interleukin-8 and Hypotension

Sepsis resulting in multiorgan failure and death is still a major problem in intensive care medicine, despite extensive attempts to interfere in the supposed underlying mechanism of a deranged immune system. This is not only due to the persistent lacunae in knowledge about the immune system in sepsis but also due to the lack of sufficient instruments for intervention. Inhibitors of the p38 mitogen-activated protein kinase (p38MAPK) have been used to study the signalling pathway of the immune response. In vitro and animal studies have demonstrated that blocking p38MAPK could mitigate the pro-inflammatory response and improve survival after endotoxaemia. Using an endotoxaemia model in healthy human volunteers we evaluated the attenuation of clinical and cytokine response to endotoxin after inhibition of p38MAPK by an oral dose of RWJ-67657, a pyrindinyl imidazole. We measured the clinical parameters temperature, blood pressure and heart rate. The proinflammatory cytokines tumour necrosis factor-alpha, interleukin-6 and interleukin-8 were measured by ELISA at various points during a 24-h period. Drug toxicity was evaluated by routine clinical and laboratory examinations. After a single dose dose of RWJ-67657 the temperature and blood pressure response remained at the basal level. The inhibition of TNF-alpha, IL-6 and IL-8 response was a dose dependent. With the maximum dosage, reduction in peak serum levels of the proinflammatory cytokines was greater than 90%. There was no drug-related toxicity.. We conclude that inhibition of p38MAPK by RWJ-67657 might be a tool to intervene in the deranged immune response in sepsis and other inflammatory diseases.

Topics: Adult; Cytokines; Dose-Response Relationship, Drug; Endotoxemia; Endotoxins; Enzyme Inhibitors; Fever; Humans; Hypotension; Imidazoles; Interleukin-6; Interleukin-8; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Pyridines; Tumor Necrosis Factor-alpha

We have previously demonstrated that the activation of the spleen tyrosine kinase (Syk)/inhibitory-κB (IκB)-α/nuclear factor-κB (NF-κB) p65 signalling pathway contributes to hypotension and inflammatory response in a rat models of zymosan (ZYM)-induced non-septic shock. The purpose of this study was to further examine the possible mechanism underlying the effect of inhibition of Syk by BAY61-3606 via NF-κB activity at the level of nuclear translocation regarding the production of vasodilator and proinflammatory mediators in lipopolysaccharide (LPS) (septic)- and ZYM (non-septic)-induced shock. Administration of LPS (10 mg/kg, ip) or ZYM (500 mg/kg, ip) to male Wistar rats decreased mean arterial pressure and increased heart rate that was associated with an increase in the activities of cyclooxygenase and nitric oxide synthase, tumour necrosis factor-α, and interleukin-8 levels, and NF-κB activation and nuclear translocation in sera and/or cardiovascular and renal tissues. BAY61-3606 (3 mg/kg, ip), the selective Syk inhibitor, given 1 hour after LPS- or ZYM injection reversed all the above-mentioned effects. These results suggest that Syk contributes to the LPS- or ZYM-induced hypotension and inflammation associated with transactivation of NF-κB in septic and non-septic shock.

Topics: Animals; Cyclooxygenase 2; Disease Models, Animal; Gene Expression Regulation; Gene Expression Regulation, Enzymologic; Hypotension; Inflammation; Interleukin-8; Lipopolysaccharides; Male; NF-kappa B; NF-KappaB Inhibitor alpha; Niacinamide; Nitric Oxide Synthase Type II; Protein Kinase Inhibitors; Pyrimidines; Rats; Rats, Wistar; Shock, Septic; Syk Kinase; Tumor Necrosis Factor-alpha; Zymosan

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; B-Lymphocytes; Capillary Leak Syndrome; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cytokines; Edema; Humans; Hypotension; Hypoxia; Infusions, Intravenous; Interleukin-6; Interleukin-8; Killer Cells, Natural; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Depletion; Multicenter Studies as Topic; Syndrome

Because of the shortage of suitable brain-dead donors, the use of non-heart-beating donor lungs has been investigated experimentally. However, no effective lung protection method has been developed. In this study, we preliminarily investigated the protective effect of partial liquid ventilation (PLV) on a non-heart-beating rabbit lung.. We used 20 male rabbits (mean weight, 3.7 kg) and divided them into 3 groups: the conventional ventilation (control) group, the PLV without cooling group, and the PLV with cooling group. After initially measuring donor cardiopulmonary function, we maintained hypotension at <50 mm Hg for 1 hour followed by 2-hour cardiac arrest. During this time, we used either conventional ventilation or PLV with or without cooling (4 degrees C) for ventilation, and we evaluated the changes in arterial blood gas analysis, pulmonary resistance and elastance, tissue interleukin-8 (IL-8) concentration, and histologic damage.. We found no significant difference in arterial oxygen concentration or in carbon dioxide tension among the 3 groups in the hypotensive phase. Pulmonary elastance increased after perfusion of preservation solution in the control group. However, we found no change in elastance in the PLV groups, which was less than that in the control group. Histologic evaluation after perfusion of preservation solution revealed that alveolar structure was damaged significantly less and cell infiltration was milder in the PLV groups than in the control group. Although IL-8 concentrations in the controls increased after cardiac arrest, IL-8 in the PLV groups remained at baseline concentrations during the study period.. In this experimental model of hypotension and cardiac arrest, PLV suppresses lung injury when compared with gas-controlled ventilation.

Topics: Airway Resistance; Animals; Blood Gas Analysis; Cytokines; Disease Models, Animal; Heart Arrest; Hypotension; Interleukin-8; Liquid Ventilation; Lung; Lung Transplantation; Male; Rabbits

In the process of developing a model of Escherichia coli endotoxin-induced acute lung injury and shock in specific pathogen-free pigs, the effects of pretreatment with metyrapone (a cortisol-synthesis inhibitor) were examined. Metyrapone was administered 1.5 h before start of endotoxin infusion at t = 0 h (MET-ETOX group, n = 6). At the end of the experiments (t = 4 h) a bronchoalveolar lavage (BAL) was performed. Control animals received only endotoxin (CON-ETOX group, n = 6) or metyrapone (MET-CON group, n = 4). The following results are presented as means +/- SEM. It was found that metyrapone successfully blocked endogenous cortisol synthesis (plasma cortisol levels were 41.0 +/- 5.9 nM in MET-ETOX vs. 339.0 +/- 37.7 nM in CON-ETOX at t = 4 h, P <0.01). At t = 4 h the MET-ETOX animals had substantially increased systemic hypotension compared to the CON-ETOX group (mean arterial pressure 26.7 +/- 4.3 vs. 77.7 +/- 12.2 mmHg, P <0.01), decreased dynamic lung compliance (10.9 +/- 0.7 vs. 13.7 +/- 0.6 ml/cmH2O, P <0.01), increased percentage of BAL neutrophils (28.4 +/- 6.5 vs. 6.6 +/-1.8, P <0.01), pulmonary edema (BAL total protein 0.82 +/- 0.21 vs. 0.42 +/- 0.09 mg/mL, P <0.05), elevated levels of interleukin-8 (1924 +/- 275 vs. 324 +/- 131 pg/mL, P <0.01) and acidosis (pH 7.11 +/- 0.03 vs. 7.23 +/- 0.06, P <0.05). The MET-ETOX group also showed an increased pulmonary hypertension between 2 and 3 h after start of endotoxin infusion and a trend toward significantly increased levels of plasma interleukin-8 (P = 0.052). Arterial pCO2, pO2/FiO2, plasma endothelin-1, plasma TNFalpha, and blood leukocytes were not markedly influenced by the plasma cortisol levels. Nitric oxide production did not seem to be altered by endotoxin infusion in this model, in contrast to other animal studies; this discrepancy could be thought to be due to endotoxin-dosage differences or species differences. It is concluded that if endogenous cortisol production is blocked by metyrapone, the reactions occurring as a result of the endotoxin-induced acute lung injury and shock are greatly enhanced and that therefore pretreatment with metyrapone might be an important addition to this model with specific pathogen-free pigs.

Topics: Acid-Base Imbalance; Animals; Blood Gas Analysis; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Endothelin-1; Endotoxins; Female; Hydrocortisone; Hypotension; Interleukin-8; Leukocytes; Male; Metyrapone; Neutrophils; Nitric Oxide; Nitrites; Peroxidase; Proteins; Pulmonary Edema; Respiratory Distress Syndrome; Respiratory Function Tests; Shock; Specific Pathogen-Free Organisms; Swine; Tumor Necrosis Factor-alpha