin (IL)-13, a cytokine with strong anti-inflammatory and cytoprotective properties. When ischemia was induced we found that the IL-13 receptor is expressed in both the normal and experimental kidneys. Prior to the induction of ischemia, rats received adenovirus-IL-13, control adenovirus or saline. IL-13 plasma levels increased more than 50-fold in adenovirus-IL-13 treated animals, confirming successful IL-13 gene delivery. Histological analysis showed decreased tubular epithelial cell damage with adenovirus-IL-13 therapy, accompanied by reduced kidney injury molecule-1 expression. Interstitial infiltration by neutrophils and macrophages was reduced by half as was interstitial fibrosis and expression of alpha-smooth muscle actin. IL-13 treatment significantly diminished the expression of E-selectin, IL-8, MIP-2, TNF-alpha and MCP-1 mRNA. These results suggest that the use of systemic IL-13 gene therapy may be useful in reducing renal tubulointerstitial damage and inflammation caused by ischemia-reperfusion.

Topics: Animals; Cell Proliferation; Chemokine CCL2; Chemokine CXCL2; Down-Regulation; E-Selectin; Epithelial Cells; Fibrosis; Genetic Therapy; Interleukin-13; Interleukin-8; Ki-67 Antigen; Kidney Tubules; Macrophages; Neutrophils; Rats; Rats, Inbred Strains; Receptors, Interleukin-13; Renal Insufficiency; Reperfusion Injury; RNA, Messenger; Tumor Necrosis Factor-alpha

The aim of this work was to verify neuroprotective and anti-inflammatory properties of FBD, a herbal formula composed of Poria cocos, Atractylodes macrocephala and Angelica sinensis, in ICR mice subjected to repetitive 10 min of common carotid arteries occlusion followed 24 h reperfusion. Intragastrical pretreatment with supercritical carbon dioxide extract (FBD-CO(2), 37.5 mg/kg) twice daily for 3.5 d, significantly reduced Evans Blue influx, neuron specific enolase (NSE) efflux, brain infarction (all p<0.05), also inhibited polymorphonuclear leukocytes (PMNs) infiltration (p<0.001), suppressed secretion of tumor necrosis factor (TNF)-alpha in blood (p<0.05), interleukin (IL)-1beta and IL-8 in brain (both p<0.01), and down-regulated cerebral expression of phosphor-IkappaB-alpha and phosphor-nuclear factor kappa-B (NF-kappaB), whether coupled with aqueous extract (FBD-H(2)O, 150 mg/kg) or not. Moreover, FBD-CO(2) (0.1-10 microg/ml) inhibited 0.1 microM phorbol myristate acetate-evoked oxidative burst in rat PMNs, 20 ng/ml TNF-alpha-triggered PMNs adhesion to ECV304 endothelial cells, and PMNs neurotoxicity to PC12 neuron-like cells as well as NSE release (IC(50) 1.30, 0.98, 0.24 and 0.82 microg/ml, respectively). Our study demonstrated that FBD-CO(2) prevented brain ischemia/reperfusion injury, at least in part, by limiting PMNs infiltration and neurotoxicity mediated by TNF-alpha, IL-1beta and IL-8, via inhibition on NF-kappaB activation.

Topics: Angelica sinensis; Animals; Atractylodes; Brain Injuries; Brain Ischemia; Disease Models, Animal; Drugs, Chinese Herbal; Inflammation; Interleukin-1beta; Interleukin-8; Male; Mice; Mice, Inbred ICR; Neuroprotective Agents; Neutrophil Infiltration; NF-kappa B; Polyporales; Reperfusion Injury; Tumor Necrosis Factor-alpha

Reperfusion after ischemic conditions induces massive endothelial cell (EC) activation, an initial step of reperfusion injury. Reperfusion is characterized by reoxygenation, realkalinization and a localized increase of inflammatory stimuli. In this study, we focused on the influence of extracellular realkalinization on human umbilical vein endothelial cell (HUVEC) activation. We examined intracellular pH (pH(in)) and intracellular free calcium concentration ([Ca(2+)](in)), a second messenger known to mediate von Willebrand factor (VWF) exocytosis in endothelium, upon realkalinization. Furthermore, we measured the agonist-stimulated exocytosis of VWF, Interleukin-8 and soluble P-selectin (sP-Selectin) as markers of EC activation. To verify a morphological correlate of EC activation, we finally observed platelet-endothelial adherence during realkalinization using shear flow. Realkalinization of HUVEC was simulated by switching from bicarbonate buffered Ringer solution of an acidotic pH(ex) of 6.4 to a physiologic pH(ex) of 7.4. Extracellular realkalinization was accompanied by pH(in) recovery from 6.5 to 7.2 within 10 min. Application of cariporide, an inhibitor of the Na(+)/H(+) exchanger subtype 1 (NHE), during extracellular realkalinization significantly delayed the early kinetics of intracellular realkalinization. Histamine stimulated [Ca(2+)](in) was significantly increased upon realkalinization compared to control cells. Also agonist-stimulated release of VWF, Interleukin-8 and sP-Selectin was massively enhanced during pH(in) recovery in comparison to control. Furthermore, we observed an increased platelet binding to endothelium. Interestingly, each of these realkalinization-induced effects were significantly reduced by early application of cariporide. Therefore, delay of acute NHE-dependent pH(in) recovery may represent a promising mechanism for inhibition of EC activation upon reperfusion.

Topics: Acidosis; Amiloride; Calcium; Cell Adhesion; Cells, Cultured; Chloride-Bicarbonate Antiporters; Cyclic AMP; Endothelial Cells; Endothelium, Vascular; Exocytosis; Guanidines; Histamine; Humans; Hydrogen-Ion Concentration; Interleukin-8; Intracellular Fluid; Kinetics; Linear Models; Methacrylates; P-Selectin; Platelet Adhesiveness; Reperfusion Injury; Sodium-Hydrogen Exchangers; Sulfones; Umbilical Veins; von Willebrand Factor

Although liberalization of donor criteria may be one of the solutions to the current serious lung donor shortage, the use of non-standard donor lungs would increase the risk of post-operative complications. In the present study, we investigated the effect of sivelestat, a neutrophil elastase inhibitor, on reperfusion injury of a donor lung that was harvested from endotoxin-primed animals in a rat lung transplantation model.. Donor rats received an intraperitoneal injection of Escherichia coli endotoxin (5 mg/kg) 2 hours before lung harvesting. The donor lungs were flushed with an organ preservation solution with or without sivelestat (300 microg/ml), and the left lung was immediately transplanted to the recipient by the cuff technique.. Endotoxin priming did not cause significant lung injury before harvesting. Although these lungs looked normal macroscopically, they were found to contain numerous neutrophils in the alveolar capillaries, even after lung flushing. There was no significant difference in the neutrophil count between the lungs flushed with and without sivelestat. The endotoxin-primed donor lung without sivelestat treatment became edematous immediately after reperfusion. In addition, the recipient's native right lungs were also pathologic. Treatment with sivelestat significantly reduced injury in both the donor and the recipient's native lungs. Treatment with sivelestat also inhibited the increase in tumor necrosis factor-alpha and cytokine-induced neutrophil chemoattractant-1 levels in the recipient circulation after reperfusion.. We conclude that sivelestat could reduce lung injury after transplantation by inhibiting the deleterious burst of inflammatory reactions that are initiated by reperfusion of the lungs from endotoxin-primed rats.

Topics: Animals; Cytokines; Endotoxins; Escherichia coli; Glycine; Injections, Intraperitoneal; Interleukin-8; Leukocyte Elastase; Lung; Lung Transplantation; Male; Neutrophils; Pneumonia; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sulfonamides; Tissue and Organ Harvesting; Tumor Necrosis Factor-alpha

Renal ischemic reperfusion injury (IRI) is unavoidable and is still one of the major problems in renal transplantation. The aim of this study was to investigate the effects of olprinone, a phosphodiesterase III inhibitor, on renal IRI.. After a right nephrectomy, renal IRI was induced in rats. Olprinone was given in two different ways: sustained systemic administration and transient local administration to the kidney. Control rats were treated with saline. Using a magnifying endoscope, the renal blood flow speed was measured at 23 h after reperfusion. Then, blood samples were collected, and kidney specimens were taken for histological study. In order to study the mechanism, we performed in vitro experiments, using human proximal renal tubular cells (HK-2) incubated with tumor necrosis factor (TNF)-alpha along with olprinone or saline, and interleukin (IL)-8 was measured in the culture supernatant.. In the saline group, the blood flow speed (BFS) was greatly reduced compared to that in normal kidneys. In both olprinone-treated groups, BFS of the renal microcirculation significantly increased, tubular damage and macrophage infiltration attenuated, and renal function greatly improved. Olprinone inhibited the increase in the IL-8 levels resulting from the incubation of HK-2 with TNF-alpha.. Our study successfully demonstrates that olprinone has renoprotective properties when applied locally as well as systemically. The results suggest that olprinone might be clinically useful in renal transplantation for the donor kidney, the recipient, and even in treating acute renal failure.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Acute Kidney Injury; Animals; Blood Flow Velocity; Blood Urea Nitrogen; Cells, Cultured; Cyclic Nucleotide Phosphodiesterases, Type 3; Disease Models, Animal; Humans; Imidazoles; Immunohistochemistry; Interleukin-8; Kidney Tubules, Proximal; Male; Microscopy, Video; Phosphodiesterase Inhibitors; Pyridones; Rats; Rats, Sprague-Dawley; Renal Circulation; Reperfusion Injury; Treatment Outcome

To investigate the protective effect of amrinone against experimental lung ischemia /reperfusion (I/R) injury.. Twenty-four Sprague-Dawley rats were randomly divided into 3 groups (n=8 each): sham- operated group, I/R group, and amrinone-treated I/R group (AMR group). The left lung of rats was subjected to ischemia for 90 minutes, followed by reperfusion for 2 hrs, to induce an I/R lung injury model. The rats of the AMR group received amrinone (10 mg/kg) intravenously 30 minutes before ischemia and 5 minutes before reperfusion. After 2 hrs of reperfusion, carotid artery blood was collected for blood-gas analysis and detection of serum levels of IL-1beta, IL-8 and TNF-alpha. The left lung was removed for detection of the lung wet/dry ratio, the erythrocuprein (SOD) activity and the malonaldehyde (MDA) content as well as the pathological changes.. After 2 hrs of reperfusion, there were no significant differences in artery partial pressure of oxygen (PO2) and partial pressure of carbon dioxide (PCO2) among the three groups. The lung wet/dry ratio (5.3 +/- 0.5 vs 4.8 +/- 0.1) and the MDA content (0.66 +/- 0.16 nmol/mg prot vs 0.47 +/- 0.06 nmol/mg prot) in the I/R group were significantly higher than those of the sham-operated group (P <0.05). The administration of amrinone markedly reduced the lung wet/dry ratio (4.8 +/- 0.2) and the MDA content (0.51 +/- 0.09 nmol/mg prot) and increased the SOD activity (54.7 +/- 6.8 vs 39.3 +/- 3.0 U/mg prot) when comparing the I/R group (P < 0.05). The serum levels of IL-1beta, IL-8 and TNF-alpha in the I/R group were 22.08 +/- 3.85, 21.92 +/- 5.56 and 30.50 +/- 3.77 pg/mL respectively, which were significantly higher than those of the sham-operated group. The AMR group showed lower serum levels of IL-1beta, IL-8 and TNF-alpha (16.66 +/- 3.02,14.73 +/- 2.75 and 22.48 +/- 3.82 pg/mL, respectively) compared with the I/R group (P < 0.01). The pathologic examination displayed that the lung tissue structure was normal and there was no hyperemia in the sham-operated and the AMR groups. The lung tissue structure of the I/R group was nearly normal but there were hyperemia and more inflammatory cells than the sham-operated and the AMR groups.. Amrinone has protections against lung I/R injury, possibly through its anti-oxidation effects and an inhibition of inflammation factors releasing.

Topics: Amrinone; Animals; Interleukin-1beta; Interleukin-8; Lung; Male; Malondialdehyde; Phosphodiesterase Inhibitors; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Local cytokine production is a pathogenic factor in ischemia-reperfusion injury in early graft dysfunction. This study analyzed interleukin 8 (IL-8) messenger RNA (mRNA) expression in lung tissue and the association between IL-8 mRNA levels and interstitial lung changes in an experimental model of warm lung ischemia-reperfusion.. We studied 16 New Zealand rabbits divided into 3 groups: control, ischemia (tissue taken from right lower lobe after 1, 2, or 3 hours of ischemia), and reperfusion (tissue taken from right upper and middle lobes after 1 hour of ischemia and 1, 2, or 3 hours of reperfusion). Expression of IL-8 mRNA was determined by reverse transcription and polymerase chain reaction. Interstitial infiltration by polymorphonuclear neutrophils was determined. The Mann-Whitney U-test was used for statistical comparisons, with P< .05 considered to indicate a significant result.. During ischemia, IL-8 mRNA levels were elevated at the end of hour 1 (P=.009) with respect to the control group, but not thereafter. Interstitial changes were minimal. IL-8 mRNA levels during reperfusion were similar to those observed during ischemia, with a slight increase at the end of hour 2. There were no significant differences between hours 1, 2, and 3. Polymorphonuclear neutrophil recruitment occurred at the beginning of reperfusion (P=.014), but no significant differences were observed at hours 2 or 3. Progressive thickening of alveolar septa and edema was documented.. Changes in IL-8 mRNA expression during ischemia precede interstitial infiltration by polymorphonuclear neutrophils during reperfusion, suggesting that the 2 processes are related. Quantification of IL-8 mRNA expression could facilitate early diagnosis of graft dysfunction.

Topics: Animals; Interleukin-8; Lung; Neutrophils; Rabbits; Reperfusion Injury

Topics: Animals; Benzylisoquinolines; Brain Ischemia; Interleukin-1beta; Interleukin-8; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

Ischemia/reperfusion injury is an inherent consequence of solid organ transplantation that increases tissue inflammation and negatively impacts organ transplant function and survival. This study investigated the expression levels of chemokine and chemokine receptor genes in living versus cadaver donor renal allografts before and after reperfusion.. This study involved 39 renal transplant patients (19 cadaveric and 20 living donor). The ischemia biopsy was taken just before graft declamping and the reperfusion biopsy 30 min after declamping. Whole-cell RNA was isolated and chemokine (IL-8, CCL2/MCP-1, CXCL10/IP-10 and CCL5/RANTES) and chemokine receptor (CCR2 and CCR5) expression was tested by quantitative PCR.. Just prior to declamping, ischemic cadaveric donor grafts had higher expression of CXCL10/IP-10 but not IL-8 or CCL2/MCP-1 than living donor grafts. IL-8 expression increased 50% from ischemia to reperfusion in living donor grafts but increased more than 13-fold during reperfusion of cadaver donor grafts. Increased total ischemia time induced greater IL-8 expression during reperfusion. MCP-1 expression also increased during reperfusion of living and cadaver donor grafts but differences were not observed between the two groups of grafts. RANTES, CCR2, and CCR5 expression did not change in ischemic vs. reperfusion biopsies.. The expression of chemokines directing neutrophil and macrophage recruitment increases during reperfusion of living and cadaveric donor renal allografts. Expression levels of IL-8 correlate with the ischemic time imposed on the renal graft. Early tissue injury may be attenuated by strategies antagonizing chemokines directing the recruitment of neutrophils and macrophages into kidney grafts.

Topics: Chemokine CCL2; Chemokine CCL5; Chemokine CXCL10; Chemokines, CXC; Cold Ischemia; Female; Humans; Interleukin-8; Kidney; Kidney Transplantation; Male; Receptors, CCR2; Receptors, CCR5; Receptors, Chemokine; Reperfusion; Reperfusion Injury; Tissue Donors

Neutrophil plays an important role in hepatic ischemia-reperfusion injury. We investigated neutrophil infiltration in liver tissue, Kupffer cells' role in neutrophil accumulation, and apoptosis and regeneration of hepatocytes in liver ischemia-reperfusion injury.. Vascular microclamps were placed across the pedicles of the median and left lateral lobes for 90 minutes after 30% hepatectomy with the resection of caudate, right lateral and quadrate lobes and papillary process. Gadolinium chloride (GdCl(3)) was used to destroy Kupffer cells. Neutrophil activity was inhibited with Urge-8, a monoclonal antibody against neutrophil produced in our laboratory. GdCl(3) (10 mg/kg) and Urge-8 (50 mg/kg) were given intravenously in respective groups. Ischemia control, GdCl(3) and Urge-8 groups were compared.. Following hepatic reperfusion, serum interleukin-8 (IL-8) levels and hepatic neutrophil counts peaked at 3 hours, and peak concentrations of alanine aminotransferase (ALT) occurred at 6 hours. Animals of the control group showed increases in neutrophil infiltration in liver tissue, liver enzyme levels, and apoptosis index of hepatocytes and decreases in overall survival rate and proliferating cell nuclear antigen (PCNA) expression of hepatocytes. The survival rates and PCNA proportion of hepatocytes were higher and the levels of hepatic neutrophil infiltration, liver enzymes, and hepatocyte apoptosis after reperfusion were lower in the GdCl(3) and Urge-8 groups than those in the ischemia control group.. Blockades of Kupffer cells' activity and neutrophil infiltration by GdCl(3) and Urge-8 eliminate neutrophil-mediated hepatic injury and enhance subsequent hepatic regeneration during liver ischemia-reperfusion.

Topics: Animals; Interleukin-6; Interleukin-8; Ketone Bodies; Liver; Liver Function Tests; Male; Neutrophils; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Innate immunity is the first line of host defense against invading microorganisms, which is mediated by specific pathogen recognition molecules called toll-like receptors (TLRs). TLRs can also recognize endogenous "danger" signals, resulting in cytokine production and activation of the adaptive immune system. We hypothesized that gene expression of TLRs during lung transplantation may be affected by the donor condition and the ischemia-reperfusion process, which may subsequently influence graft function.. Lung biopsies from 14 patients were collected before and after reperfusion, and mRNA levels of TLRs, cytokines (interleukin [IL]-1beta, IL-6, IL-8, IL-10 and interferon-gamma) and heat-shock protein 70 (HSP70) were measured by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR).. In cold-preserved donor lungs, all TLRs (except TLR3) showed significant correlations with one another and also with the cytokines examined. Expression of several TLRs and cytokines correlated with the intubation time of donors. TLR4 gene expression correlated closely with IL-8 before and after reperfusion (p

Topics: Adult; Aged; Biomarkers; Biopsy; Cytokines; Female; Gene Expression Regulation; Graft Survival; HSP70 Heat-Shock Proteins; Humans; Inflammation; Interleukin-8; Lung; Lung Transplantation; Male; Middle Aged; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Toll-Like Receptors

Intestinal transplantation (ITx) is severely limited by ischemia-reperfusion (I/R) injury. This study investigates I/R injury and ameliorates its consequences by using a recombinant protein targeted against selectins (recombinant P-selectin glycoprotein ligand-immunoglobulin [rPSGL-Ig]).. An isogeneic model of ITx was undertaken with control animals (no therapy) and treatment animals (rPSGL-Ig). Survival was assessed. Separate groups underwent an analysis examining tissue at multiple time points after I/R injury including histopathology; myeloperoxidase staining; immunostaining for CD3 and ED2; polymerase chain reaction analysis of interleukin (IL)-8/cytokine-inducible neutrophil chemoattractant, IL1beta, IL-6, interferon-gamma, IL-2, IL-4, and IL10; and western blots for hemoxygenase-1, BCL-2, and BCL-xl. Standard statistical analysis was undertaken.. Treatment with rPSGL-Ig resulted in significantly improved survival after ITx. Analysis demonstrated diminished injury on histopathology and reduced tissue infiltration of neutrophils and lymphocytes. Significant differences in the cytokine profile after ITx were seen between the two groups including the production of inflammatory cytokines at 24 hr and the Th1 and Th2 cytokines at 2 and 4 hr. Last, treatment resulted in increased production of hemoxygenase, BCL-2, and BCL-xl.. The results of this investigation of I/R injury after ITx revealed that rPSGL-Ig treatment led to marked improvement in outcome. The mechanism of action seems to involve the blockade of neutrophil and lymphocyte infiltration leading to a decreased inflammatory response possibly driven by Th2 cytokines. The results not only lend insight into the mechanisms behind I/R injury after ITx but also demonstrate a potential therapeutic modality to ameliorate its consequences.

Topics: Animals; CD3 Complex; Cytokines; Immunoglobulins; Interleukin-8; Intestines; Male; Membrane Glycoproteins; Neutrophils; P-Selectin; Peroxidase; Rats; Rats, Inbred Lew; Recombinant Fusion Proteins; Reperfusion Injury; RNA, Messenger

In recent years it has become increasingly clear that a cross-talk between the inflammatory response and blood coagulation exists, although many of the underlying mechanisms remain unclear. In the present study we investigated the potential anti-inflammatory properties of two different anticoagulant compounds, i.e. active-site inactivated FVIIa (FVIIai) and fondaparinux sodium, a selective FXa inhibitor, administered as pretreatment in a model of intestinal I/R in rats.. Endothelial barrier permeability was assessed using the vascular leakage of radiolabelled human serum albumin, tissue neutrophil sequestration was quantitated by myeloperoxidase (MPO) activity, and plasma levels of macrophage inflammatory protein (MIP)-2 were examined using an enzyme-linked-immuno-sorbent assay after 40 min of intestinal ischaemia and 6 h of reperfusion in the rat (n = 34). Pretreatment with FVIIai or fondaparinux sodium was administered 90 min before initiation of ischaemia.. Endothelial-barrier permeability in all examined organs, myeloperoxidase activity in the lungs, and ileum and MIP-2 levels in plasma increased after intestinal I/R. Pretreatment with FVIIai decreased the endothelial barrier permeability and MPO activity in the ileum, and a tendency towards decreased permeability was also observed in the lungs. Fondaparinux did not affect the endothelial barrier permeability or MPO activity. Both FVIIai and fondaparinux decreased the MIP-2 levels in plasma after intestinal I/R.. Inhibition of the TF-FVIIa complex by FVIIai can attenuate inflammatory responses in connection with intestinal I/R-injury and could represent a potentially important therapeutic strategy for the prevention of organ dysfunction. Potential anti-inflammatory properties of fondaparinux and other inhibitors of FXa are not excluded and need further investigation.

Topics: Animals; Anticoagulants; Blood Cell Count; Cell Membrane Permeability; Chemokine CXCL2; Chemokines, CXC; Endothelium; Factor VIIa; Factor Xa Inhibitors; Fondaparinux; Hemostasis; Intercellular Signaling Peptides and Proteins; Interleukin-8; Intestines; Ischemia; Male; Neutrophil Infiltration; Peroxidase; Polysaccharides; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Reperfusion Injury

Ischemia/reperfusion (I/R) injury after organ transplantation is a major cause of delayed graft function. Following I/R, locally produced CXC chemokines attract and activate granulocytes, which in turn promote graft damage.. We examined the involvement of granulocyte recruitment via the CXCR2 pathway in a rat model of 4 hours cold ischemia followed by kidney transplantation. Serum creatinine and intragraft granulocyte infiltration were monitored in the early phase posttransplant. A CXCR2 inhibitor, repertaxin, was given to recipients before transplantation (at -24 hours or -8 hours or -2 hours), immediately before reperfusion and 2 hours later.. An increase of granulocyte chemoattractant CINC-1/interleukin-8 (IL-8) mRNA expression after I/R both in syngeneic and allogeneic transplantation was associated with a marked infiltration of granulocytes in renal tissue. In syngeneic transplantation, Lewis rats given 15 mg/kg repertaxin 24 hours before surgery had granulocyte graft infiltration and serum creatinine levels significantly reduced in respect to vehicle-treated animals. Intermediate effects were observed with 5 mg/kg, whereas the dose of 30 mg/kg had toxic effects. We found that reducing the pretreatment time to 8 hours before surgery was still effective. Prevention of granulocyte infiltration and serum creatinine increase was also obtained in allogeneic transplantation, when Brown Norway recipients of Lewis kidneys were given 15 mg/kg repertaxin starting 8 hours before surgery.. Repertaxin treatment of the recipient animal was effective in preventing granulocyte infiltration and renal function impairment both in syngeneic and in allogeneic settings. The possibility to modulate I/R injury in this rat model opens new perspectives for preventing posttransplant delayed graft function in humans.

Topics: Animals; Base Sequence; Chemokine CXCL1; Chemokines, CXC; Granulocytes; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-8; Kidney; Kidney Transplantation; Kinetics; Male; Rats; Rats, Inbred BN; Rats, Inbred Lew; Receptors, Interleukin-8B; Reperfusion Injury; RNA, Messenger; Sulfonamides; Transplantation, Homologous; Transplantation, Isogeneic

Lung transplantation has evolved to become an effective treatment for a variety of end-stage lung diseases. However, severe reperfusion injury is still a major cause for postoperative morbidity and mortality. Although lung reperfusion injury is complex and has not been fully comprehended yet, neutrophil infiltration and cytokine activation have been postulated to play a main role. Recent studies showed that nitric oxide (NO) therapy has salutary effects on lung chronic and acute pathologies because it inhibits interleukin-8 (IL-8) release, but no data have been found on its effects during organ harvest. The aim of this study was to assess whether low doses of inhaled NO pre-treatment at the time of harvesting improves allograft function during early reperfusion in a porcine model.. Twenty-two Landrace pigs were randomly assigned to NO-treated and control groups. In NO-treated pigs, NO at 20 ppm was administered 30 min before harvest. During the early allograft reperfusion period IL-8 content, dynamic and static compliance and gas exchange (Pa/FiO2 and PaO2) were measured in both control and NO-treated lungs.. Pre-treatment with NO at the time of harvesting showed improvement of allograft function in terms of dynamic (92 +/- 8% in NO vs 72 +/- 7% in the control group, p < .05) and static (83 +/- 8% in NO vs 63 +/- 7% in the control group, p < 0.05) compliance and gas exchange (PaO2: 96 +/- 4% in NO vs 74 +/- 4.5% in the control group, p < 0.01; Pa/FiO2: 97 +/- 5% in NO vs 74 +/- 5% in the control group, p < 0.01) by diminishing IL-8 (66.5 +/- 4.7 pg/ml in NO versus 208 +/- 43 pg/ml in the control group, p < 0.05) release in pigs.. These results show for the first time that NO pre-treatment at the time of harvesting reduces allograft reperfusion injury in part due to its effects on IL-8 release.

Topics: Administration, Inhalation; Animals; Dose-Response Relationship, Drug; Drug Administration Schedule; Endothelium-Dependent Relaxing Factors; Interleukin-8; Lung; Lung Transplantation; Models, Animal; Nitric Oxide; Peroxidase; Premedication; Reperfusion Injury; Swine

Activated leukocytes are implicated in development of ischemia/reperfusion (I/R)-induced organ injuries. Phosphodiesterase 3 inhibitors have anti-inflammatory effects by preventing cyclic adenosine monophosphate (cAMP) degradation. We examined the effects of olprinone, a specific phosphodiesterase 3 inhibitor, on I/R-induced acute renal injury model in rats. Forty-five minute renal I/R was induced in uni-nephrectomized rats. Rats were divided into a vehicle group, an olprinone group, and a dibutyril (DB) cAMP group. Olprinone (0.2 microg/kg/minute) infusion began 30 min after reperfusion and continued for 3 h. DBcAMP (5 mg/kg), a stable analog of cAMP, was intraperitoneally administered 5 min after reperfusion to clarify the effect of cAMP in our model. Olprinone reduced the I/R-induced increases in serum levels of blood urea nitrogen and creatinine, and improved histological changes, including acute tubular necrosis in the outer medulla. Hemodynamic status was not affected by olprinone. I/R-induced a decrease in renal tissue blood flow, an increase in renal vascular permeability, and an enhancement of leukocyte activation, reflected by renal tissue levels of myeloperoxidase activity, and the tissue levels of cytokine-induced neutrophil chemoattractant (an equivalent of human interleukin 8) and tumor necrosis factor-alpha were all significantly decreased by olprinone. Olprinone also increased the renal tissue and plasma levels of cAMP in rats subjected to renal I/R. DBcAMP showed similar effects. Our results indicated that olprinone reduced the I/R-induced acute renal injury, probably by inhibiting leukocyte activation. The effects of olprinone could be explained through its action on cAMP levels.

Topics: Animals; Blood Urea Nitrogen; Cardiotonic Agents; Creatinine; Cyclic AMP; Hemodynamics; Imidazoles; Inflammation; Interleukin-8; Kidney; Leukocytes; Lymphocyte Activation; Male; Necrosis; Neutrophils; Peroxidase; Phosphodiesterase Inhibitors; Pyridones; Rats; Rats, Wistar; Reperfusion Injury; Time Factors; Tumor Necrosis Factor-alpha

A better understanding of lung tissue environment after circulatory arrest would allow more accurate cell culture models to study ischemia-reperfusion lung injury and facilitate retrieval of lungs from non-heart-beating donors.. To establish the time course of changes in pH and PO2 in lung tissue after circulatory arrest, 12 Sprague-Dawley rats were sacrificed. After sternotomy, pH and PO2 microelectrodes were inserted into the lungs and sealed by application of Focal Seal. Rats were maintained at normothermia (37 degrees C). Two groups of rats (n = 6 atelectatic, n = 6 room air-inflated) were followed for 4 hours after arrest, when lung tissue adenine nucleotide levels were measured by chromatography and cell death was quantified by trypan blue exclusion. Human umbilical vein endothelial cells underwent simulated ischemia and 6 hours of cold storage by replacement of culture medium with cold Perfadex. Interleukin (IL)-6 and IL-8 were measured in medium 21 hours later by enzyme-linked immunosorbent assay (ELISA).. In both groups of rats, lung [H+] increased linearly with time. In atelectatic lungs, PO2 fell precipitously, but in inflated lungs, PO2 decreased linearly for 60 to 75 minutes post-mortem and then became stable. After 4 hours at 37 degrees C, most parenchymal lung cells were dead in both groups. IL-6 and IL-8 levels increased significantly in medium of cultured endothelial cells subjected to cold storage without hypoxia.. In room-air-inflated lungs maintained at 37 degrees C, oxygen consumption continues for at least 1 hour after circulatory arrest. Warm atelectasis is poorly tolerated. Hypothermic storage can induce elaboration of cytokines by endothelial cells in the absence of hypoxia.

Topics: Animals; Cell Culture Techniques; Cell Hypoxia; Cell Survival; Chromatography, High Pressure Liquid; Circulatory Arrest, Deep Hypothermia Induced; Cytokines; Endothelial Cells; Heart Arrest; Hydrogen-Ion Concentration; Interleukin-6; Interleukin-8; Lung; Lung Transplantation; Models, Biological; Oxygen; Oxygen Consumption; Pulmonary Atelectasis; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Umbilical Cord

Antithrombin (AT) reveals its antiinflammatory activity by promoting endothelial release of prostacyclin (PGI(2)) in vivo. Since neuroinflammation is critically involved in the development of ischemia/reperfusion (I/R)-induced spinal cord injury (SCI), it is possible that AT reduces the I/R-induced SCI by attenuating the inflammatory responses. We examined this possibility using rat model of I/R-induced SCI in the present study. AT significantly reduced the mortality and motor disturbances by inhibiting reduction of the number of motor neurons in animals subjected to SCI. Microinfarctions of the spinal cord seen after reperfusion were markedly reduced by AT. AT significantly enhanced the I/R-induced increases in spinal cord tissue levels of 6-keto-PGFIalpha, a stable metabolite of PGI2. AT significantly inhibited the I/R-induced increases in spinal cord tissue levels of TNF-alpha, rat interleukin-8 and myeloperoxidase. In contrast,Trp(49) -modified AT did not show any protective effects. Pretreatment with indomethacin significantly reversed the protective effects of AT. An inactive derivative of factor Xa, which selectively inhibits thrombin generation, has been shown to fail to reduce SCI. Taken together, these observations strongly suggested that AT might reduce I/R-induced SCI mainly by the antiinflammatory effect through promotion of endothelial production of PGI(2). These findings also suggested that AT might be a potential neuroprotective agent.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antithrombins; Coloring Agents; Disease Models, Animal; Epoprostenol; Factor Xa; Humans; Inflammation; Interleukin-8; Ischemia; Male; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury; Spinal Cord; Spinal Cord Injuries; Tetrazolium Salts; Time Factors; Tryptophan; Tumor Necrosis Factor-alpha

We have demonstrated that macrophages/microglia were activated during post-ischemic inflammation in a mouse model of ischemic retinal neovascularization, and that the angiogenesis induced by tumor necrosis factor-alpha (TNF-alpha) appeared to be modulated through such angiogenic factors as interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) in microvascular endothelial cells. We have extended these studies, and investigated whether TNF-alpha is localized in macrophages/microglia in the mouse model of retinal neovascularization, and whether TNF-alpha can induce angiogenic factors in retinal glial cells.. C57BL/6 J pups were placed in a 75% oxygen environment on postnatal day 7 (P7) for 5 days and then returned to room air. The co-localization of TNF-alpha with macrophages/microglia in the ischemic retina was examined by fluorescent immunohistochemistry. Bovine retinal glial cells were isolated for Northern blot analysis to quantify the expression levels of monocyte chemotactic protein-1 (MCP-1), IL-8, bFGF, and VEGF.. Double staining of retinas revealed that the TNF-alpha expression level was enhanced in macrophages/microglia 4 days after the hypoxia. Cellular mRNA levels of MCP-1, IL-8, and bFGF, but not VEGF, were increased after treating retinal glial cells with TNF-alpha (100 U/ml).. The results indicate that TNF-alpha is produced by activated macrophages/microglia and may participate in retinal neovascularization during post-ischemic inflammation through the induction of potent angiogenic factors in an autocrine or paracrine manner.

Topics: Animals; Blotting, Northern; Chemokine CCL2; Fibroblast Growth Factor 2; Fluorescent Antibody Technique, Indirect; Interleukin-8; Macrophage Activation; Mice; Mice, Inbred C57BL; Microglia; Polymerase Chain Reaction; Reperfusion Injury; Retina; Retinal Neovascularization; RNA, Messenger; Tumor Necrosis Factor-alpha

It has been suggested that inflammatory mediators such as cytokines released during intestinal ischemia and reperfusion increase permeability in the lungs. Cytokines exist at concentrations several hundred times higher at the site of inflammation than in the blood. When absorbed, the locally produced cytokines may affect multiple remote organs. We thus investigated whether the isolation of the intestine in a bag during ischemia and reperfusion can reduce subsequent lung injury.. Rats were divided into three groups: group 1, simple laparotomy (sham); group 2, intestinal ischemia and reperfusion (I/R); and group 3, intestinal ischemia and reperfusion with an intestinal bag (IB). Lung permeability was assessed using the Evans Blue leakage method. Cytokines (interleukin-1beta, tumor necrosis factor alpha, interleukin-8) in the plasma and ascites were measured by enzyme-linked immunosorbent assay.. The increase in lung permeability of I/R significantly decreased in IB (1.73 +/- 0.48 vs 1.05 +/- 0.22, P < 0.01). The plasma cytokine concentrations were also lower in IB than in I/R. In addition, the cytokine levels in the intestinal bag fluid were extremely high.. The isolation of the intestine during ischemia and reperfusion was found to reduce the degree of subsequent lung injury, possibly due to the reduced absorption of locally produced cytokines via the parietal peritoneum.

Topics: Analysis of Variance; Animals; Biomarkers; Capillary Permeability; Cytokines; Disease Models, Animal; Interleukin-1; Interleukin-8; Intestines; Ischemia; Lung Diseases; Male; Probability; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Sensitivity and Specificity; Tumor Necrosis Factor-alpha

Previous studies have suggested reductions in lung reperfusion injury when initial reperfusion is undertaken with the addition of pharmacological modulators. We investigated three pharmacological agents in a porcine model of left single lung transplantation to determine the effect on lung compliance and its relationship with the expression of the cytokine, interleukin-8 (IL-8).. Donor lungs were preserved with modified Euro-Collins for a mean ischaemic time of 18.6 h. Pulmonary venous oxygenation, lung compliance and IL-8 expression were assessed over a 12-h period. Group A (n=5) was a control group with no interventions added, Group B was reperfused with the addition of intravenous inositol hexakisphosphate (InSP6) (0.02 mg/kg per min), Group C received the nitric oxide donor, 3-morpholinosydnonimine (SIN-1) (0.02 mg/kg per min) and Group D received intravenous Pentoxifylline (2 mg/kg per h). All interventions were administered at a pulmonary artery pressure of 20 mmHg.. Group D yielded the best oxygenation (P=0.0041) while Groups B and C were similar. All were superior to Group A (P<0.001). Lung compliance was significantly improved in Groups B, C and D compared to group A. In Group D, the greatest improvements in lung compliance were observed (P<0.0001). Similar observations were seen with regard to pulmonary vascular resistance. IL-8 expression was delayed until after 30 min of reperfusion in Group D, but was evident after 10 min in all the other groups. This correlates with the compliance and oxygenation data.. The addition of InSP6 or SIN-1 at reperfusion significantly attenuates reperfusion injury compared with controls and improves lung compliance. The unique comparison with Pentoxifylline afforded by this study indicates that at the doses studied Pentoxifylline appears to be superior, correlating with a greater inhibition of IL-8 expression.

Topics: Animals; Area Under Curve; Chromosomal Proteins, Non-Histone; DNA-Binding Proteins; Female; Interleukin-8; Lung; Lung Compliance; Lung Transplantation; Nitric Oxide Donors; Pentoxifylline; Phytic Acid; Polymerase Chain Reaction; Pulmonary Artery; Regional Blood Flow; Reperfusion Injury; RNA, Messenger; Saccharomyces cerevisiae Proteins; Swine; Vascular Resistance; Vasodilator Agents

Nuclear factor-kappaB (NF-kappaB) and interleukin (IL)-8 play important roles in the pathophysiology of acute lung injury after lung transplantation. Because alveolar epithelium is one of the most important sites at which IL-8 production takes place after reperfusion of donor lungs, we examined the effects of cold/rewarming on NF-kappaB and IL-8 expression in alveolar epithelial cells.. A549 cells were preserved at 4 degrees C for 5 hr and then rewarmed for up to 20 hr. NF-kappaB was analyzed by electrophoretic mobility shift assay. IL-8 mRNA expression was examined by reverse transcription-polymerase chain reaction. IL-8 concentration in the cell culture medium after rewarming was measured by enzyme-linked immunosorbent assay.. NF-kappaB was increased in the nuclear extracts as early as 30 min after rewarming. There was a marked increase in the IL-8 mRNA expression at 1 and 3 hr after rewarming. IL-8 concentration in the cell culture medium was progressively increased during 20 hr following rewarming. The cell culture medium inhibited apoptosis of neutrophils significantly. The cold/rewarming-induced IL-8 production was reduced to approximately 50% by introducing an antisense oligonucleotide for the p65 subunit of NF-kappaB and by treatment with N-acetyl-leucinyl-leucinyl-norleucinal and pyrrolidine dithiocarbamate. The effect of dexamethasone treatment was dose dependent (reduced to approximately 30% at 10-5 M dexamethasone).. Our results indicate that rewarming of cold-preserved alveolar epithelial cells itself may be an important initiator of the inflammatory cascades, including NF-kappaB activation and IL-8 release. Inhibition of NF-kappaB would be worth trying to control unnecessary IL-8 production and the inflammatory response in the donor lungs.

Topics: Apoptosis; Cell Line; Cold Temperature; Gene Expression; Humans; Interleukin-8; Lung Transplantation; Neutrophils; NF-kappa B; Pulmonary Alveoli; Reperfusion Injury; Respiratory Mucosa; Rewarming; RNA, Messenger; Tissue Preservation

To investigate the protective role of ischemic preconditioning (IPC) during lung ischemia-reperfusion (I/R) injury and its influence on inflammatory cytokine production.. In vivo I/R injury of rabbit was induced by blocking hilum of the left lung. The wet/dry ratio of the lung, lung permeability index and neutrophils percentage in bronchoalveolar lavage fluid (BALF) were detected as indexes of the lung injury. Serum levels of tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6) and interleukin-8 (IL-8) were also detected using enzyme-linked immunosorbent assay. The protective role of IPC and its influence on inflammatory cytokine production were observed.. The wet/dry ratio of the lung, lung permeability index and neutrophils percentage in BALF of I/R group were 9.73 +/- 1.14, (41.62 +/- 5.77) x 10(-4) and (58.1 +/- 10.0)% respectively. The IPC group indexes were 6.23 +/- 0.69, (20.31 +/- 4.03) x 10(-4) and (23.8 +/- 5.2)% respectively. There was a significant difference between the two groups (P < 0.01). Serum levels of TNFalpha, IL-6 and IL-8 of I/R group were (0.9078 +/- 0.1062), (0.2137 +/- 0.0598) and (0.7211 +/- 0.0979) ng/ml respectively. The IPC group indexes were (0.7478 +/- 0.0843), (0.1271 +/- 0.0089) and (0.5903 +/- 0.0746) ng/ml respectively, significantly lower than that of I/R group (P < 0.01).. Lung IPC has a marked protection effect against I/R injury. The effect was related to its inhibition of inflammatory cytokines such as TNFalpha, IL-6 and IL-8, thus reducing activation and infiltration of neutrophils.

Topics: Animals; Cytokines; Disease Models, Animal; Interleukin-6; Interleukin-8; Ischemic Preconditioning; Lung; Rabbits; Random Allocation; Reperfusion Injury; Tumor Necrosis Factor-alpha

To evaluate chemokine expression at various retinal sites after ischemia-reperfusion injury, using reverse transcription-polymerase chain reaction (RT-PCR) analysis of selected tissue obtained by laser capture microdissection.. Retinal ischemia was produced in Lewis rats by increasing intraocular pressure for 75 minutes. At 3, 6, 12, and 24 hours after reperfusion, RT-PCR was used to measure the levels of monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, interleukin (IL)-8, and interferon-gamma-inducible 10-kDa protein (IP-10) mRNA expression in the ganglion cell layer (GCL), inner nuclear layer (INL), outer nuclear layer (ONL), and retinal vessels, after laser capture microdissection of these retinal layers. These chemokines were further localized by immunohistochemical methods, using antibodies specific to MCP-1 and MIP-1alpha. Leukocyte infiltration into the retina was detected with immunostaining for leukocyte common antigen.. Ischemia-reperfusion induced expression of MCP-1, MIP-1alpha, and MIP-1beta mRNA in the retinal vessels 3 hours after reperfusion. Six hours after reperfusion, expression of these chemokines and IL-8 mRNA was seen in the GCL and INL. Twelve hours after reperfusion, IP-10 mRNA expression was seen in the GCL and INL. Immunoreactive MCP-1 and MIP-1alpha were detected in the GCL, INL, and the retinal vessels 24 hours after reperfusion. No chemokine mRNA expression or immunoreactivity was detected in the ONL at any time. Leukocyte infiltration was noted at 12 hours, increasing markedly 24 hours after reperfusion.. Ischemia-reperfusion retinal injury results in generation of highly chemotactic agents, initially in the retinal vasculature, then in the other inner retinal layers. Such differential chemokine expression may play a role in leukocyte recruitment and selective leukocyte infiltration in the inner retina, leading to retinal damage primarily localized to the ganglion cells and other inner neuronal structures.

Topics: Animals; Chemokine CCL2; Chemokine CCL3; Chemokine CCL4; Chemokine CXCL10; Chemokines; Chemokines, CXC; Endothelium, Vascular; Female; Immunoenzyme Techniques; Interleukin-8; Macrophage Inflammatory Proteins; Rats; Rats, Inbred Lew; Reperfusion Injury; Retinal Degeneration; Retinal Ganglion Cells; Retinal Vessels; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation

To observe the changes of tumor necrosis factor alpha (TNF alpha), interleukin 8 (IL-8) in liver ischemia/reperfusion injury and the protective effect of hydrophilic Salvia monomer MP-1 on them.. Hypothermic hypoxia reoxygenation model of human liver sinusoidal endothelial cell line and ischemia/reperfusion model of isolated rat liver were used. TNF alpha and IL-8 were measured with ELISA kits. Cell injury was excluded by trypan blue stain, sinusoidal endothelial cell function was assessed by hyaluronic acid uptake rate through RIA. Liver function was assayed by alanine transaminase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) release as well as output of bile flow.. During hypoxia reoxygenation, sinusoidal endothelial cell injury, TNF alpha and IL-8 increased significantly in time-dependent manner, while sinusoidal cell function decreased. Cell injury was positively correlated to the released amount of TNF alpha (r = 0.949, P < 0.05) and IL-8 (r = 0.892, P < 0.05), respectively, the mortality could be reduced within 6 hrs by adding anti-TNF alpha monoclonal antibody and increased by treating with recombinant human TNF alpha. Function of isolated rat liver lowered alone the increasing of low temperature ischemia/reperfusion time. MP-1 could markedly lower the mortality of endothelial cells and TNF alpha and IL-8 release, it also could alleviate ischemia/reperfusion injury to isolated rat liver.. TNF alpha participated in liver ischemia/reperfusion injury directly, and MP-1 might alleviate the injury through inhibiting TNF alpha and IL-8.

Topics: Animals; Cell Hypoxia; Cells, Cultured; Drugs, Chinese Herbal; Endothelium; In Vitro Techniques; Interleukin-8; Liver; Male; Phytotherapy; Protective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Salvia miltiorrhiza; Tumor Necrosis Factor-alpha

Cytokines have been shown to play an important role in promoting inflammation in the setting of ischemia-reperfusion injury. However, their role in human lung transplantation has not been systematically explored. This study was undertaken to examine the kinetics of cytokine release in 18 consecutive human lung transplantation procedures and to examine the relationships between their levels and donor factors, length of ischemic time, and allograft function. TNF-alpha, IFN-gamma, IL-10, IL-12, and IL-18 were found at higher levels during the ischemic time, whereas IL-8 predominantly increased after reperfusion. IL-8 levels after 2 h of reperfusion correlated with lung function assessed by the Pa(O2 )/FI(O(2)) ratio, the mean airway pressure, and the APACHE score during the first 24 postoperative hours. The length of ICU stay also correlated with IL-8 levels after 2 h of reperfusion. Longer ischemic time was associated with significantly higher levels of IL-18 before reperfusion, and older donors had significantly lower levels of IL-10 after reperfusion. We have demonstrated the importance of IL-8 in predicting early graft function after human lung transplantation. In addition, we showed that donor age and ischemic time may influence release of specific cytokines during ischemia-reperfusion.

Topics: Adult; Age Factors; Aged; APACHE; Female; Graft Survival; Humans; Interferon-gamma; Interleukin-10; Interleukin-12; Interleukin-18; Interleukin-8; Ischemia; Length of Stay; Lung; Lung Transplantation; Male; Middle Aged; Predictive Value of Tests; Reperfusion Injury; Respiratory Function Tests; Time Factors; Tissue Donors; Tumor Necrosis Factor-alpha

Increased intra-abdominal pressure has been shown to result in a myriad of physiologic aberrations that result in the abdominal compartment syndrome (ACS). The clinically relevant combination of hemorrhagic shock and resuscitation and subsequent ACS, however, has not been studied in detail. We hypothesized that sequential hemorrhagic shock (HS) and ACS would result in greater cytokine activation and polymorphonuclear neutrophil (PMN)-mediated lung injury than with either insult alone.. Twenty Yorkshire swine (20-30 kg) were studied. Group 1 (n = 5) was hemorrhaged to a mean arterial pressure of 25 to 30 mm Hg for 60 minutes and resuscitated to baseline mean arterial pressure. Intra-abdominal pressure was then increased to 30 mm Hg above baseline and maintained for 60 minutes. Group 2 (n = 5) was subjected to HS alone and Group 3 (n = 5) to ACS alone. Group 4 (n = 5) had sham experiment without HS or ACS. Central and portal venous interleukin-1beta, interleukin-8, and tumor necrosis factor-alpha levels were serially measured. Bronchoalveolar lavage (BAL) for protein and PMNs was performed at baseline and 24 hours after resuscitation. Lung myeloperoxidase was evaluated at 24 hours after resuscitation.. Portal and central vein cytokine levels were equivalent but were significantly higher in Group 1 than in other groups. BAL PMNs were higher (p < 0.05) in Group 1 (4.1 +/- 2.0 x 106) than in the other groups (0.6 +/- 0.5, 1.4 +/- 1.3, and 0.1 +/- 0.0 x 106, respectively) and lung myeloperoxidase activity was higher (p < 0.05) in Group 1 (134.6 +/- 57.6 x 106/g) than in the other groups (40.3 +/- 14.7, 46.1 +/- 22.4, and 7.73 +/- 4.4 x 106/g, respectively). BAL protein was higher (p < 0.01) in Group 1 (0.92 +/- 0.32 mg/mL) compared with the other groups (0.22 +/- 0.08, 0.29 +/- 0.11, and 0.08 +/- 0.06 mg/mL, respectively).. In this clinically relevant model, sequential insults of ischemia-reperfusion (HS and resuscitation) and ACS were associated with significantly increased portal and central venous cytokine levels and more severe lung injury than HS or ACS alone.

Topics: Abdominal Injuries; Animals; Compartment Syndromes; Cytokines; Gastric Mucosa; Hydrogen-Ion Concentration; Interleukin-1; Interleukin-8; Lung; Lung Injury; Models, Animal; Neutrophils; Reperfusion Injury; Shock, Hemorrhagic; Swine; Tumor Necrosis Factor-alpha

A previous study demonstrated that continuous enteric luminal perfusion of fetal bovine serum (FBS) protects the small intestine from total ischemia/reperfusion injury (IRI) and increases the intestinal mass. In this study, we further investigated the changes in plasma interleukin-8 (IL-8) level caused by total ischemia/reperfusion of the small intestine and the effect of FBS on plasma IL-8 levels. A 3-h total ischemia was induced in a 15-cm segment of terminal ileum and then reperfusion was instituted. Luminal perfusion of FBS was conducted via an osmotic minipump connected to the stomach through a fine polyethylene tube, starting 3 days prior to total ischemia. The rats were killed after 10 and 30 min and 1 and 3 h of total ischemia, and 1, 6, and 12 h or 1, 2, and 3 days after initiation of reperfusion. Plasma IL-8 was measured by enzyme-linked immunosorbent assay. The results were compared among the FBS-treated and untreated groups. The plasma IL-8 level was elevated from 1 h of total ischemia to 6 h after initiation of reperfusion ( P< 0.05) with a peak of 641.5 +/- 36.9 pg/ml in the untreated group and 471.6 +/- 42.2 pg/ml in the treated group. Luminal perfusion of FBS significantly suppressed plasma IL-8 levels after 1 h of total ischemia and 1 h after initiation of reperfusion ( P< 0.05). The results suggest that FBS might play a role in the treatment of total IRI of the small intestine.

Topics: Animals; Enzyme-Linked Immunosorbent Assay; Interleukin-8; Intestine, Small; Ischemia; Male; Rats; Rats, Inbred Lew; Reperfusion Injury; Serum Albumin, Bovine

The interrelation of adhesion between leukocyte and endothelium was studied by several irritation factors.. Leukocyte adhesion was observed by impulse electricity irritation, ischemia/reperfusion, endotoxin and IL-8 in venular of rat mesentery.. The results showed these irritation factors resulted in a significant increase in the number of leukocytes adhesion along the venular endothelium of rat mesentery. IL-8 leaded to the most increase of leukocytes adhesion. Especially treated by IL-8 for 30 minutes. The number of leukocytes adhesion of the others was approximately identical.. The study suggests that impulse electricity irritation, ischemia/reperfusion, endotoxin and IL-8 are able to induce leukocytes and endothelium adhesion, and IL-8 of them has the most effect.

Topics: Animals; Cell Adhesion; Electric Stimulation; Endotoxins; Interleukin-8; Ischemia; Leukocytes; Microvessels; Rats; Rats, Wistar; Reperfusion Injury

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor whose activation has been linked to several physiologic pathways including those related to the regulation of intestinal inflammation. We sought to determine whether PPAR gamma could function as an endogenous anti-inflammatory pathway in a murine model of intestinal ischemia-reperfusion (I/R) injury.. PPAR gamma-deficient and wild-type mice were examined for their response to I/R procedure. Treatment with a PPAR gamma-specific ligand was also performed.. In a murine model of intestinal I/R injury, we observed more severe injury in PPAR gamma-deficient mice and protection against local and remote tissue injury in mice treated with a PPAR gamma-activating ligand, BRL-49653. Activation of PPAR gamma resulted in down-regulation of intercellular adhesion molecule 1 expression by intestinal endothelium and tissue tumor necrosis factor alpha messenger RNA levels most likely by inhibition of the NF-kappa B pathway.. These data strongly suggest that an endogenous PPAR gamma pathway exists in tissues that may be amenable to therapeutic manipulation in I/R-related injuries.

Topics: Animals; Cells, Cultured; Colitis; Epithelial Cells; Gastric Mucosa; Gene Expression; Hypoglycemic Agents; In Vitro Techniques; Intercellular Adhesion Molecule-1; Interleukin-8; Intestinal Mucosa; L-Lactate Dehydrogenase; Liver; Mice; Mice, Inbred BALB C; Mice, Knockout; NF-kappa B; Peroxidase; Pneumonia; Receptors, Cytoplasmic and Nuclear; Reperfusion Injury; RNA, Messenger; Rosiglitazone; Stomach; Thiazoles; Thiazolidinediones; Transcription Factors; Tumor Necrosis Factor-alpha

Cerebral ischemia-reperfusion injury is associated with a developing inflammatory response with pathologic contributions from vascular leukocytes and endogenous microglia. Signaling chemokines orchestrate the communication between the different inflammatory cell types and the damaged tissue leading to cellular chemotaxis and lesion occupation. Several therapies aimed at preventing this inflammatory response have demonstrated neuroprotective efficacy in experimental models of stroke, but to date, few investigators have used the chemokines as potential therapeutic targets. In the current study, the authors investigate the neuroprotective action of NR58-3.14.3, a novel broad-spectrum inhibitor of chemokine function (both CXC and CC types), in a rat model of cerebral ischemia-reperfusion injury. Rats were subjected to 90 minutes of focal ischemia by the filament method followed by 72 hours of reperfusion. Both the lesion volume, measured by serial magnetic resonance imaging, and the neurologic function were assessed daily. Intravenous NR58-3.14.3 was administered, 2 mg/kg bolus followed by 0.5 mg/kg hour constant infusion for the entire 72-hour period. At 72 hours, the cerebral leukocytic infiltrate, tumor necrosis factor-alpha (TNF-alpha), and interleukin-8 (IL-8)-like cytokines were analyzed by quantitative immunofluorescence. NR58-3.14.3 significantly reduced the lesion volume by up to 50% at 24, 48, and 72 hours post-middle cerebral artery occlusion, which was associated with a marked functional improvement to 48 hours. In NR58-3.14.3-treated rats, the number of infiltrating granulocytes and macrophages within perilesional regions were reduced, but there were no detectable differences in inflammatory cell numbers within core ischemic areas. The authors reported increased expression of the cytokines, TNF-alpha, and IL-8-like cytokines within the ischemic lesion, but no differences between the NR58-3.14.3-treated rats and controls were reported. Although chemokines can have pro- or antiinflammatory action, these data suggest the overall effect of chemokine up-regulation and expression in ischemia-reperfusion injury is detrimental to outcome.

Topics: Animals; Brain; Cerebral Arteries; Chemokines; Constriction; Fluorescent Antibody Technique; Granulocytes; Interleukin-8; Ischemic Attack, Transient; Leukocytes; Lipopolysaccharide Receptors; Macrophages; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

Hepatic ischemia/reperfusion (I/R) results in tumor necrosis factor (TNF) release. Kupffer cells (KC) are one source of this TNF. This study investigates the effects of hepatic I/R combined with lipopolysaccharide (LPS) on the lung and liver injury that follow hepatic I/R and on hepatic release of TNF, epithelial neutrophil activating protein (ENA-78), and macrophage inflammatory protein-2 (MIP-2). The effects of these experimental conditions on TNF production by primary rat KC in vitro were also investigated. Rats were subjected to hepatic I/R alone, hepatic I/R + LPS, sham laparotomy alone, or sham laparotomy + LPS and pulmonary MPO, pulmonary microvascular permeability, hepatic neutrophil influx, hepatic injury, and hepatic TNF, ENA-78, and MIP-2 production were measured. These experiments demonstrated that hepatic I/R in conjunction with LPS results in a more severe lung and liver injury and increased hepatic TNF, ENA-78, and MIP-2 release. The effects of these experimental conditions on rat KC TNF production demonstrated that hepatic I/R + LPS results in a more significant release of TNF as compared to LPS alone or I/R alone. Hepatic I/R plus LPS results in a more severe lung and liver injury and is likely secondary to a more significant and prolonged release of TNF by KC. This may provide a mechanism for development of multiple organ system failure in some patients undergoing hepatic resection, hepatic transplantation, complex vascular operations, or in the setting of hypovolemic shock. Portal endotoxemia related to mesenteric venous congestion or other systemic insults may have a significant impact on post-operative complications and recovery in the setting of a local or global hepatic I/R injury.

Topics: Animals; Cells, Cultured; Chemokine CXCL2; Chemokine CXCL5; Chemokines; Chemokines, CXC; Interleukin-8; Ischemia; Kupffer Cells; Lipopolysaccharides; Liver; Lung; Lung Injury; Male; Neutrophils; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

The objectives of this study were to analyze changes in serum interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) levels in patients that restored spontaneous circulation after cardiopulmonary arrest (CPA), and to clarify the cause and significance of elevated serum cytokines after resuscitation. Twenty-eight patients who were admitted to our hospital after out of hospital CPA were studied. Patients' IL-8 levels and TNF-alpha levels in serum increased to a peak within 12 h and within 6 h after the return of spontaneous circulation (ROSC), respectively. Serum IL-8 levels in patients who died or became brain dead within 1 week after ROSC were significantly higher than those in other patients. In stepwise multiple regression analysis, maximum IL-8 values were significantly correlated with maximum TNF-alpha values within post-ROSC 24 h, with the total dose of administered epinephrine and with peripheral neutrophil counts. It is especially noteworthy that the total dose of epinephrine administered during and after resuscitation markedly influenced the elevation of serum IL-8 after ROSC. The increases in serum IL-8 induced by excessive administration of epinephrine might be harmful in the ROSC-patients resuscitated after CPA.

Topics: Cardiopulmonary Resuscitation; Epinephrine; Female; Heart Arrest; Humans; Interleukin-8; Male; Middle Aged; Regression Analysis; Reperfusion Injury; Time Factors; Tumor Necrosis Factor-alpha

A neutralizing anti-interleukin-(IL-)8 monoclonal antibody was humanized by grafting the complementary determining regions onto the human IgG framework. Subsequent alanine scanning mutagenesis and phage display enabled the production of an affinity matured antibody with a >100-fold improvement in IL-8 binding. Antibody fragments can be efficiently produced in Escherichia coli but have the limitation of rapid clearance rates in vivo. The Fab' fragment of the antibody was therefore modified with polyethylene glycol (PEG) in order to obtain a more desirable pharmacokinetic profile. PEG (5-40 kDa) was site-specifically conjugated to the Fab' via the single free cysteine residue in the hinge region. In vitro binding and bioassays showed little or no loss of activity. The pharmacokinetic profiles of the 20 kDa, 30 kDa, 40 kDa, and 40 kDa branched PEG-Fab' molecules were evaluated in rabbits. Relative to the native Fab', the clearance rates of the PEGylated molecules were decreased by 44-175-fold. In a rabbit ear model of ischemia/reperfusion injury, all PEGylated Fab' molecules were as efficacious in reducing oedema as the original monoclonal antibody. These studies demonstrate that it is possible to customize the pharmacokinetic properties of a Fab' while retaining its antigen binding activity.

Topics: Alanine; Animals; Antibodies, Monoclonal; Antigen-Antibody Reactions; DNA, Complementary; Edema; Electrophoresis, Polyacrylamide Gel; Humans; Immunoglobulin G; Inhibitory Concentration 50; Interleukin-8; Kinetics; Mice; Mutagenesis; Peptide Library; Polyethylene Glycols; Protein Binding; Rabbits; Recombinant Fusion Proteins; Reperfusion Injury; Time Factors; Trypsin

Hepatic ischemia/reperfusion (I/R) results in a neutrophil-dependent lung and liver injury. The process of neutrophil recruitment and activation in this injury is at least partially dependent on the presence of the ELR+ CXC chemokines. Other investigations have shown that ELR- CXC chemokines can block ELR+ CXC chemokine neutrophil recruitment and activation in vitro. To begin to investigate the role of the balance between these 2 types of molecules in vivo in neutrophil recruitment and activation following hepatic I/R, we used our rat model of lobar hepatic I/R and pretreated animals with pharmacologic doses of gamma-interferon (gamma-IFN). gamma-IFN is known to upregulate some of the ELR- CXC chemokines, including gamma-IFN-inducible protein (IP-10) and monokine-induced by gamma-IFN (MIG), as well as down-regulate ELR+ CXC chemokine production. Following hepatic I/R or sham laparotomy, hepatic and pulmonary levels of the ELR- chemokines, IP-10 and MIG, and the ELR+ chemokines, rat cytokine-induced neutrophil chemoattractant (KC), macrophage inflammatory protein-2 (MIP-2), and epithelial neutrophil activating protein (ENA-78) were determined by ELISA, and lung and liver injury were assessed. In response to gamma-IFN, hepatic and pulmonary levels of the ELR- chemokines were increased and the levels of the ELR+ chemokines were decreased. Immunohistochemical staining confirmed the hepatocyte as the source of these molecules, as well as the changes in chemokine levels in response to gamma-IFN. There was an associated significant decrease in liver and lung injury, although there was no significant decrease in neutrophil influx in either tissue. This suggests that the alteration in the balance of ELR+ to ELR- CXC chemokines results in a decrease in tissue injury through a mechanism other than through an alteration in tissue neutrophil levels.

Topics: Amino Acid Sequence; Animals; Chemokine CXCL10; Chemokine CXCL5; Chemokines, CXC; Interleukin-8; Ischemia; Liver; Liver Circulation; Lung; Male; Neutrophils; Rats; Rats, Sprague-Dawley; Reperfusion Injury

The objectives of this study were to 1) determine the time-course of T-lymphocyte adhesion to monolayers of human umbilical vein endothelial cell (HUVEC) that were exposed to 60 min of anoxia followed by 24 h of reoxygenation, and 2) define the mechanisms responsible for the hyperadhesivity of postanoxic HUVEC to human T-lymphocytes.. Human peripheral blood mononuclear leukocytes were isolated from heparinized peripheral blood. T-lymphocytes were obtained by negative selection using a MACS column. HUVEC monolayers were exposed to anoxia/reoxygenation (A/R), and then reacted with 51Cr -labeled T-lymphocytes in adhesion assays.. A/R leads to an increased adhesion of T-lymphocytes to HUVEC monolayers, with peak responses occurring at 8 h after reoxygenation. This adhesion response was largely attributed to the CD4+ T-cell subset. The hyperadhesivity of A/R-exposed HUVEC was inhibited by monoclonal antibodies directed against either LFA-1, VLA-4, ICAM-1, or VCAM-1, indicating a contribution of these adhesion molecules and their ligands. Moreover, T-cell hyperadhesivity was attenuated by anti- IL-8. consistent with a role for this chemokine in the adhesion response. Protein synthesis inhibitors (actinomycin D and cycloheximide) as well as chemical inhibitors of (and binding ds-oligonucleotides to) NFkappaB and AP-1 significantly attenuated the A/R-induced T-lymphocyte adhesion responses. The kinetics of VCAM-1 on post-anoxic HUVEC correlated with the T-lymphocyte adhesion response.. A/R elicits a T-lymphocyte-endothelial cell adhesion response that involves transcription-dependent surface expression of VCAM-1.

Topics: Antibodies, Monoclonal; Benzamides; Cell Adhesion; Cell Adhesion Molecules; Cell Hypoxia; Cells, Cultured; Cysteine Endopeptidases; Endothelium, Vascular; Humans; Interleukin-8; Ischemia; Kinetics; Leupeptins; Multienzyme Complexes; NF-kappa B; Oxygen; Proteasome Endopeptidase Complex; Protein Synthesis Inhibitors; Reperfusion Injury; T-Lymphocyte Subsets; Thionucleotides; Time Factors; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; Umbilical Veins; Vascular Cell Adhesion Molecule-1

We examined whether activated protein C (APC) reduces ischemia/reperfusion (I/R)-induced renal injury by inhibiting leukocyte activation. In a rat model, intravenous administration of APC markedly reduced I/R-induced renal dysfunction and histological changes, whereas intravenous administration of dansyl glutamylglycylarginyl chloromethyl ketone-treated factor Xa (DEGR-FXa; active-site-blocked factor Xa), heparin or diisopropyl fluorophosphate-treated APC (DIP-APC; inactive derivative of ARC) had no effect. Furthermore, APC significantly inhibited the I/R-induced decrease in renal tissue blood flow and the increase in the vascular permeability, whereas neither DEGR-FXa, heparin, nor DIP-APC produced such effects. Renal I/R-induced increases in plasma levels of fibrin degradation products were significantly inhibited by APC, DEGR-FXa, and heparin. These observations suggest that APC reduces I/R-induced renal injury independently of its anticoagulant effects but in a manner dependent on its serine protease activity. Renal levels of tumor necrosis factor-alpha (TNF-alpha), rat interleukin-8, and myeloperoxidase were significantly increased after renal I/R. These increases were significantly inhibited by APC but not by DEGR-FXa, heparin, or DIP-APC. Leukocytopenia produced effects similar to those of APC. These findings strongly suggest that APC protects against I/R-induced renal injury not by inhibiting coagulation abnormalities but by inhibiting activation of leukocytes that play an important role in I/R-induced renal injury. Inhibition of leukocyte activation by APC could be explained by the inhibitory activity of TNF-alpha. (Blood. 2000;95:3781-3787)

Topics: Amino Acid Chloromethyl Ketones; Animals; Antithrombins; Cytokines; Factor Xa; Heparin; Humans; Interleukin-8; Isoflurophate; Kidney; Male; Peroxidase; Protein C; Rats; Rats, Wistar; Regional Blood Flow; Reperfusion Injury; Tumor Necrosis Factor-alpha

FR167653 is a potent suppressant of interleukin-1 and tumor necrosis factor production. We previously reported that FR167653 inhibited the expression of interleukin-1 messenger RNA (mRNA) after ischemia-reperfusion and provided a protective effect against ischemia-reperfusion injury after extended liver resection. In this study we investigated the optimal end point of FR167653 administration and the inhibition of interleukin-8 (IL-8) mRNA expression caused by the administration of FR167653 during extended liver resection with ischemia in a dog model.. The right portal pedicle was clamped for 60 minutes but the left portal vein was left patent to avoid portal congestion. After reperfusion 75% of the liver was resected. EXPERIMENT I: Adult mongrel dogs were divided into three groups: the control group (n = 9); the FR-2 group (n = 6), which received FR167653 through the portal vein starting 30 minutes before the onset of ischemia until 2 hours after reperfusion; and the FR-6 group (n = 6), which received FR167653 starting 30 minutes before ischemia until 6 hours after reperfusion. Hepatic venous blood was collected to measure liver enzymes. Liver specimens were harvested for histologic study 6 hours after reperfusion and polymorphonuclear neutrophils were counted. EXPERIMENT II: The expression of IL-8 was measured by reverse-transcriptase polymerase chain reaction.. Aspartate aminotransferase and alanine aminotransferase levels after reperfusion and hyaluronic acid levels 6 hours after reperfusion were significantly (p < 0.05) lower in the FR-2 and FR-6 groups than in the control group. There were no significant differences between the FR-2 and FR-6 groups after reperfusion. Histologically liver tissue damage was mild in the FR-2 and FR-6 groups, and polymorphonuclear neutrophil infiltration was significantly lower in the FR-2 and FR-6 groups than in the control group. The 3-day survival rate was statistically (p < 0.05) better in the FR-2 and FR-6 groups than in the control group. IL-8 mRNA expression was inhibited in the FR-treated group.. FR167653 should be administered until shortly after reperfusion and need not be administered for many hours after reperfusion. FR167653 inhibits IL-8 mRNA production and inhibits polymorphonuclear neutrophil infiltration.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Dogs; Growth Inhibitors; Interleukin-8; Pyrazoles; Pyridines; Reperfusion Injury; RNA, Messenger

Topics: Biomarkers; Carrier Proteins; Cell Survival; Cytokines; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Fatty Acids; Humans; Immunoenzyme Techniques; Interleukin-6; Interleukin-8; Interleukins; Intestinal Mucosa; Intestines; Myelin P2 Protein; Neoplasm Proteins; Reperfusion Injury; Sensitivity and Specificity; Transplantation, Isogeneic; Tumor Necrosis Factor-alpha; Tumor Suppressor Proteins

Ischemic cerebral injury follows a well-attested sequence of events, including 3 phases: depolarization, biochemical cascade, and reperfusion injury. Leukocyte infiltration and cytokine-mediated inflammatory reaction are known to play a pivotal role in the reperfusion phase. These events exacerbate the brain injury by impairing the normal microvascular perfusion and through the release of cytotoxic enzymes. The aim of the present study was to determine whether a leukocyte-depleting filter (LeukoGuard LG6, Pall Biomedical, Portsmouth, United Kingdom) could improve the cerebral outcome after hypothermic circulatory arrest.. Twenty pigs (23-30 kg) were randomly assigned to undergo cardiopulmonary bypass with or without a leukocyte-depleting filter before and after a 75-minute period of hypothermic circulatory arrest at 20 degrees C. Electroencephalographic recovery, S-100beta protein levels, and cytokine levels (interleukin 1beta, interleukin 8, and tumor necrosis factor alpha) were recorded up to the first postoperative day. Postoperatively, all animals were evaluated daily until death or until electively being put to death on day 7 by using a quantitative behavioral score. A postmortem histologic analysis of the brain was carried out on all animals.. The rate of mortality was 2 of 10 in the leukocyte-depletion group and 5 of 10 in control animals. The risk for early death in control animals was 2.5 (95% confidence interval, 0.63-10.0) times higher than that of the leukocyte-depleted animals. The median behavioral score at day 7 was higher in the leukocyte-depletion group (8.5 vs 3.5; P =.04). The median of total histopathologic score was 8.5 in the leukocyte-depletion group and 15.5 in the control group (P =.005).. A leukocyte-depleting filter improves brain protection after a prolonged period of hypothermic circulatory arrest.

Topics: Animals; Brain Injuries; Calcium-Binding Proteins; Chronic Disease; Disease Models, Animal; Electroencephalography; Female; Heart Arrest, Induced; Hemofiltration; Hypothermia, Induced; Inflammation; Interleukin-1; Interleukin-8; Leukocyte Count; Leukocytes; Morbidity; Nerve Growth Factors; Random Allocation; Reperfusion Injury; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Severity of Illness Index; Swine; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Topics: Cell Line; Chemokine CXCL1; Chemokines, CXC; Chemotactic Factors; Endothelium; Growth Substances; Humans; Hypoxia; Intercellular Signaling Peptides and Proteins; Interleukin-8; Lipopolysaccharides; Reperfusion Injury; Tumor Necrosis Factor-alpha

To study the mechanisms responsible for ischemia-reperfusion lung injury, we developed an anesthetized rabbit model in which the effects of lung deflation, lung inflation, alveolar gas composition, hypothermia, and neutrophils on reperfusion pulmonary edema could be studied. Rabbits were anesthetized and ventilated, and the left pulmonary hilum was clamped for either 2 or 4 h. Next, the left lung was reperfused and ventilated with 100% oxygen. As indexes of lung injury, we measured arterial oxygenation, extravascular lung water, and the influx of a vascular protein (131I-labeled albumin) into the extravascular space of the lungs. The principal results were that 1) all rabbits with the deflation of the lung during ischemia for 4 h died of fulminant pulmonary edema within 1 h of reperfusion; 2) inflation of the ischemic lung with either 100% oxygen, air, or 100% nitrogen prevented the reperfusion lung injury; 3) hypothermia at 6-8 degreesC also prevented the reperfusion lung injury; 4) although circulating neutrophils declined during reperfusion lung injury, there was no increase in interleukin-8 levels in the plasma or the pulmonary edema fluid, and, furthermore, neutrophil depletion did not prevent the reperfusion injury; and 5) ultrastructural studies demonstrated injury to both the lung endothelium and the alveolar epithelium after reperfusion in deflated lungs, whereas the inflated lungs had no detectable injury. In summary, ischemia-reperfusion injury to the rabbit lung can be prevented by either hypothermia or lung inflation with either air, oxygen, or nitrogen.

Topics: Animals; Body Fluids; Cell Count; Hypothermia, Induced; Interleukin-8; Ischemia; Lung; Neutrophils; Osmolar Concentration; Oxygen; Pulmonary Alveoli; Pulmonary Circulation; Pulmonary Edema; Rabbits; Reperfusion Injury; Vinblastine

To investigate whether gabexate mesilate, a synthetic protease inhibitor with anticoagulant properties, prevents hepatic damage by inhibiting leukocyte activation, we examined its effect on ischemia/reperfusion injury of rat liver in which activated leukocytes play a critical role.. Prospective, randomized, controlled study.. Research laboratory at a university medical center.. Male Wistar rats weighing 220 to 280 g.. Hepatic damage was evaluated by changes in bile flow and serum transaminase concentrations after ischemia/ reperfusion. Rats received continuous intravenous infusions of gabexate mesilate (10 mg/kg/hr) or intravenous administration of an inactive derivative of activated factor X (Xa), a selective inhibitor of thrombin generation (3 mg/kg), immediately before the induction of ischemia in the median and left lobes of the liver. To determine whether gabexate mesilate inhibits leukocyte activation, we examined the effects of gabexate mesilate on hepatic concentrations of tumor necrosis factor-alpha and rat interleukin-8 and on hepatic myeloperoxidase activity after ischemia/reperfusion.. Hepatic dysfunction, observed after 60 mins of ischemia/reperfusion, showed a reduction in bile flow. The ischemia/reperfusion-induced decrease in bile flow was prevented by administration of gabexate mesilate. Serum transaminase concentrations increased after hepatic ischemia/reperfusion, peaking 12 hrs after reperfusion. Gabexate mesilate significantly inhibited the ischemia/reperfusion-induced increase in serum transaminase levels seen 12 hrs after reperfusion. Although an inactive derivative of factor Xa inhibited the increases in serum levels of fibrin and fibrinogen degradation products 6 hrs after reperfusion, it did not prevent ischemia/ reperfusion-induced liver injury. Hepatic levels of tumor necrosis factor-alpha, rat interleukin-8, and myeloperoxidase were significantly increased after ischemia/reperfusion. These increases were significantly inhibited by gabexate mesilate but unaffected by an inactive derivative of factor Xa.. Gabexate mesilate reduced ischemia/reperfusion-induced hepatic injury not by inhibiting coagulation, but by inhibiting leukocyte activation.

Topics: Analysis of Variance; Animals; Gabexate; Interleukin-8; Leukocytes; Liver; Liver Circulation; Liver Function Tests; Male; Neutrophils; Prospective Studies; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Serine Proteinase Inhibitors; Tumor Necrosis Factor-alpha

Topics: Animals; Gabexate; Humans; Interleukin-8; Liver Circulation; Neutrophils; Rats; Reperfusion Injury; Serine Proteinase Inhibitors; Tumor Necrosis Factor-alpha

Polymorphonuclear neutrophil elastase might contribute to postperfusion lung injury, so we evaluated the protective effect of ONO-5046*Na, a specific inhibitor of polymorphonuclear neutrophil elastase, against such an injury.. The study was done using 8 mongrel dogs that received ONO-5046*Na (15 mg/kg per hour) (group O) and 8 control dogs (group C), all of which had 1 hour of partial bypass and 5 hours of observation.. The respiratory index showed no significant changes in group O, but increased significant in group C (1.4+/-2.0 versus 5.1+/-4.7, p = 0.0047). Pulmonary extravascular water volume increased markedly in group C but only slightly in group O (group C 20.6+/-8.7, group O 11.2+/- 2.7 mL/kg; p = 0.0005). Blood concentrations of polymorphonuclear neutrophil elastase and interleukin-6 showed more than a tenfold increase in group C (PMN elastase, group C 12.9+/-12.8, group O 2.4+/-1.3 ng/mL; IL-b, group C 11.0+/-9.3, group O 2.9+/-3.8 pg/mL; p < 0.05) but were only slightly higher in group O. Histologic examination revealed interstitial and intraalveolar edema in group C, but group O was virtually normal.. ONO-5046*Na inhibits polymorphonuclear neutrophil elastase and maintains better pulmonary function, so it should reduce postperfusion lung injury.

Topics: Animals; Cardiopulmonary Bypass; Dogs; Extravascular Lung Water; Glycine; Hemodynamics; Interleukin-6; Interleukin-8; Leukocyte Count; Leukocyte Elastase; Lung; Oxygen; Protective Agents; Pulmonary Circulation; Reperfusion Injury; Serine Proteinase Inhibitors; Sulfonamides; Vascular Resistance

Topics: Animals; Antibodies, Monoclonal; Chemokines, CXC; Chemotactic Factors; Growth Substances; Intercellular Signaling Peptides and Proteins; Interleukin-8; Intestine, Small; Ischemia; Rats; Rats, Inbred Lew; Reperfusion Injury; Tumor Necrosis Factor-alpha

Increased levels of endothelin-1 (Et-1), a potent vasoconstrictor, have been correlated with hypertension and neuronal damage in ischemic/reperfusion injury. The presence of polymorphonuclear cells (PMNs) in the brain has been shown to be directly responsible for this observed pathology. To address the question of whether Et-1 plays a role in this process, human brain-derived endothelial cells (CNS-ECs) were cultured with Et-1. The results demonstrate that Et-1 induces production of the neutrophil chemoattractant interleukin-8 (IL-8) twofold to threefold after 72 hours; mRNA was maximal after 1 hour of stimulation. Conditioned culture medium derived from Et-1-stimulated CNS-ECs induced a chemotactic response in the PMN migration assay. The inflammatory cytokines tumor necrosis factor-alpha (TNF) and IL-1beta functioned additively with Et-1 in increasing IL-8 production. In contrast, transforming growth factor-beta (TGF-beta), but not IL-10, completely abolished the effect of Et-1 on IL-8 production. However, Et-1 did not modulate intercellular adhesion molecule-1 (ICAM-1) expression. These data demonstrate that Et-1 may be a risk factor in ischemic/reperfusion injury by inducing increased levels of the neutrophil chemoattractant IL-8.

Topics: Brain Ischemia; Cells, Cultured; Cerebral Arteries; Cerebral Veins; Chemotaxis, Leukocyte; Culture Media, Conditioned; Drug Synergism; Endothelin-1; Endothelium, Vascular; Gene Expression Regulation; Humans; Intercellular Adhesion Molecule-1; Interleukin-1; Interleukin-10; Interleukin-8; Protein Isoforms; Reperfusion Injury; Risk Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Chemokines are a family of cytokines regulating the migration and functions of leukocytes in a cell-type specific manner. A prototype of C-X-C chemokines, interleukin-8 (IL-8), chemoattracts and activates neutrophils in vitro, and IL-8 concentrations in body fluids are markedly increased in several neutrophil-mediated acute inflammation. Moreover, we previously reported that the administration of a neutralizing antibody to IL-8 prevented neutrophil-mediated tissue injury, as well as neutrophil infiltration, in several animal disease models. These observations implicate IL-8 as a major mediator of neutrophil-mediated tissue injury. Furthermore, we recently showed that an anti-IL-8 antibody effectively prevented two models that are very relevant to clinical situations; endotoxemia-induced acute respiratory distress syndrome (ARDS)-like lung injury and cerebral reperfusion injury. These results raise the possibility that IL-8 is a novel target for therapeutic intervention in neutrophil-mediated acute inflammation.

Topics: Animals; Antibodies, Monoclonal; Brain Ischemia; Chemokines; Endotoxemia; Female; Immunization, Passive; Inflammation; Interleukin-8; Macrophages; Mice; Neutrophils; Rabbits; Reactive Oxygen Species; Reperfusion Injury; Respiratory Distress Syndrome

Reperfusion after a transient ischemia is a frequently encountered clinical condition that often causes greater tissue damage than persistent ischemia itself. Reperfusion to rabbit brain, after a transient focal ischemia, induced neutrophil infiltration and aggregation--neither of which were observed in rabbit brain rendered ischemic alone for the same time interval--thereby leading to severe brain edema and infarct. Brain tissue levels of interleukin-8 (IL-8), a potent neutrophil chemotactic cytokine (chemokine), increased significantly at 6 hours after reperfusion, but without a noticeable elevation of plasma IL-8 levels. Moreover, we detected IL-8 protein immunohistologically in the vascular wall and, to a lesser degree, in infiltrated neutrophils, suggesting a local production of IL-8 in reperfused brain tissues. Furthermore, a neutralizing anti-IL-8 antibody significantly reduced brain edema and infarct size in comparison to rabbits receiving a control antibody. These results implicate locally produced IL-8 as a pivotal mediator of cerebral reperfusion and suggest that IL-8 is a novel target for the intervention of this injury.

Topics: Animals; Antibodies, Monoclonal; Blood-Brain Barrier; Brain Edema; Cerebral Infarction; Female; Interleukin-8; Mice; Neutrophils; Rabbits; Reperfusion Injury

This study investigates the protective mechanism of prostaglandin E1 (PGE1) against hepatic ischemia-reperfusion injury in vivo. It has been demonstrated that activated leukocytes contribute to ischemia-reperfusion injury, and that administration of the monoclonal antibody (mAb) for adhesion molecules reduces the injury by inhibiting leukocyte-endothelial cell adhesion. We therefore attempted to find out whether PGE1 has an effect on the inhibition of neutrophil adherence to endothelial cells after reperfusion.. We administered anti-intercellular adhesion molecule 1 (ICAM-1) mAb, antiserum against rat polymorphonuclear leukocytes, or PGE1 to a rat model of left lobar ischemia for 60 min followed by reperfusion. Leukocyte adherence was observed by intravital fluorescence microscopy. The effect of PGE1 on the expression of adhesion molecules was analyzed by immunohistochemistry and flow cytometry.. Ischemia-reperfusion caused endothelial dysfunction and hepatocellular injury with leukostasis in postsinusoidal venules. Anti-ICAM-1 mAb administration or leukopenia ameliorated both the hepatocellular injury and endothelial dysfunction. Although PGE1 administration did not affect the serum interleukin-8 level, it significantly decreased hepatic injury and leukostasis in the reperfused liver. Immunohistochemical findings showed that PGE1 decreased ICAM-1 expression on endothelial cells, but did not affect lymphocyte function-associated antigen 1, and membrane attack complex 1 on neutrophils in flow cytometric analysis.. We conclude that PGE1 protects the liver against ischemia-reperfusion injury by reducing leukocyte-endothelial cell adhesion via down-modulation of ICAM-1 expression on the endothelium.

Topics: Alprostadil; Animals; Antibodies, Monoclonal; Aspartate Aminotransferases; Cell Adhesion; Endothelium, Vascular; Flow Cytometry; Intercellular Adhesion Molecule-1; Interleukin-8; Ischemia; Liver; Lymphocyte Function-Associated Antigen-1; Macrophage-1 Antigen; Male; Microscopy, Fluorescence; Neutrophils; Rats; Rats, Sprague-Dawley; Reperfusion Injury

The liver is highly susceptible to a number of pathological insults, including ischemia/reperfusion injury. We have previously employed an animal model of hepatic ischemia/reperfusion injury, and have shown that this injury induces the production and release of hepatic-derived tumor necrosis factor alpha (TNF-alpha), which mediates, in part, local liver injury following hepatic reperfusion. In the present study, we have extended these previous observations to assess whether an interrelationship exists between TNF-alpha and the neutrophil chemoattractant/activating factor, epithelial neutrophil activating protein, that may account for some of the pathology of neutrophil-mediated ischemia/reperfusion-induced liver injury. We observed that hepatic ischemia/reperfusion injury leads to: (1) a coincident increase in hepatic neutrophil sequestration, elevated serum alanine aminotransferase (ALT) levels, and hepatic production of epithelial neutrophil activating protein; (2) passive immunization with neutralizing antibodies to TNF-alpha resulted in significant suppression of hepatic-derived epithelial neutrophil activating protein; and (3) neutralization of epithelial neutrophil activating protein by passive immunization significantly attenuated neutrophil sequestration in the liver and serum ALT levels. These findings support the notion that local expression of hepatic epithelial neutrophil activating protein produced in response to TNF-alpha is an important mediator of the local neutrophil-dependent hepatic injury associated with hepatic ischemia/reperfusion.

Topics: Alanine Transaminase; Animals; Chemokine CXCL5; Chemokines, CXC; Cytokines; Interleukin-8; Ischemia; Liver; Male; Neutrophil Activation; Neutrophils; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

Topics: Animals; Interleukin-8; Intestinal Mucosa; Intestine, Small; Ischemia; Male; Mesenteric Arteries; Rats; Rats, Inbred Lew; Reperfusion Injury; Temperature; Time Factors; Tumor Necrosis Factor-alpha

Topics: Animals; Interleukin-8; Intestine, Small; Ischemia; Male; Rats; Rats, Inbred Lew; Reperfusion; Reperfusion Injury; Time Factors

The contribution of granulocytes and their byproducts to acute gastric mucosal lesion (AGML) is unclear. Our previous study showed that granulocytes produced O2- in the gastric mucosa of rats treated with 300 mg/kg of cinchophen (cinchophen ulcer, CU) and in rats subjected to 30 min-ischemia-reperfusion (IR). The present study investigated the effects of granulocytes and O2- on microcirculatory injury (MCI) in the gastric mucosa in both models. To evaluate MCI, we measured the amount of extravasated Evans blue, and monitored changes in blood flow and the formation of vascular casts in the gastric mucosa of rats with and without leukopenia. Mucosal levels of interleukin-8 (IL-8) were also measured, to determine granulocyte migration into the stomach. Our findings were: (1) IL-8 was decreased 30-45 min after CU injection (C-I) or after the start of occlusion (S-O), and levels had increased 90 min after either treatment. (2) Evans blue increased 120-150 min after C-I or S-O. These increases were lower in leukopenic than in non-leukopenic rats. (3) The blood flow decreased after C-I or reperfusion and continued at the same level during the 180-min measurement period. In CU leukopenic rats, the blood flow decreased slowly and was restored gradually. In IR leukopenic rats, the blood flow did not decrease. (4) There was a partial lack of capillary network, narrowing of capillaries, and extravasation of resin 90-120 min after C-I and S-O, and the disturbances were reduced in leukopenic rats in both models. (5) The extravasation of resin was reduced by the administration of superoxide dismutase (SOD) at the time O2- from granulocytes was being produced. (6) These reductions in the extravasation of resin due to leukopenia or SOD were smaller in CU than in IR rats. These findings indicate that granulocytes and O2- contribute to some extent to the MCI in CU rats.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Gastric Mucosa; Granulocytes; Hemodynamics; Interleukin-8; Leukopenia; Male; Microcirculation; Quinolines; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury

Topics: Animals; Arsenites; Biomarkers; HSP70 Heat-Shock Proteins; Interleukin-8; Intestine, Small; Ischemic Preconditioning; Male; Mesenteric Arteries; Rats; Rats, Inbred Lew; Reperfusion Injury; Sodium Compounds; Time Factors

Hepatic ischemia followed by reperfusion causes the release of a cascade of mediators, including tumor necrosis factor-alpha and epithelial neutrophil activating protein (ENA-78), which are important in the subsequent development of the lung and liver injury associated with this insult. We hypothesize that preferential post-ischemic shunting of blood into the nonischemic hepatic lobes at the time of reperfusion may increase the ischemic injury. To test this hypothesis, we utilized a rat model of lobar no-flow hepatic ischemia/reperfusion and removed the nonischemic hepatic lobes at the time of reperfusion to eliminate the preferential shunting of blood into the nonischemic tissues. We assessed pulmonary and hepatic tissue levels of ENA-78, pulmonary neutrophil influx and changes in pulmonary capillary permeability, and liver injury as measured by hepatic neutrophil influx and serum transaminase levels. Our results demonstrated that there were no significant differences in pulmonary and hepatic levels of ENA-78, or in the development of the lung and liver injury in animals undergoing resection of the nonischemic hepatic lobes at the time of reperfusion, as compared with animals undergoing hepatic ischemia/reperfusion alone.

Topics: Animals; Chemokine CXCL5; Chemokines, CXC; Interleukin-8; Liver; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

Topics: Animals; Chemokines, CXC; Chemotactic Factors; Gadolinium; Gene Expression; Growth Substances; Intercellular Signaling Peptides and Proteins; Interleukin-8; Ischemia; Kupffer Cells; Liver; Male; Rats; Rats, Wistar; Reperfusion Injury

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Bilirubin; Biomarkers; Chemokines, CXC; Chemotactic Factors; Graft Rejection; Growth Substances; Intercellular Signaling Peptides and Proteins; Interleukin-8; Liver Transplantation; Rats; Rats, Inbred ACI; Rats, Inbred BN; Rats, Inbred Lew; Reperfusion Injury; Time Factors; Transplantation, Homologous; Transplantation, Isogeneic

The neutrophil chemoattractants generated in a model of myocardial infarction in the anesthetized rabbit were investigated. Coronary artery occlusion was followed by reperfusion for periods from 5 min to 4.5 h. Extracts of myocardial tissue in normal and post-ischemic zones were tested for C5a and interleukin-8 (IL-8) using specific radioimmunoassays. In the post-ischemic zone, immunoreactive C5a was detected within 5 min and rose progressively to reach a plateau at 3-4.5 h. In contrast, immunoreactive IL-8 concentrations rose after a delay and were highest at the last time point tested, 4.5 h. Myeloperoxidase activity levels, an index of neutrophil accumulation, rose progressively as the concentrations of chemoattractants increased. Using cation exchange and reversed phase HPLC, immunoreactive C5a and IL-8 co-eluted with authentic standards. Fractions taken at the C5a and IL-8 peaks from reversed phase HPLC exhibited neutrophil aggregating activity which was neutralized by the respective antibody used in the radioimmunoassays. Depletion of circulating neutrophils virtually abolished immunoreactive IL-8 in the post-ischemic myocardial tissue. These observations suggest a sequential release of chemoattractants: the first, C5a is generated in interstitial fluid, followed by IL-8 generated by infiltrating neutrophils. Thus, over the time period studied, IL-8 generation would be expected to be indirectly dependent on C5a production.

Topics: Animals; Blood Pressure; Cell Aggregation; Chemotactic Factors; Chemotaxis, Leukocyte; Complement C5a; Female; Heart; Heart Rate; Interleukin-8; Male; Myocardial Ischemia; Myocardium; Neutrophils; Peroxidase; Rabbits; Reperfusion Injury

The liver is highly susceptible to a number of pathological insults, including ischemia/reperfusion injury. One of the striking consequences of liver injury is the associated pulmonary dysfunction that may be related to the release of hepatic-derived cytokines. We have previously employed an animal model of hepatic ischemia/reperfusion injury, and demonstrated that this injury causes the production and release of hepatic-derived TNF, which mediates a neutrophil-dependent pulmonary microvascular injury. In this study, we have extended these previous observations to assess whether an interrelationship between TNF and the neutrophil chemoattractant/activating factor, epithelial neutrophil activating protein-78 (ENA-78), exists that may be accountable for the pathology of lung injury found in this model. In the context of hepatic ischemia/reperfusion injury, we demonstrated the following alterations in lung pathophysiology: (a) an increase in pulmonary microvascular permeability, lung neutrophil sequestration, and production of pulmonary-derived ENA-78; (b) passive immunization with neutralizing TNF antiserum resulted in a significant suppression of pulmonary-derived ENA-78; and (c) passive immunization with neutralizing ENA-78 antiserum resulted in a significant attenuation of pulmonary neutrophil sequestration and microvascular permeability similar to our previous studies with anti-TNF. These findings support the notion that pulmonary ENA-78 produced in response to hepatic-derived TNF is an important mediator of lung injury.

Topics: Animals; Base Sequence; Capillary Permeability; Chemokine CXCL5; Chemokines, CXC; Immunohistochemistry; Interleukin-8; Liver; Lung; Male; Microcirculation; Molecular Sequence Data; Neutrophils; Rats; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger

Aortic surgery results in ischemia/reperfusion of the lower body. This may liberate inflammatory mediators that activate neutrophils, and may result in lung microvascular changes with increased permeability and respiratory failure. We studied circulating inflammatory mediators and the pulmonary leak index (PLI) of 67Ga, a measure of transvascular transferrin transport and permeability, in patients scheduled for elective aortic and peripheral vascular surgery, before and after surgery. Aortic surgery patients in Groups 1 (n = 10) and 2 (n = 7) were studied before and at a median of 2.5 and 21.0 h after surgery, respectively. A control Group 3 (n = 6) was studied before and at a median of 2.9 h after peripheral vascular surgery. The PLI (median) increased from a median of 9.1 (range, 6.6 to 14.7) before to a median of 23.4 (range, 18.7 to 86.4) x 10(-3)/min after surgery in Group 1 but not in the other groups (p < 0.001). The postoperative increase in circulating neutrophils and elastase-alpha 1-antitrypsin, a marker of neutrophil activation, was similar among the groups. Plasma levels of activated complement 3a and tumor necrosis factor (TNF-alpha) did not change in any of the groups. In contrast, plasma levels of interleukin-8 (IL-8) increased in Group 1 from < 3 (range, < 3 to 37) before to 324 (range, 36 to 868) pg/ml after surgery, but did not change in the other groups (p < 0.005). The decrease in plasma levels of angiotensin converting enzyme (ACE) was greater in Group 1 than in the other groups (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Aortic Diseases; Capillary Permeability; Citrates; Citric Acid; Erythrocytes; Female; Gallium Radioisotopes; Humans; Inflammation Mediators; Interleukin-8; Lung; Male; Middle Aged; Neutrophil Activation; Peptidyl-Dipeptidase A; Peripheral Vascular Diseases; Postoperative Complications; Radionuclide Imaging; Reperfusion Injury; Respiratory Distress Syndrome; Sodium Pertechnetate Tc 99m

Topics: Dinoprostone; Endothelins; Humans; In Vitro Techniques; Interleukin-6; Interleukin-8; Lipopolysaccharides; Monocytes; Reperfusion Injury; Time Factors

Topics: Adhesiveness; Age Factors; Animals; Antibodies, Monoclonal; Antigens, CD; CD11 Antigens; CD18 Antigens; Cell Adhesion Molecules; Cell Movement; Disease Models, Animal; Endothelium; Humans; Infant, Newborn; Inflammation; Interleukin-8; Multiple Organ Failure; Neutrophils; Platelet Activating Factor; Receptors, Leukocyte-Adhesion; Reperfusion Injury; Respiratory Distress Syndrome

Re-establishing blood flow to ischaemic tissues causes greater injury than that induced during the ischaemic period. This type of tissue injury, reperfusion injury, is involved in frostbite, multiple organ failure after hypovolaemia and in myocardial infarction. Depletion of neutrophils alleviates reperfusion injury, implying a causal role of neutrophil infiltration. Among members of the recently discovered family of chemotactic cytokines (chemokines), interleukin-8 (IL-8) is a major neutrophil chemotactic and activating factor produced by various types of human cells. We investigated its pathophysiological role in a rabbit model of a lung reperfusion injury. Reperfusion of ischaemic lung caused neutrophil infiltration and destruction of pulmonary structure, as well as local production of IL-8. Furthermore, the administration of a neutralizing monoclonal antibody against IL-8 prevented neutrophil infiltration and tissue injury, proving a causal role of locally produced IL-8 in this model.

Topics: Animals; Antibodies, Monoclonal; Bronchoalveolar Lavage Fluid; Chemotaxis, Leukocyte; Female; Guinea Pigs; Interleukin-8; Ischemia; Lung; Lung Diseases; Neutrophils; Rabbits; Reperfusion Injury

Previous studies of myocardial ischemia suggest that complement activation may play a central role in the inflammatory response during reperfusion. Our previous work has demonstrated neutrophil chemotactic activity to be present in reperfusion canine cardiac lymph after myocardial ischemia and infarction. To evaluate the contribution of the complement-dependent anaphylatoxin C5a to this neutrophil chemotactic activity, rabbit antiserum to canine C5a was prepared. At dilutions > 1:500 but < 1:2,000, the antiserum abolished the ability of zymosan-activated dog serum to induce a ruffled, bipolar morphology in isolated neutrophils used as a bioassay of chemotactic stimulation. This antiserum did not affect similar morphological changes in neutrophils exposed to platelet activating factor (10(-7)-10(-6) M) or recombinant human interleukin-8 (10(-9)-10(-8) M); thus, we deemed it functionally specific for canine C5a. In a pattern similar to what we previously reported, cardiac lymph collected before a 1-hour ligation of the left circumflex coronary artery had little ability to alter the morphology of canine neutrophils (shape change index, 11.3 +/- 4.6, mean +/- SEM; n = 7), but by 1 hour of reperfusion, lymph activated neutrophils significantly in five of seven dogs (mean shape change index, 72.6 +/- 17.7; p < 0.01). At 2 hours of reperfusion, neutrophil activation by lymph occurred in six of seven dogs (mean shape change index, 103.1 +/- 22.2). At 3 hours of reperfusion, cardiac lymph of only three of six dogs caused neutrophil activation, and at 4 hours of reperfusion, this activity was evident in lymph from only two of five dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Chemotactic Factors; Chemotaxis, Leukocyte; Complement C5a; Dogs; Immune Sera; Immunochemistry; Interleukin-8; Lymph; Myocardium; Neutrophils; Platelet Activating Factor; Rabbits; Reperfusion Injury; Time Factors

Ischemia-reperfusion and hyperoxia-induced pulmonary injury are associated with the presence of activated neutrophils (PMN) and cellular injury. Although the signals orchestrating the directed migration of these PMN during the pathogenesis of these disease states remain to be fully elucidated, it appears they may be dependent upon the production of certain neutrophil activating/chemotactic factors such as C5a, leukotriene B4, platelet-activating factor, and IL-8. The production of the latter chemotaxin by mononuclear phagocytes is especially intriguing as these cells can mediate inflammatory cell migration by either directly generating IL-8, or by inducing its production from surrounding nonimmune cells. In light of these observations, we propose that ischemia-reperfusion and oxidant stress, in vivo, may be simulated by anoxia-hyperoxia induced stress in vitro, and that this stress may act as a stimulus for the production of IL-8. We now show that isolated human blood monocytes respond to such an oxygen stress with augmented production of IL-8. In initial studies, monocytes demonstrated an increase in the production of IL-8 under anoxic preconditioning. Subsequently, monocytes were cultured under one of the following conditions for 24 h: (a) room air/5% CO2; (b) 95% N2/5% CO2 for 6 h, followed by room air/5% CO2 for 18 h; (c) 95% N2/5% CO2 for 6 h, followed by 95% O2/5% CO2 for 18 h; (d) room air/5% CO2 for 6 h, followed by 95% O2/5% CO2 for 18 h; or (e) 95% O2/5% CO2. Supernatants were isolated and analyzed for IL-8 antigen by specific IL-8 ELISA, demonstrating the production of monocyte-derived IL-8: 5.9 +/- 0.9, 11.4 +/- 1.7, 21.1 +/- 2.3, 14.6 +/- 2.4, and 26.3 +/- 4.7, ng/ml by designated conditions a, b, c, d, and e listed above, respectively. This variance in IL-8 production reflects altered rates of transcription as shown by Northern blot analysis and nuclear run-off assay. Furthermore, when monocytes were concomitantly treated with LPS (100 ng/ml) under in vitro hyperoxic conditions, both IL-8 steady-state mRNA and antigenic activity were two- to threefold greater than under room air conditions. The association of anoxic preconditioning and oxygen stress with augmented production of monocyte-derived IL-8 support the potential role for ischemia-reperfusion and hyperoxia-induced IL-8 production in vivo, providing a possible mechanism for PMN migration/activation in disease states characterized by altered tissue oxygenation.

Topics: Animals; Base Sequence; Cells, Cultured; Humans; Hypoxia; Interleukin-8; Lipopolysaccharides; Molecular Sequence Data; Monocytes; Neutrophils; Oxygen; Rabbits; Reperfusion Injury; RNA, Messenger