leukotriene-b4 and Acute-Disease

Topics: Acute Disease; Animals; Humans; Inflammation; Leukotriene B4; Neutrophils; Respiratory Distress Syndrome; Sheep; SRS-A; Tetradecanoylphorbol Acetate; Vasoconstriction

Topics: Acute Disease; Animals; Humans; Inflammation; Leukotriene B4; SRS-A

Omega-3 polyunsaturated fatty acid (ω-3 PUFA) have been reported to have beneficial cardiovascular effects, but its mechanism of protection against acute myocardial infarction (AMI) who are under guideline-based therapy is not fully understood. Here, we used a metabolomic approach to systematically analyze the eicosanoid metabolites induced by ω-3 PUFA supplementation and investigated the underlying mechanisms.. Participants with AMI after successful percutaneous coronary intervention were randomized to 3 months of 2 g daily ω-3 PUFA and guideline-adjusted therapy (n = 30, ω-3 therapy) or guideline-adjusted therapy alone (n = 30, Usual therapy). Functional PUFA-derived eicosanoids in plasma were profiled by metabolomics. Clinical and laboratory tests were obtained before and 3 months after baseline and after the study therapy.. By intent-to-treat analysis, the content of 11-HDoHE, 20-HDoHE and 16,17-EDP and that of epoxyeicosatetraenoic acids (EEQs), derived from docosahexaenoic acid and eicosapentaenoic acid, respectively, were significantly higher with ω-3 group than Usual therapy, whereas that of prostaglandin J2 (PGJ2) and leukotriene B4, derived from arachidonic acid, was significantly decreased. As compared with Usual therapy, ω-3 PUFA therapy significantly reduced levels of triglycerides (-6.3%, P < 0.05), apolipoprotein B (-4.9%, P < 0.05) and lipoprotein(a) (-37.0%, P < 0.05) and increased nitric oxide level (62.2%, P < 0.05). In addition, the levels of these variables were positively correlated with change in 16,17-EDP and EEQs content but negatively with change in PGJ2 content.. ω-3 PUFA supplementation may improve lipid metabolism and endothelial function possibly by affecting eicosanoid metabolic status at a systemic level during convalescent healing after AMI.. URL: http://www.chictr.org.cn. Unique identifier: ChiCTR1900025859.

Topics: Acute Disease; Aged; Atrial Fibrillation; Death, Sudden, Cardiac; Dietary Supplements; Eicosanoids; Endothelium, Vascular; Fatty Acids, Omega-3; Female; Humans; Intention to Treat Analysis; Leukotriene B4; Lipid Metabolism; Male; Metabolome; Metabolomics; Middle Aged; Myocardial Infarction; Nitric Oxide; Nutrition Policy; Percutaneous Coronary Intervention; Prostaglandin D2

Acute respiratory failure in neonates (e.g. ARDS, meconium aspiration pneumonitis, pneumonia) is characterized by an excessive inflammatory response, governing the migration of polymorpho-nuclear leukocytes (PMNLs) into lung tissue and causing consecutive impairment of gas exchange and lung function. Critical to this inflammatory response is the activation of nuclear factor-kappaB (NF-kappaB) that is required for transcription of the genes for many pro-inflammatory mediators. We asked whether the inhibition of NF-kappaB activity using either a selective inhibitor (IKK-NBD peptide) or dexamethasone would be more effective in decreasing NF-kappaB activity and chemokine expression in pulmonary cells. Changes in lung function were repeatedly assessed for 24h following induction of acute respiratory failure and therapeutic intervention. We conducted a randomized, controlled, prospective animal study with mechanically ventilated newborn piglets which underwent repeated airway lavage (20+/-2 [SEM]) to remove surfactant and to induce lung inflammation. Admixed to 100 mg kg(-1) surfactant, piglets then received either IKK-NBD peptide (S+IKK), a selective inhibitor of NF-kappaB activation, its control peptide without intrinsic activity, dexamethasone (S+Dexa), its solvent aqua, or an air bolus only (all groups n=8). After 24h of mechanical ventilation, the following differences were measured: PaO(2)/FiO(2) (S+IKK 230+/-9 mm Hg vs. S+Dexa 188+/-14, p<0.05); ventilation efficiency index (0.18+/-0.01 [3800/(PIP-PEEP)(*)f(*)PaCO(2)] vs. 0.14+/-0.01, p<0.05); extravascular lung water (24+/-1 ml kg(-1) vs. 29+/-2, p<0.05); PMNL in BAL fluid (112+/-21 cells microl(-1) vs. 208+/-34, p<0.05), IL-8 (351+/-117 pg ml(-1) vs. 491+/-144, p=ns) and leukotriene B(4) (23+/-7 pg ml(-1) vs. 71+/-11, p<0.01) in BAL fluid. NF-kappaB activity in the nucleus of pulmonary cells differed by 32+/-5% vs. 55+/-3, p<0.001. Differences between these two intervention groups were more pronounced in the second half of the observation period (hours 12-24). At 24h of mechanical ventilation, inhibition of NF-kappaB activity by IKK-NBD peptide admixed to surfactant as a carrier caused improved gas exchange, lung function and reduced pulmonary inflammation, as evidenced by reduction in PMNL migration into lung tissue due to reduced nuclear NF-kappaB activity. We conclude that IKK-NBD admixture to surfactant in acute neonatal respiratory failure is superior to dexamethasone administration within the fir

Topics: Acute Disease; Animals; Animals, Newborn; Anti-Inflammatory Agents; Blood Cell Count; Bronchoalveolar Lavage Fluid; Dexamethasone; Inflammation; Interleukin-8; Leukotriene B4; Lung Diseases; Neutrophils; NF-kappa B; Organ Size; Pulmonary Gas Exchange; Pulmonary Surfactants; Respiration, Artificial; Respiratory Tract Diseases; Swine

Acute right lower abdominal pain may present a diagnostic dilemma. Leukotrienes have been found to be elevated in familial Mediterranean fever (FMF), a disease manifesting with recurrent episodes of "acute abdomen.". To determine whether urine leukotriene B4 (LTB4) may differentiate between an FMF attack and some other forms of acute right lower abdominal pain.. The LTB4 level was determined, using a commercial enzyme-linked immunosorbent assay (ELISA), in urine samples obtained from 36 patients with acute (< 24 hours) right lower abdominal pain presenting to the emergency department, and from 18 healthy volunteers.. Compared with the healthy control subjects, LTB4 was significantly higher in those who had FMF (12 patients, p < 0.03). In other forms of acute right lower abdominal pain, including appendicitis (eight patients), urologic disorders (eight patients), and nonspecific abdominal pain (eight patients), intermediate levels of LTB4 were observed, not significantly different from those of either FMF patients or healthy control subjects.. In the samples tested, urine LTB4 levels were not instrumental in differentiating FMF from other acute right lower abdominal pain.

Topics: Abdominal Pain; Acute Disease; Adult; Appendicitis; Diagnosis, Differential; Familial Mediterranean Fever; Female; Humans; Leukotriene B4; Male; Middle Aged; Reference Values; Sensitivity and Specificity

Two potent mediators of acute inflammation, histamine and leukotriene B4 (LTB4), have been shown to play important roles in the pathogenesis and clinical course of acute otitis media (AOM) in children. The purpose of this study was to evaluate the ability of adjuvant drugs, antihistamine and corticosteroid, in reduction of the levels of histamine and LTB4 in the middle ear and their ability to improve outcomes of AOM.. Eighty children with AOM (aged 3 months to 6 years) were enrolled in a prospective, randomized, double-blind, placebo controlled study. All children received one dose of intramuscular ceftriaxone and were randomly assigned to receive either chlorpheniramine maleate (0.35 mg/kg per day) and/or prednisolone (2 mg/kg per day) or placebos three times a day for 5 days. Tympanocentesis was performed at enrollment and after 5 days of adjuvant drug treatment. MEFs were collected for bacterial and viral studies and histamine and LTB4 levels. The subjects were followed for the duration of middle ear effusion or up to 3 months.. Histamine or LTB4 levels in the MEF after 5 days of treatment were not significantly reduced by adjuvant drug treatment. However, subjects receiving corticosteroid had a lower rate of treatment failure during the first 2 weeks and shorter duration of middle ear effusion.. Five day of antihistamine or corticosteroid treatment does not reduce the levels of histamine or leukotriene B4 in the MEF of children with AOM. Positive clinical outcomes of AOM cases associated with corticosteroid treatment needs to be confirmed in a larger clinical trial of children with intact tympanic membranes, who do not receive tympanocentesis.

Topics: Acute Disease; Anti-Bacterial Agents; Anti-Inflammatory Agents; Ceftriaxone; Child; Child, Preschool; Chlorpheniramine; Double-Blind Method; Drug Therapy, Combination; Ear, Middle; Female; Histamine; Histamine H1 Antagonists; Humans; Infant; Leukotriene B4; Male; Otitis Media with Effusion; Prednisolone; Prospective Studies

We investigated whether pretreatment with eicosapentaenoic acid, an inhibitor of leukotriene (LT) B4, could ameliorate acute colonic graft-versus-host disease (GVHD) after bone marrow transplantation (BMT). Seventeen patients undergoing unrelated BMT were divided into two groups, with eight patients receiving eicosapentaenoic acid and nine not receiving it. The grade of GVHD after transplantation was compared with that estimated from the pretransplantation LTB4 level. The levels of LTB4 and several cytokines were also monitored. The actual grade of GVHD was lower than that estimated from LTB4 levels in three of the eight patients from the treated group, and there was a significant difference between the treated and untreated groups (p < 0.05, chi 2 test). The levels of LTB4, tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) were all significantly lower in the treated group (p < 0.05, Student's t-test). These findings suggest that eicosapentaenoic acid may ameliorate acute colonic GVHD when administered from before BMT.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Bone Marrow Transplantation; Chi-Square Distribution; Colitis; Eicosapentaenoic Acid; Fatty Acids, Unsaturated; Female; Graft vs Host Disease; Humans; Leukotriene B4; Male

Leukotrienes are proinflammatory mediators. Ethanol inhibits the catabolism of both cysteinyl leukotrienes (leukotriene E(4) [LTE(4)] and N-acetyl-LTE(4)) and leukotriene B(4) (LTB(4)) in hepatocytes. We examined the metabolic derangement of leukotriene inactivation by ethanol in humans in vivo.. LTE(4), N-acetyl-LTE(4), LTB(4), and 20-hydroxy-LTB(4) were quantified in urine samples from 16 patients with acute alcohol intoxication (mean blood ethanol, 75 mmol/L). In 9 healthy volunteers, urinary LTE(4) was determined before and after ethanol consumption (mean blood ethanol, 14 mmol/L).. The excretion of LTE(4) during alcohol intoxication was 286 compared with 36 nmol/mol creatinine in healthy subjects (P < 0.01); the corresponding values for N-acetyl-LTE(4) were 101 and 11 nmol/mol creatinine, respectively (P < 0.001). This excretion of cysteinyl leukotrienes decreased when the blood ethanol concentration returned to normal. LTB(4) and 20-hydroxy-LTB(4) were detectable only in patients with excessive blood ethanol concentrations (mean, 95 mmol/L). In healthy volunteers, LTE(4) excretion increased 3-5 hours after ethanol consumption (mean peak concentration of 1.5 nmol/L compared with 0.5 nmol/L for basal values; P < 0.005).. Ethanol at high concentration induces increased leukotriene excretion into urine. These changes are consistent with inhibition of leukotriene catabolism and inactivation induced by ethanol, as well as with a higher leukotriene formation caused by ethanol-induced endotoxemia.

Topics: Acute Disease; Adult; Alcohol Drinking; Alcoholic Intoxication; Central Nervous System Depressants; Chromatography, High Pressure Liquid; Cysteine; Ethanol; Female; Humans; Leukotriene B4; Leukotriene E4; Liver Cirrhosis, Alcoholic; Liver Function Tests; Male; Middle Aged

We assessed the effects of physical and chemical irritants on a profile of acute inflammatory mediators in normal human skin. Skin damage in both cases is accompanied by a flux of inflammatory processes and repair mechanisms, which remain imprecisely understood. We used 10 sequential cellotape strips or topical application of 0.075% capsaicin as skin irritants and characterized the subsequent production and/or release of inflammatory mediators in suction blister fluids from human skin in vivo. In tape stripped skin, levels of prostaglandin E2 and interleukin-1alpha were increased 3.4-fold and 3.3-fold, respectively (p<0.0001; p<0.02), levels of tumour necrosis factor-alpha were decreased 3.0-fold (p<0.01), whereas levels of interleukin-6 and leukotriene B4 in blister fluids remained relatively unchanged. For the capsaicin-treated skin, levels of mediators showed only minor differences when compared with matched controls. However, a correlation was observed between levels of prostaglandin E2 and interleukin-1alpha in capsaicin pre-treated blister fluids (r=0.58, p<0.01, n=19). These data are consistent with prostaglandin E2 and interleukin-1alpha playing key roles in acute skin responses to mild irritants.

Topics: Acute Disease; Adhesives; Capsaicin; Cytokines; Dermatitis, Irritant; Dinoprostone; Eicosanoids; Humans; Inflammation Mediators; Interleukin-1; Interleukin-6; Leukotriene B4; Skin; Tumor Necrosis Factor-alpha

To compare the analgesic and anti-inflammatory effects of the nonsteroidal anti-inflammatory drugs (NSAID), ketoprofen (2.20 and 3.63 mg/kg of body weight) and phenylbutazone (4.40 mg/kg), in an acute equine synovitis model.. 4 groups of 6 horses received NSAID or saline solution in a randomized design.. 24 clinically normal mares and geldings.. Left intercarpal joints were injected with sterile carrageenan to induce synovitis at the same time as IV administration of NSAID or saline solution. Clinical assessments were made and synovial fluid was withdrawn at 0, 1, 3, 6, 9, 12, 24, and 48 hours.. The eicosanoids, prostaglandin E2 (PGE2) and leukotriene B4, increased in synovial fluid after synovitis induction in all horses then returned to near baseline by 48 hours. All NSAID-treated horses had decreased PGE2, compared with saline-treated horses. This effect lasted longer in phenylbutazone-treated horses than in ketoprofen-treated horses. There were no treatment effects on leukotriene B4. In saline-treated animals, lameness, joint temperature, and synovial fluid volume, protein concentration, and nucleated cells increased 3 to 12 hours after induction, with marked reduction by 48 hours. Only phenylbutazone treatment reduced lameness, joint temperature, and synovial fluid volume.. Phenylbutazone was more effective than ketoprofen in reducing lameness, joint temperature, synovial fluid volume, and synovial fluid PGE2. Results do not support lipoxygenase inhibition by either NSAID.. This reversible model induced synovial fluid alterations similar to those observed in horses with septic arthritis. Results indicate that phenylbutazone may be more useful than ketoprofen in treating acute joint inflammation.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Horse Diseases; Horses; Joints; Ketoprofen; Lameness, Animal; Leukotriene B4; Male; Phenylbutazone; Proteins; Synovial Fluid; Synovitis

5-Lipoxygenase products of arachidonic acid metabolism are thought to play a central role in the secondary amplification of the inflammatory response in a number of human inflammatory diseases, such as ulcerative colitis. MK-0591 (3-(1((4-chlorophenyl)methyl)-3((1,1-dimethyl-ethyl)thio)-5(quinolin+ ++-2ylmethyl-oxy)-1H-indol-2yl)-2,2-dimethyl-propanoate) exerts its effect by binding to the 5-lipoxygenase activating protein, thereby inhibiting the translocation and activation of 5-lipoxygenase.. Concentrations of leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) in rectal dialysis fluid, ex vivo biosynthesis of LTB4 in whole blood, and urinary excretion of leukotriene E4 (LTE4) from 16 patients with mild to moderately active distally located ulcerative colitis were measured by use of radioimmunoassays in a double-blind, placebo-controlled parallel-design study before and after oral administration of a 250 mg dose of MK-0591 or placebo.. The mean LTB4 concentration in rectal dialysis fluid was lowered after MK-0591 by > 90% (p < 0.05) from 4 to 8 hours, with a maximum inhibition of 97.5% +/- 3.4% (mean +/- SD) at 20 to 24 hours after dosing, whereas PGE2 was unchanged. In whole blood, MK-0591 decreased ex vivo biosynthesis of LTB4 (p < 0.01), with a maximum inhibition of 96.4% +/- 2.1% at 4 hours after dosing. Urinary excretion of LTE4 was reduced by more than 85% (p < 0.001) from 4 to 48 hours. No adverse events were observed.. These findings show that a single oral 250 mg dose of MK-0591 results in nearly complete blockade of systemic leukotriene production and LTB4 formation in the target tissue of inflammation (the rectum). Controlled multiple-dose trials to assess the clinical efficacy of this novel 5-lipoxygenase-activating protein inhibitor seem to be worthwhile.

Topics: Acute Disease; Administration, Oral; Adult; Colitis, Ulcerative; Dinoprostone; Double-Blind Method; Female; Humans; Indoles; Leukotriene B4; Male; Middle Aged; Quinolines

This study investigates the participation of PI3Kγ in the development of joint inflammation and dysfunction in an experimental model of acute gout in mice. Acute gout was induced by injection of monosodium urate (MSU) crystals into the tibiofemoral joint of mice. The involvement of PI3Kγ was evaluated using a selective inhibitor and mice deficient for PI3Kγ (PI3Kγ

Topics: Acute Disease; Animals; Arthritis, Gouty; Caspase 1; Cell Adhesion; Cell Movement; Class Ib Phosphatidylinositol 3-Kinase; Cytoplasm; Enzyme Activation; Inflammasomes; Inflammation; Interleukin-1beta; Joints; Leukotriene B4; Male; Mice, Inbred C57BL; Microvessels; Neutrophil Infiltration; Neutrophils; Nociception; Phosphorylation; Proto-Oncogene Proteins c-akt; Synovial Membrane; Uric Acid

Monosodium urate-induced inflammation plays a vital role in acute gout (AG). Inflammation is a multi-stage process involved in the acute release of arachidonic acid and its metabolites. However, the function of the metabolism of arachidonic acid and other polyunsaturated fatty acids in AG is not well understood. This study aimed to investigate the modification of polyunsaturated fatty acid metabolism by AG.. Plasma samples from patients with an AG attack (n = 26) and gender-matched healthy controls (n = 26) were analysed by metabolic profiling of polyunsaturated fatty acids. The findings were further validated with a second cohort (n = 20 each group). The associated mechanisms were investigated in whole blood cells from the second cohort and neutrophils in vitro.. Plasma metabolic profiling revealed a significant increase in leukotriene B4 (LTB4) for AG patients in both cohorts. The increase in plasma LTB4 was accounted for by the dynamic balance between the activation of 5-lipoxygenase and CYP4F3, the former mediating the biosynthesis of LTB4 and the latter mediating its metabolism. This was supported by significantly increased transcriptional levels of 5-lipoxygenase and CYP4F3 in whole blood cells from AG patients compared with those of controls, and the uric acid-caused dose-relevant and time-dependent activation of 5-lipoxygenase and CYP4F3 at the transcriptional and molecular levels in vitro.. Increased LTB4 in AG patients is mainly due to activation of 5-lipoxygenase. 5-Lipoxygenase inhibition may be of therapeutic value clinically.

Topics: Acute Disease; Adolescent; Adult; Aged; Arachidonate 5-Lipoxygenase; Arthritis, Gouty; Case-Control Studies; Cells, Cultured; Cytochrome P450 Family 4; Dose-Response Relationship, Drug; Enzyme Activation; Fatty Acids, Unsaturated; Female; Humans; Leukotriene B4; Male; Metabolome; Middle Aged; Neutrophils; Uric Acid; Young Adult

The aim of this study was to investigate the predicting value of miR-146a/b for acute exacerbation chronic obstructive pulmonary disease (AECOPD) and COPD, and to explore their associations with inflammatory cytokines in AECOPD and stable COPD patients.One hundred six AECOPD, 122 stable COPD patients, and 110 health volunteers with age and sex matched to total COPD patients (AECOPD and stable COPD) were enrolled. Blood samples were collected from all participants. Relative expression of miR-146a/b was determined by real-time polymerase chain reaction. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), leukotriene B4 (LTB-4) expression in serum from AECOPD and stable COPD patients were assessed using commercial ELISA kit.Serum levels of miR-146a and miR-146b were down regulated in AECOPD patients compared with stable COPD patients and HCs. miR-146a and miR-146b are of good values for predicting the risk of AECOPD in HCs with AUC of 0.702 and 0.715. Additionally, miR-146a and miR-146b could distinguish AECOPD from stable COPD patients with AUC of 0.670 and 0.643. In AECOPD patients, levels of miR-146a in AECOPD patients were negatively associated with TNF-α, IL-6, IL-8, and LTE-4 expression. In stable COPD patients, miR-146a expressions were negatively correlated with TNF-α, IL-1β, IL-6, IL-8, and LTE-4 levels. And, the expressions of miR-146b in AECOPD patients were negatively associated with IL-1β and LTB-4 expression. While in stable COPD patients, miR-146b expressions were only negatively correlated with TNF-α level.In conclusion, miR-146a and miR-146b were negatively correlated with inflammatory cytokines, and could be promising biomarkers for predicting the risk of AECOPD in stable COPD patients and healthy individuals.

Topics: Acute Disease; Aged; Biomarkers; Case-Control Studies; Cytokines; Disease Progression; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-1beta; Interleukin-6; Interleukin-8; Leukotriene B4; Male; MicroRNAs; Middle Aged; Pulmonary Disease, Chronic Obstructive; Real-Time Polymerase Chain Reaction; Risk Factors; Tumor Necrosis Factor-alpha

Respiratory infection with Francisella tularensis (Ft) is characterized by a muted, acute host response, followed by sepsis-like syndrome that results in death. Infection with Ft establishes a principally anti-inflammatory environment that subverts host-cell death programs to facilitate pathogen replication. Although the role of cytokines has been explored extensively, the role of eicosanoids in tularemia pathogenesis is not fully understood. Given that lipoxin A

Topics: Acute Disease; Animals; Apoptosis; Arachidonate 5-Lipoxygenase; Bone Marrow Cells; Cell Death; Chemokines; Chronic Disease; Dinoprostone; Disease Susceptibility; Down-Regulation; Francisella tularensis; Immunity; Indoles; Inflammation Mediators; Leukotriene B4; Lipoxins; Macrophages; Metabolome; Mice, Inbred C57BL; Organ Specificity; Respiratory Tract Infections; Tularemia

Neutrophils are essential to the acute inflammatory response, where they serve as the first line of defense against infiltrating pathogens. We report that, on receiving the necessary signals, teleost (Carassius auratus) neutrophils leave the hematopoietic kidney, enter into the circulation, and dominate the initial influx of cells into a site of inflammation. Unlike mammals, teleost neutrophils represent <5% of circulating leukocytes during periods of homeostasis. However, this increases to nearly 50% immediately after intraperitoneal challenge with zymosan, identifying a period of neutrophilia that precedes the peak influx of neutrophils into the challenge site at 18 h after injection). We demonstrate that neutrophils at the site of inflammation alter their phenotype throughout the acute inflammatory response, and contribute to both the induction and the resolution of inflammation. However, neutrophils isolated during the proinflammatory phase (18 h after injection) produced robust respiratory burst responses, released inflammation-associated leukotriene B(4), and induced macrophages to increase reactive oxygen species production. In contrast, neutrophils isolated at 48 h after infection (proresolving phase) displayed low levels of reactive oxygen species, released the proresolving lipid mediator lipoxin A(4), and downregulated reactive oxygen species production in macrophages before the initiation of apoptosis. Lipoxin A(4) was a significant contributor to the uptake of apoptotic cells by teleost macrophages and also played a role, at least in part, in the downregulation of macrophage reactive oxygen species production. Our results highlight the contributions of neutrophils to both the promotion and the regulation of teleost fish inflammation and provide added context for the evolution of this hematopoietic lineage.

Topics: Acute Disease; Animals; Apoptosis; Goldfish; Immunity, Innate; Kidney; Leukotriene B4; Lipoxins; Macrophage Activation; Macrophages, Peritoneal; Neutrophils; Peritonitis; Phagocytosis; Reactive Oxygen Species; Respiratory Burst; Time Factors; Zymosan

Microvascular plasma protein leakage is an essential component of the inflammatory response and serves an important function in local host defense and tissue repair. Mediators such as histamine and bradykinin act directly on venules to increase the permeability of endothelial cell (EC) junctions. Neutrophil chemoattractants also induce leakage, a response that is dependent on neutrophil adhesion to ECs, but the underlying mechanism has proved elusive. Through application of confocal intravital microscopy to the mouse cremaster muscle, we show that neutrophils responding to chemoattractants release TNF when in close proximity of EC junctions. In vitro, neutrophils adherent to ICAM-1 or ICAM-2 rapidly released TNF in response to LTB4, C5a, and KC. Further, in TNFR(-/-) mice, neutrophils accumulated normally in response to chemoattractants administered to the cremaster muscle or dorsal skin, but neutrophil-dependent plasma protein leakage was abolished. Similar results were obtained in chimeric mice deficient in leukocyte TNF. A locally injected TNF blocking antibody was also able to inhibit neutrophil-dependent plasma leakage, but had no effect on the response induced by bradykinin. The results suggest that TNF mediates neutrophil-dependent microvascular leakage. This mechanism may contribute to the effects of TNF inhibitors in inflammatory diseases and indicates possible applications in life-threatening acute edema.

Topics: Acute Disease; Animals; Antigens, CD; Capillary Permeability; Cell Adhesion; Cell Adhesion Molecules; Chemokine CXCL1; Complement C5a; Edema; Endothelial Cells; Intercellular Adhesion Molecule-1; Intercellular Junctions; Leukotriene B4; Mice; Mice, Knockout; Neutrophils; Plasma; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha

Acute transplant rejection is the leading cause of graft loss in the first months after kidney transplantation. Lipoxygenase products mediate pro- and anti-inflammatory actions and thus we aimed to correlate the histological reports of renal transplant biopsies with urinary lipoxygenase products concentrations to evaluate their role as a diagnostic marker. This study included a total of 34 kidney transplant recipients: 17 with an acute transplant rejection and 17 controls. LTE4, LTB4, 12-HETE and 15-HETE concentrations were measured by enzyme immunoassay. Urinary lipoxygenase product concentrations were not significantly changed during an acute allograft rejection. Nevertheless, LTB4 concentrations correlated significantly with the body temperature (P ≤ 0.05) 3 months after transplantation, and 12- and 15-HETE concentrations correlated significantly with renal function (P ≤ 0.05) 2 weeks after transplantation. In conclusion, our data show a correlation for LTB4 with the body temperature 3 months after transplantation and urinary 12- and 15-HETE concentrations correlate positively with elevated serum creatinine concentrations but do not predict acute allograft rejection.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Acute Disease; Adult; Body Temperature; Female; Graft Rejection; Humans; Hydroxyeicosatetraenoic Acids; Kidney; Kidney Transplantation; Leukotriene B4; Leukotriene E4; Lipoxygenase; Male; Middle Aged

Mechanisms underlying delays in resolution programs of inflammation are of interest for many diseases. Here, we addressed delayed resolution of inflammation and identified specific microRNA (miR)-metabolipidomic signatures. Delayed resolution initiated by high-dose challenges decreased miR-219-5p expression along with increased leukotriene B(4) (5-fold) and decreased (~3-fold) specialized pro-resolving mediators, e.g. protectin D1. Resolvin (Rv)E1 and RvD1 (1 nM) reduced miR-219-5p in human macrophages, not shared by RvD2 or PD1. Since mature miR-219-5p is produced from pre-miRs miR-219-1 and miR-219-2, we co-expressed in human macrophages a 5-lipoxygenase (LOX) 3'UTR-luciferase reporter vector together with either miR-219-1 or miR-219-2. Only miR-219-2 reduced luciferase activity. Apoptotic neutrophils administered into inflamed exudates in vivo increased miR-219-2-3p expression and PD1/NPD1 levels as well as decreased leukotriene B(4). These results demonstrate that delayed resolution undermines endogenous resolution programs, altering miR-219-2 expression, increasing pro-inflammatory mediators and compromising SPM production that contribute to failed catabasis and homeostasis.

Topics: 3' Untranslated Regions; Acute Disease; Animals; Apoptosis; Arachidonate 5-Lipoxygenase; Cells, Cultured; Dinoprostone; Exudates and Transudates; Gene Expression; Humans; Inflammation; Inflammation Mediators; Leukotriene B4; Lipid Metabolism; Macrophages; Male; Mice; MicroRNAs; Neutrophils; Peritonitis; Prostaglandin D2; RNA Interference; Zymosan

The receptor for advanced glycation end products (RAGE) contributes to the inflammatory response in many acute and chronic diseases. In this context, RAGE has been identified as a ligand for the beta(2)-integrin Mac-1 under static in vitro conditions. Because intercellular adhesion molecule (ICAM)-1 also binds beta(2)-integrins, we studied RAGE(-/-), Icam1(-/-), and RAGE(-/-) Icam1(-/-) mice to define the relative contribution of each ligand for leukocyte adhesion in vivo. We show that trauma-induced leukocyte adhesion in cremaster muscle venules is strongly dependent on RAGE and ICAM-1 acting together in an overlapping fashion. Additional in vivo experiments in chimeric mice lacking endothelium-expressed RAGE and ICAM-1 located the adhesion defect to the endothelial compartment. Using microflow chambers coated with P-selectin, CXCL1, and soluble RAGE (sRAGE) demonstrated that sRAGE supports leukocyte adhesion under flow conditions in a Mac-1- but not LFA-1-dependent fashion. A static adhesion assay revealed that wild-type and RAGE(-/-) neutrophil adhesion and spreading were similar on immobilized sRAGE or fibrinogen. These observations indicate a crucial role of endothelium-expressed RAGE as Mac-1 ligand and uncover RAGE and ICAM-1 as a new set of functionally linked adhesion molecules, which closely cooperate in mediating leukocyte adhesion during the acute trauma-induced inflammatory response in vivo.

Topics: Acute Disease; Animals; Cell Adhesion; Cell Shape; Chemotaxis, Leukocyte; Endothelium, Vascular; Humans; Intercellular Adhesion Molecule-1; Leukotriene B4; Ligands; Macrophage-1 Antigen; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases; Muscle, Skeletal; Neutrophils; Radiation Chimera; Recombinant Fusion Proteins; Tumor Necrosis Factor-alpha; Vasculitis; Venules

This study was designed to evaluate the protective effect of the cysteinyl leukotriene receptor antagonist montelukast against pancreatic injury during acute pancreatitis.. Acute pancreatitis was induced in rats by 20-μg/kg (intraperitoneal) cerulein given at 1-hour intervals within 4 hours. Montelukast was administered intraperitoneally at a dose of 10 mg/kg 15 minutes before the first cerulein injection. Six hours after the cerulein or saline injections, the animals were killed by decapitation. Blood samples were collected to analyze amylase, lipase, and the proinflammatory cytokines tumor necrosis factor α and interleukin 1β. Pancreas tissues were taken for the determination of tissue glutathione and malondialdehyde levels and Na,K-adenosine triphosphatase and myeloperoxidase activities. The extent of tissue injury was analyzed microscopically.. Acute pancreatitis caused significant decreases in tissue glutathione level and Na,K-adenosine triphosphatase activity, which were accompanied with significant increases in the pancreatic malondialdehyde level, myeloperoxidase activity, and plasma cytokine level. On the other hand, montelukast treatment reversed all these biochemical indices and histopathological alterations that were induced by cerulein.. These results suggest that cysteinyl leukotrienes may be involved in the pathogenesis of acute pancreatitis and that the cysteinyl leukotriene receptor antagonist, montelukast, might be of therapeutic value for treatment of acute pancreatitis.

Topics: Acetates; Acute Disease; Animals; Ceruletide; Cyclopropanes; Cytokines; Female; Glutathione; Leukotriene Antagonists; Leukotriene B4; Lipid Peroxidation; Male; Pancreas; Pancreatitis; Peroxidase; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Leukotriene; Sodium-Potassium-Exchanging ATPase; Sulfides

The authors investigated the role of leukotrienes (LTs) in the pathogenesis of silica-induced pulmonary fibrosis in mice during the progression from acute to chronic phases. Intratracheal instillation of silica particles induced progressive pulmonary fibrosis. The tissue content of cysteinyl (Cys) LTs and LTB(4) was markedly increased in the acute phase after silica instillation, concurrently with the up-regulation of LTB(4) receptor, transforming growth factor (TGF)-beta1, and tumor necrosis factor (TNF)-alpha, along with down-regulation of the CysLT type 2 receptor. Importantly, the tissue content of CysLTs and mRNA levels of TGF-beta1 and TNF-alpha were increased in the fibrotic lung in the chronic phase. Furthermore, strong immunohistochemical staining for the CysLT type 1 receptor, TNF-alpha, and TGF-beta1, but not for the CysLT type 2 receptor, was codetected in the pathological lesions during both acute and chronic phases. These findings suggest that an increase in LT production in the lung and modulation of homeostatic balance among LT receptors may contribute to the progression of pulmonary fibrosis.

Topics: Acute Disease; Animals; Bronchoalveolar Lavage Fluid; Cysteine; Disease Models, Animal; Disease Progression; Female; Hydroxyproline; Immunohistochemistry; Leukotriene B4; Leukotrienes; Lung; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Receptors, Leukotriene; Receptors, Leukotriene B4; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Silicon Dioxide; Time Factors; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

We investigated the effect of nitric oxide synthase (NOS) inhibition on polymorphonuclear cell (PMN) influx in zymosan or lipopolysaccharide (LPS)-induced arthritis and peritonitis.. Wistar rats received intra-articular (i.art.) zymosan (30-1000 microg) or LPS (1-10 microg). Swiss C57/Bl6 mice genetically deficient in intercellular adhesion molecule-1 (ICAM-1(-/-)) or in beta(2)-integrin (beta(2)-integrin(-/-)) received zymosan either i.art. or i.p. PMN counts, leukotriene B(4) (LTB(4)), tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) levels were measured in joint and peritoneal exudates. Groups received the NOS inhibitors N(G)-nitro-L-arginine methyl ester (LN), nitro-L-arginine, N-[3-(aminomemethyl)benzyl] acetamide or aminoguanidine, prior to zymosan or LPS, given i.p. or s.c. in the arthritis and peritonitis experiments respectively. A group of rats received LN locally (i.art. or i.p.), 30 min prior to 1 mg zymosan i.art.. Systemic or local NOS inhibition significantly prevented PMN migration in arthritis while increasing it in peritonitis, regardless of stimuli, concentration of NOS inhibitors and species. NOS inhibition did not alter TNF-alpha and IL-10 but decreased LTB(4) in zymosan-induced arthritis. LN administration significantly inhibited PMN influx into the joints of ICAM-1(-/-) and beta(2)-integrin(-/-) mice with zymosan-arthritis, while not altering PMN influx into the peritoneum of mice with zymosan-peritonitis.. Nitric oxide has a dual modulatory role on PMN influx into joint and peritoneal cavities that is stimulus- and species-independent. Differences in local release of LTB(4) and in expression of ICAM-1 and beta(2)-integrin account for this dual role of NO on PMN migration.

Topics: Acute Disease; Animals; Arthritis; CD18 Antigens; Cell Movement; Intercellular Adhesion Molecule-1; Interleukin-10; Joints; Leukotriene B4; Lipopolysaccharides; Male; Mice; Mice, Knockout; Neutrophil Infiltration; Nitric Oxide; Nitric Oxide Synthase; Peritoneal Cavity; Peritonitis; Rats; Rats, Wistar; Species Specificity; Tumor Necrosis Factor-alpha; Zymosan

Leukotrienes (LTs) are proinflammatory lipid mediators synthesized by the conversion of arachidonic acid (AA) to LTA(4) by the enzyme 5-lipoxygenase (5-LO) in the presence of 5-LO-activating protein (FLAP). 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103) is a novel selective FLAP inhibitor in development for the treatment of respiratory conditions such as asthma. In a rat ex vivo whole-blood calcium ionophore-induced LTB(4) assay, AM103 (administered orally at 1 mg/kg) displayed >50% inhibition for up to 6 h with a calculated EC(50) of approximately 60 nM. When rat lung was challenged in vivo with calcium ionophore, AM103 inhibited LTB(4) and cysteinyl leukotriene (CysLT) production with ED(50) values of 0.8 and 1 mg/kg, respectively. In this model, the EC(50) derived from plasma AM103 was approximately 330 nM for inhibition of both LTB(4) and CysLT. In an acute inflammation setting, AM103 displayed dose-dependent inhibition of LTB(4), CysLT, and plasma protein extravasation induced by peritoneal zymosan injection. In a model of chronic lung inflammation using ovalbumin-primed and challenged BALB/c mice, AM103 reduced the concentrations of eosinophil peroxidase, CysLTs, and interleukin-5 in the bronchoalveolar lavage fluid. Finally, AM103 increased survival time in mice exposed to a lethal intravenous injection of platelet-activating factor. In summary, AM103 is a novel, potent and selective FLAP inhibitor that has excellent pharmacodynamic properties in vivo and is effective in animal models of acute and chronic inflammation and in a model of lethal shock.

Topics: 5-Lipoxygenase-Activating Proteins; Acute Disease; Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Carrier Proteins; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Extravasation of Diagnostic and Therapeutic Materials; Female; Humans; Indoles; Inflammation; Leukotriene B4; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Pneumonia; Propionates; Rats; Rats, Sprague-Dawley; Zymosan

Chemokine receptors are G-protein coupled receptors (GPCRs) phosphorylated by G-protein receptor kinases (GRKs) after ligand-mediated activation. We hypothesized that GRK subtypes differentially regulate granulocyte chemotaxis and clinical disease expression in the K/BxN model.. Clinical, histologic, and cytokine responses in GRK6-/-, GRK5-/-, GRK2+/-, and wildtype mice were evaluated using K/BxN serum transfer. Granulocyte chemotaxis was analyzed by transendothelial migration assays.. Both GRK6-/- and GRK2+/- mice had increased arthritis disease severity (p<0.001); whereas GRK5-/- was not different from controls. Acute weight loss was enhanced in GRK6-/- and GRK2+/- mice (p<0.001, days 3-10). However, GRK6-/- mice uniquely had more weight loss (>10%), elevated serum IL-6, and enhanced migration toward LTB4 and C5a in vitro.. GRK6 and -2, but not GRK5, are involved in the pathogenesis of acute arthritis in the K/BxN model. In particular, GRK6 may dampen inflammatory responses by regulating granulocyte trafficking toward chemoattractants.

Topics: Acute Disease; Animals; Arthritis; Arthritis, Experimental; Chemotaxis, Leukocyte; Complement C5a; G-Protein-Coupled Receptor Kinase 2; G-Protein-Coupled Receptor Kinases; Granulocytes; Interleukin-6; Leukotriene B4; Male; Mice; Mice, Inbred C57BL; Mice, Knockout

We have recently shown that the leukotriene B(4) (LTB(4))-BLT1 pathway is important in early effector T-cell recruitment in mouse models of inflammation. Here we characterize the phenotype and function of human peripheral blood BLT1(+) T cells in health and illustrate their involvement in asthma and acute infection. In healthy individuals, BLT1(+) T cells are a rare peripheral blood T-cell population enriched for the activation markers CD38 and HLA-DR. Compared with BLT1(-) T cells, a larger proportion of peripheral blood BLT1(+) T cells express the effector cytokines IFNgamma and IL-4 and inflammatory chemokine receptors, CCR1, CCR2, CCR6, and CXCR1. Consequently, in healthy individuals peripheral blood BLT1(+) T cells are a rare antigen-primed T-cell subset with unique phenotypic, migratory, and functional properties. BLT1 expression on T cells is tightly regulated by inflammation and only transiently expressed after naive T-cell activation by dendritic cells. Although rare in the peripheral blood of healthy individuals, BLT1(+) T cells are markedly increased in frequency in the peripheral blood in response to acute Epstein-Barr virus (EBV) infection and moderately increased in the airways of asymptomatic allergic asthmatics. Our studies provide novel insights into the LTB(4)-BLT1 lipid chemoattractant pathway in human T-cell responses, and how it may link innate and adaptive immunity.

Topics: Acute Disease; ADP-ribosyl Cyclase 1; Asthma; Bronchoalveolar Lavage Fluid; Case-Control Studies; Cells, Cultured; Epstein-Barr Virus Infections; Herpesvirus 4, Human; HLA-DR Antigens; Humans; Inflammation; Interferon-gamma; Interleukin-4; Leukotriene B4; Lymphocyte Activation; Protein Serine-Threonine Kinases; Receptors, CCR2; Receptors, CCR6; Receptors, Chemokine; Receptors, Interleukin-8A; Receptors, Leukotriene B4; Receptors, Purinergic P2; T-Lymphocytes

Leptin is an adipocyte-derived hormone that declines dramatically during fasting and plays a pivotal role in the neuroendocrine response to starvation. Previously, we employed leptin-deficient (ob/ob) mice to identify an important role for leptin in the host defense against Klebsiella pneumonia.. To assess the effects of fasting on the innate immune response against pneumococcal pneumonia and to determine the effects of maintaining circulating leptin levels on host defense in fasted mice.. C57BL/6 mice were either fed ad libitum or fasted for 48 h and given an intraperitoneal injection of saline or recombinant leptin (1 microg/g of body weight) twice daily for 48 h before bacterial challenge. Mice were challenged with 10(5) cfu of Streptococcus pneumoniae via the intranasal route.. Lung homogenate S. pneumoniae burden was nearly 20-fold greater in the fasted as compared with fed mice. The impairment in bacterial clearance observed in fasted animals was associated with reduced bronchoalveolar lavage neutrophil counts and interleukin-6 and macrophage inflammatory protein-2 levels. Alveolar macrophages from fasted animals also exhibited defective phagocytosis and killing of S. pneumoniae and reduced calcium-ionophore-stimulated leukotriene B(4) synthesis in vitro. In contrast, the provision of exogenous leptin to fasted animals restored bacterial clearance, bronchoalveolar lavage levels of neutrophils and cytokines, alveolar macrophage bacterial killing, and leukotriene B(4) synthesis.. These results suggest that reduced leptin levels substantially contribute to the suppression of pulmonary antibacterial host defense during starvation and that administration of this adipokine may be of therapeutic benefit clinically.

Topics: Acute Disease; Animals; Blood Glucose; Body Weight; Bronchoalveolar Lavage; Corticosterone; Disease Models, Animal; Fasting; Interleukin-6; Leptin; Leukocytes; Leukotriene B4; Lung; Mice; Mice, Inbred C57BL; Neutrophils; Phagocytosis; Pneumonia, Pneumococcal; Sodium Chloride; Starvation; Streptococcus pneumoniae

Staphylococcus aureus is a gram-positive bacterium that produces several enterotoxins, which are responsible for most part of pathological conditions associated to staphylococcal infections, including lung inflammation. This study aimed to investigate the underlying inflammatory mechanisms involved in leukocyte recruitment in rats exposed to staphylococcal enterotoxin B (SEB). Rats were anesthetized with pentobarbital sodium and intratracheally injected with either SEB or sterile phosphate-buffered saline (PBS, 0.4 ml). Airways exposition to SEB (7.5-250 ng/trachea) caused a dose- and time-dependent neutrophil accumulation in BAL fluid, the maximal effects of which were observed at 4 h post-SEB exposure (250 ng/trachea). Eosinophils were virtually absent in BAL fluid, whereas mononuclear cell counts increased only at 24 h post-SEB. Significant elevations of granulocytes in bone marrow (mature and immature forms) and peripheral blood have also been detected. In BAL fluid, marked elevations in the levels of lipid mediators (LTB(4) and PGE(2)) and cytokines (TNF-alpha, IL-6 and IL-10) were observed after SEB instillation. The SEB-induced neutrophil accumulation in BAL fluid was reduced by pretreatment with dexamethasone (0.5 mg/kg), the COX-2 inhibitor celecoxib (3 mg/kg), the selective iNOS inhibitor compound 1400 W (5 mg/kg) and the lipoxygenase inhibitor AA-861 (200 microg/kg). In separate experiments carried out with rat isolated peripheral neutrophils, SEB failed to induce neutrophil adhesion to serum-coated plates and chemotaxis. In conclusion, rat airways exposition to SEB causes a neutrophil-dependent lung inflammation at 4 h as result of the release of proinflammatory (NO, PGE(2), LTB(4), TNF-alpha, IL-6) and anti-inflammatory mediators (IL-10).

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Benzoquinones; Bone Marrow; Bronchoalveolar Lavage Fluid; Celecoxib; Chemotaxis, Leukocyte; Cytokines; Dexamethasone; Dinoprostone; Dose-Response Relationship, Immunologic; Enterotoxins; Intubation, Intratracheal; Leukocyte Count; Leukotriene B4; Lipoxygenase Inhibitors; Male; Neutrophils; Pneumonia, Staphylococcal; Pyrazoles; Rats; Rats, Wistar; Sulfonamides; Time Factors

The participation of 5-lipoxygenase (5-LO) in the development of atherosclerosis has been suggested by recent studies. However, a role for 5-LO as a modulator of atherosclerotic plaque instability has not been previously reported in humans. Thus, the aims of this study was to analyze the expression of 5-LO in human carotid plaques and to investigate the mechanism by which this enzyme could lead to plaque instability and rupture.. We obtained atherosclerotic plaques from 60 patients undergoing carotid endarterectomy. We divided the plaques into symptomatic and symptomatic according to clinical evidence of plaque instability. Clinical evidence of plaque instability was provided by the assessment of recent ischemic symptoms attributable to the stenosis and by the presence of ipsilateral cerebral lesion(s) determined by computed tomography. Plaques were analyzed for CD68+ macrophages, CD3+ T cells, alpha-actin+ smooth muscle cells, 5-LO, cyclooxygenase 2, matrix metalloproteinase (MMP)-2, and MMP-9 by immunohistochemical, immunoblotting, and densitometric analyses. MMP activity was assessed by zymography. Leukotriene (LT) B4 and collagen were quantified by ELISA and Sirius red polarization, respectively. The percentage of macrophage-rich and T-cell-rich areas was larger in symptomatic compared with asymptomatic patients (25+/-6% versus 8+/-4%, P<0.0001, and 74+/-17 versus 18+/-4 cell/mm2, P<0.003). 5-LO expression was higher in symptomatic compared with asymptomatic plaques (24+/-4% versus 6+/-3%, P<0.0001) and was associated with increased MMP-2 and MMP-9 expression (27+/-4% versus 7+/-3%, P<0.0001, and 29+/-5% versus 8+/-2%, P<0.0001) and activity and with decreased collagen content (6.9+/-2.4% versus 17.8+/-3.1%, P<0.01). Immunofluorescence showed that 5-LO and MMPs colocalize in activated macrophages. Notably, higher 5-LO in symptomatic plaques correlated with increased LTB4 production (18.15+/-3.56 versus 11.27+/-3.04 ng/g tissue, P<0.0001).. The expression of 5-LO is elevated in symptomatic compared with asymptomatic plaques and is associated with acute ischemic syndromes, possibly through the generation of LTB4, subsequent MMP biosynthesis, and plaque rupture.

Topics: Acute Disease; Aged; Arachidonate 5-Lipoxygenase; Brain Ischemia; Carotid Artery Diseases; Cells, Cultured; Collagen; Female; Humans; Leukotriene B4; Macrophages; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Rupture; Signal Transduction; Vasculitis, Central Nervous System

Acute inflammation can be considered in terms of a series of checkpoints where each phase of cellular influx, persistence, and clearance is controlled by endogenous stop and go signals. It is becoming increasingly apparent that in addition to initiating the inflammatory response, eicosanoids may also mediate resolution. This suggests there are two phases of arachidonic acid release: one at onset for the generation of proinflammatory eicosanoids and one at resolution for the synthesis of proresolving eicosanoids. What is unclear is the identity of the phospholipase (PLA2) isoforms involved in this biphasic release of arachidonic acid. We show here that type VI iPLA2 drives the onset of acute pleurisy through the synthesis of PGE2, LTB4, PAF, and IL-1beta. However, during resolution there is a switch to a sequential induction of first sPLA2 (types IIa and V) that mediates the release of PAF and lipoxin A4, which, in turn, are responsible for the subsequent induction of type IV cPLA2 that mediates the release of arachidonic acid for the synthesis of proresolving prostaglandins. This study is the first of its kind to address the respective roles of PLA2 isoforms in acute resolving inflammation and to identify type VI iPLA2 as a potentially selective target for the treatment of inflammatory diseases.

Topics: Acute Disease; Animals; Arachidonic Acid; Carrageenan; Cells, Cultured; Convalescence; Corticosterone; Cyclooxygenase 2; Disease Progression; Enzyme Induction; Epithelial Cells; Fibroblasts; Group II Phospholipases A2; Group IV Phospholipases A2; Group V Phospholipases A2; Group VI Phospholipases A2; Interleukin-1; Isoenzymes; Leukotriene B4; Lipoxins; Macrophages; Male; Phospholipases A; Phospholipases A2; Platelet Activating Factor; Pleurisy; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar

We prospectively studied the levels of eicosanoids in intubated patients with severe bronchiolitis and compared them to electively intubated non-infected infants. LeukotrieneE(4) (LTE(4)), leukotrieneB(4) (LTB(4)), and prostaglandinE(2) (PGE(2)) levels were significantly increased (P <.01) from endotracheal (ET) aspirates of infants with bronchiolitis compared with controls, as were urinary LTE(4) levels (P <.001). We conclude that eicosanoids are increased in the tracheal aspirates and urine of children with bronchiolitis.

Topics: Acute Disease; Bronchiolitis, Viral; Case-Control Studies; Child, Preschool; Dinoprostone; Female; Humans; Infant; Intubation, Intratracheal; Leukotriene B4; Leukotriene E4; Male; Prospective Studies; Respiratory Syncytial Virus Infections

Non-invasive diagnostic tools to evaluate the severity of acute, radiation-induced proctitis are not readily available. The faecal excretion of eight markers of gut inflammation was therefore examined. Five proteins and three lipid derivates were analysed in sequential stool samples taken before and during radiation therapy.. Stool samples from 15 patients with prostate cancer scheduled for radiation therapy were examined. Pretreatment and in-treatment samples (2nd and 6th weeks) were measured by enzyme-linked immunosorbent assay (ELISA) (calprotectin, lactoferrin, transferrin, leukotriene B4, prostaglandin E2, thromboxane B2 and TNF alpha) or nephelometry (alpha 1-antitrypsin).. Calprotectin and lactoferrin concentrations increased significantly during radiation treatment (P = 0.0005 and P = 0.019). Transferrin was detected in only 9 out of 45 samples. There were no changes in tumour necrosis factor alpha (TNF alpha), leukotriene B4, prostaglandin E2 and thromboxane B2 during treatment. alpha 1-antitrypsin could not be detected in any sample.. This study indicates that faecal calprotectin and lactoferrin concentrations could be markers of acute, radiation-induced proctitis. Patient compliance and stability of the markers make this a promising method for clinical research. Eicosanoids could be measured in stool samples, but the concentrations did not increase with increasing radiation dose.

Topics: Acute Disease; Aged; alpha 1-Antitrypsin; Biomarkers; Dinoprostone; Enzyme-Linked Immunosorbent Assay; Feces; Humans; Lactoferrin; Leukocyte L1 Antigen Complex; Leukotriene B4; Male; Middle Aged; Pilot Projects; Proctitis; Prostatic Neoplasms; Radiation Injuries; Transferrin; Tumor Necrosis Factor-alpha

The involvement of arachidonic acid (AA) and PGE2 during the E. coli lipopolysaccharide (LPS)-induced acute lung injury was investigated.. Adult male Wistar rats were used. For in vitro studies, rat neutrophils, bronchoalveolar lavage (BAL) fluid, and lug vascular endothelium were used, as described below.. Rats were given an intratracheal injection of LPS (750 microg).. Total and differential cell counts in BAL fluid; enzyme-linked immunoassay (ELISA) analyses of TNF-alpha, IL-1beta, LTB4 and PGE2 in BAL, and immunohistochemical detection of ICAM-1 on lung vascular endothelium were performed six h after LPS challenge. Fatty acid composition of blood neutrophils and plasma was analyzed by HPLC.. Rats instilled with LPS presented a sixty three-fold increase in the number of neutrophils in BAL (from 0.5 x 10(6) to 31.5 x 10(6) cells), accompanied by increased levels of TNF-alpha and IL-1beta (p < 0.001), and a three-fold increase in ICAM-1 expression on vascular endothelium. The content of AA in blood neutrophils was reduced by 50%, whereas the level of PGE2 in BAL was increased by 3.5 fold, without changes in the levels of LTB4.. These findings suggest that AA and PGE2 are associated with LPS challenge.

Topics: Acute Disease; Animals; Arachidonic Acid; Bronchoalveolar Lavage Fluid; Dinoprostone; Escherichia coli; Immunohistochemistry; Intercellular Adhesion Molecule-1; Interleukin-1; Leukocyte Count; Leukotriene B4; Lipopolysaccharides; Lung; Male; Neutrophils; Pneumonia; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Transfusion of PLT concentrates may cause TRALI, a life-threatening reaction that has been linked to the infusion of anti-WBC immunoglobulins or older, stored PLTs that contain bioactive lipids. We hypothesize that lipids generated during storage of PLTs cause TRALI in a two-event animal model.. Plasma from both whole-blood PLTs (WB-PLTs) and apheresis PLTs (A-PLTs) was isolated on Day 0 (D.0) and Day 5 (D.5) of storage and heat-treated before use. Rats were pretreated with saline or 2 mg per kg endotoxin (LPS), anesthetized, and the lungs were ventilated, isolated, and perfused with saline or 5-percent PLT plasma. Pulmonary artery pressure, pulmonary edema, and leukotriene B4 levels (perfusate) were measured.. Plasma from D.5, but not D.0, of the identical WB-PLT and A-PLT units caused injury in lungs from LPS-pretreated rats (LPS/D.5) evidenced by increases in pulmonary edema and leukotriene B4 (p < 0.05). Lipid extracts and purified lipids from D.5 PLT plasma also elicited injury in lungs from LPS-pretreated rats (p < 0.05). Saline/D.5 plasma or lipids or LPS/D.0 did not cause pulmonary edema. Prestorage WBC reduction was ineffective in inhibiting TRALI.. PLT-induced TRALI may be the result of two events: 1) the clinical condition of the patient and 2) the infusion of lipids in stored PLTs.

Topics: Acute Disease; Adult; Animals; Blood Physiological Phenomena; Blood Platelets; Blood Preservation; Blood Pressure; Humans; In Vitro Techniques; Leukapheresis; Leukotriene B4; Lipids; Lung; Lung Diseases; Male; Perfusion; Pulmonary Artery; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Transfusion Reaction

A new lipidic acid-amido ether derivative (LAAE-14) able to reduce dose-dependently the calcium increases mediated either by calcium ionophore ionomycin, by the endoplasmic reticular Ca(2+)-ATPase inhibitor thapsigargin, or by the chemotactic tripeptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), in human neutrophils as well as in murine peritoneal macrophages, but not ATP, has been evaluated as a potential anti-inflammatory drug. This compound attenuated leukocyte activation by means of its inhibitory effect on the respiratory burst elicited in both types of cells by 12-O-tetradecanoyl phorbol 13-acetate, by inhibition of the degranulation process induced by cytochalasin B+fMLP or cytochalasin B+platelet activating factor, as well as by reduction of leukotriene B(4) synthesis induced by the calcium ionophore A23187. In addition, in zymosan-stimulated mouse peritoneal macrophages LAAE-14 caused a potent inhibition of nitrite and prostaglandin E(2) production. This compound exerted acute and chronic anti-inflammatory effects by oral route, that may be related with several mechanisms such as attenuation of leukocyte activation, inhibition of inducible nitric oxide synthase, cyclo-oxygenase-2 and cytosolic phospholipase A(2) expression as well as reduction in tumour necrosis factor-alpha production. Its anti-inflammatory profile is clearly correlated with its behavior as inhibitor of intracellular calcium mobilization. The profile and potency of this compound may have relevance for the inhibition of the inflammatory response at different levels and may represent a new approach to the development of new anti-inflammatory drugs.

Topics: Acute Disease; Animals; Arthritis, Experimental; Calcium; Carrageenan; Cell Movement; Chronic Disease; Dinoprostone; Disease Models, Animal; Edema; Humans; Inflammation; Leukotriene B4; Luminescent Measurements; Macrophages, Peritoneal; Mice; Neutrophils; Nitrites; Pancreatic Elastase; Rats; Tumor Necrosis Factor-alpha; Zymosan

Leukotriene B4 (LTB4) is a potent chemoattractant for myeloid leukocytes, which express BLT1, the high-affinity receptor for LTB4. We report here that BLT1 is induced substantially in CD8+ effector T cells and at lower amounts in CD8+ central memory T cells. LTB4 elicited BLT1-dependent chemotaxis in effector cells, but not in naive or central memory cells. Intravital microscopy showed that BLT1 signaling induced rapid integrin-mediated arrest of rolling effector and central memory cells in postcapillary venules. In competitive homing experiments, wild-type effector cells were three times more efficient at migrating to the inflamed peritoneal cavity than were BLT-deficient effector cells. These results identify LTB4-BLT1 as a potent nonchemokine pathway for cytotoxic effector cell traffic.

Topics: Acute Disease; Animals; Chemotaxis, Leukocyte; Flow Cytometry; Immunologic Memory; Integrins; Leukotriene B4; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Peritonitis; Receptors, Leukotriene B4; Receptors, Lymphocyte Homing; Signal Transduction; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory

Directed migration of polymorphonuclear neutrophils (PMN) is required for adequate host defense against invading organisms and leukotriene B(4) (LTB(4)) is one of the most potent PMN chemoattractants. LTB(4) exerts its action via binding to BLT1, a G protein-coupled receptor. G protein-coupled receptors are phosphorylated by G protein-coupled receptor kinases (GRK) in an agonist-dependent manner, resulting in receptor desensitization. Recently, it has been shown that the human BLT1 is a substrate for GRK6. To investigate the physiological importance of GRK6 for inflammation and LTB(4) signaling in PMN, we used GRK6-deficient mice. The acute inflammatory response (ear swelling and influx of PMN into the ear) after topical application of arachidonic acid was significantly increased in GRK6(-/-) mice. In vitro, GRK6(-/-) PMN showed increased chemokinetic and chemotactic responses to LTB(4). GRK6(-/-) PMN respond to LTB(4) with a prolonged increase in intracellular calcium and prolonged actin polymerization, suggesting impaired LTB(4) receptor desensitization in the absence of GRK6. However, pre-exposure to LTB(4) renders both GRK6(-/-) as well as wild-type PMN refractory to restimulation with LTB(4), indicating that the presence of GRK6 is not required for this process to occur. In conclusion, GRK6 deficiency leads to prolonged BLT1 signaling and increased neutrophil migration.

Topics: Actins; Acute Disease; Administration, Topical; Animals; Arachidonic Acid; Calcium Signaling; Chemotaxis, Leukocyte; Ear, External; Edema; G-Protein-Coupled Receptor Kinases; Inflammation; Leukotriene B4; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Protein Serine-Threonine Kinases; Receptors, G-Protein-Coupled; Signal Transduction; Up-Regulation

Persistent accumulation of inflammatory cells in the udder, with neutrophils being the predominant cell type, is a characteristic feature of chronic mastitis in dairy cows. Leukotriene (LT) B4 is a potent chemotactic agent, known to induce recruitment and accumulation of neutrophils in the bovine mammary gland. The LTB4-stimulated neutrophil functional responses are closely opposed by lipoxin (LX) A4, which promotes the resolution of inflammation. We thus hypothesized that the chronic inflammation of the udder could be associated with an unfavorable ratio between these two eicosanoids and that the persistence of neutrophil accumulation could be due to an increase in LTB4 synthesis and/or an impaired LXA4 production. In an attempt to verify this hypothesis, we first measured LXA4, LTB4, and their ratio in the milk of healthy and acute and chronic mastitis-affected quarters. Next, we studied the relationships between these variables and the degree of udder inflammation as assessed by somatic cell count measurement. The LTB4 concentration was low in healthy quarters, drastically increased in acute mastitis, and reached intermediate levels in chronic mastitis-affected quarters. However, whereas LXA4 concentration was highly increased in acute mastitis, healthy and chronic quarters had similarly low values. The LXA4:LTB4 ratio was thus significantly lower in chronic mastitis-affected cows. The LTB4 concentrations measured in chronic quarters were highly correlated to somatic cell count and to milk neutrophil and macrophage numbers. A weaker correlation was observed between LXA4 and these variables. For both eicosanoids, the highest correlation was observed with the number of neutrophils. These results show the existence of an LXA4:LTB4 imbalance in chronic mastitis-affected cows because of low LXA4 concentrations. Further studies are needed to determine whether administration of LX or stable analogs could have therapeutic potential in the control of chronic bovine mastitis.

Topics: Acute Disease; Animals; Case-Control Studies; Cattle; Cell Count; Chronic Disease; Female; Leukotriene B4; Lipoxins; Macrophages; Mammary Glands, Animal; Mastitis, Bovine; Milk; Neutrophils

Investigations were carried out to study the production of factors associated with the innate immune response in the systemic and mucosal compartments in adults and children infected with Vibrio cholerae O1 and V. cholerae O139. The levels of nonspecific mediators of the innate defense system, i.e., prostaglandin E(2) (PGE(2)), leukotriene B(4) (LTB(4)), and lactoferrin (Lf), as well as myeloperoxidase (MPO), were elevated at the acute stage of the disease in stools obtained from both O1- and O139-infected adults and children. In the systemic compartment, the levels of Lf were increased after onset of disease, which in children remained elevated up to convalescence compared to the healthy controls. Increased concentrations of C-reactive protein were seen in the sera of adult cholera patients at the acute stage of infection. Elevated levels of the nitric oxide (NO*) metabolites (nitrite and nitrate [NO(2)(-) and NO(3)(-)]) were detected in plasma but not in urine. The activity of the scavenger of reactive oxygen species, superoxide dismutase, was higher in the plasma of adults immediately after the onset of disease, suggesting that an active scavenging of reactive oxygen species was taking place. The concentration of 8-iso-prostaglandin F(2 alpha) remained unchanged in the systemic and mucosal compartments in the study subjects. After the recovery of patients from cholera, the concentration of the majority of the metabolites decreased to baseline levels by day 30 after the onset of infection. Immunohistochemical staining showed increased tissue expression of MPO, Lf, and inducible nitric oxide synthase at the acute stage in the duodenal biopsies of adults and rectal biopsies obtained from children with cholera. Very little difference was seen in the levels of the different inflammatory mediators in patients infected with V. cholerae O1 or the encapsulated V. cholerae O139. In summary, these results suggest that elevated concentrations of Lf, MPO, PGE(2), LTB(4), and NO*, as well as other metabolites, during the acute stage of the disease indicate that the innate defense system, as well as the inflammatory process, is activated in both adults and pediatric patients infected with V. cholerae O1 and O139.

Topics: Acute Disease; Adult; Biopsy; C-Reactive Protein; Child, Preschool; Cholera; Creatinine; Dinoprostone; Feces; Female; Humans; Inflammation Mediators; Intestinal Mucosa; Lactoferrin; Leukocyte Count; Leukotriene B4; Male; Nitrates; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrites; Oxidative Stress; Peroxidase; RNA, Messenger; Superoxide Dismutase; Vibrio cholerae

There are little data describing noncellular changes in bronchial inflammation during exacerbations of chronic bronchitis. The relationship between sputum colour and airway inflammation at presentation has been assessed during an exacerbation in patients with chronic bronchitis and a primary care diagnosis of chronic obstructive pulmonary disease. Sputum myeloperoxidase, neutrophil elastase, leukotriene B4 (LTB4), interleukin-8 (IL-8), sol:serum albumin ratio and serum C-reactive protein were measured in patients presenting with an exacerbation and mucoid (n = 27) or purulent sputum (n = 42). Mucoid exacerbations were associated with little bronchial or systemic inflammation at presentation, and sputum bacteriology was similar to that obtained in the stable state. Purulent exacerbations were associated with marked bronchial and systemic inflammation (p < 0.025 for all features) and positive sputum cultures (90%). Resolution was related to a significant reduction in LTB4 (p < 0.01), but no change in IL-8, suggesting that LTB4 may be more important in neutrophil recruitment in these mild, purulent exacerbations. In the stable state, IL-8 remained higher in patients who had experienced a purulent exacerbation (2p < 0.02). The presented results indicate that exacerbations of chronic bronchitis, defined by sputum colour, differ in the degree of bronchial and systemic inflammation. Purulent exacerbations are related to bacterial infection, and are associated with increased neutrophilic inflammation and increased leukotriene B4 concentrations.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Bacterial Infections; Bronchitis; Female; Humans; Inflammation Mediators; Leukotriene B4; Male; Middle Aged; Neutrophils; Primary Health Care; Pulmonary Disease, Chronic Obstructive; Sputum

Acute systemic hypoxia produces rapid leukocyte adherence in the rat mesenteric microcirculation, although the underlying mechanisms are not fully known. Hypoxia is known to increase reactive oxygen species (ROS) generation, which could result in formation of the lipid inflammatory mediator leukotriene B(4) (LTB(4)). The goal of this study was to examine the role of LTB(4) in hypoxia-induced microvascular alterations. Using intravital microscopy, we determined the effect of the LTB(4) antagonist, LTB(4)-dimethyl amide (LTB(4)-DMA), on ROS generation and leukocyte adherence in mesenteric venules during hypoxia. Exogenous LTB(4) increased ROS generation to 144 +/- 8% compared with control values and also promoted leukocyte adherence. These responses to LTB(4) were blocked by pretreating the mesentery with LTB(4)-DMA. Leukopenia did not significantly attenuate the LTB(4)-induced increase in ROS generation (142 +/- 12.1%). LTB(4)-DMA substantially, though not completely, reduced hypoxia-induced ROS generation from 66 +/- 18% to 11 +/- 4% above control values. Hypoxia-induced leukocyte adherence was significantly attenuated by LTB(4)-DMA. Our results support a role for LTB(4) in the mechanism of hypoxia-induced ROS generation and leukocyte adherence in the rat mesenteric microcirculation.

Topics: Acute Disease; Animals; Cell Adhesion; Hypoxia; Leukocytes; Leukotriene B4; Male; Mesenteric Veins; Microcirculation; Microscopy, Fluorescence; Oxidants; Oxygen; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Leukotriene B4; Venules

This work studied the effects of hydrocortisone treatment in experimental acute pancreatitis on cytokines, phospholipase A2, and breakdown products of arachidonic acid and survival. Edematous and necrotizing pancreatitis were induced in Wistar rats by cerulein hyperstimulation and retrograde intraductal infusion of sodium taurocholate, respectively. Hydrocortisone (10 mg/kg) was administered intravenously 10 minutes after induction of acute pancreatitis. Serum was assayed for phospholipase A2; interleukin (IL) 1beta, IL-6, IL-10, thromboxane B2; Prostaglandin E2; and leukotriene B4 at five different time points. A significant release of inflammatory mediators was seen only in the severe model. Hydrocortisone powerfully suppressed arachidonic acid breakdown products and only mildly attenuated the systemic increase of phospholipase A2 and pro- and antiinflammatory cytokines. The mortality rate after 72 hr in the severe model was 86%. Hydrocortisone treatment reduced mortality to 13% (P = 0.001; Fisher's exact test). Hydrocortisone seems to be effective in the treatment of the early systemic inflammatory response syndrome associated with severe acute pancreatitis.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Cytokines; Dinoprostone; Disease Models, Animal; Female; Hydrocortisone; Leukotriene B4; Pancreatitis; Rats; Rats, Wistar; Systemic Inflammatory Response Syndrome; Thromboxane B2

Phospholipase D (PLD) hydrolyzes phosphatidylcholine and produces lipid second messengers. Although cellular PLD has recently been recognized as an important signal-transmitting enzyme, the role of PLD in pathophysiologic conditions is largely unknown. In particular, the regulation of PLD in intestinal inflammation has not been previously investigated. The aim of the present study was to elucidate the role of PLD in experimental colitis.. Rats were intracolonically administered acetic acid and assessed for mucosal damage, mucosal PLD activity, mucosal myeloperoxidase activity, mucosal chemiluminescence and luminal concentration of leukotriene B4. Acetic acid treatment induced acute mucosal injury that was maximal at 24 h after treatment.. Mucosal PLD activity was significantly elevated and correlated with mucosal damage. Chemiluminescence in colitic mucosa was inhibited by the addition of ethanol which suppresses the formation of phosphatidic acid catalyzed by PLD.. These results suggest that PLD is activated in experimental colitis in rats and that PLD may play a role in mucosal damage induced by reactive oxygen metabolites.

Topics: Acetates; Acute Disease; Animals; Central Nervous System Depressants; Colitis; Colon; Data Interpretation, Statistical; Disease Models, Animal; Enzyme Activation; Ethanol; Female; Immunoenzyme Techniques; Intestinal Mucosa; Leukotriene B4; Luminescent Measurements; Peroxidase; Phospholipase D; Phospholipids; Rats; Rats, Wistar; Time Factors

Arachidonic acid metabolism by 5-lipoxygenase leads to production of the potent inflammatory mediators, leukotriene (LT) B4 and the cysteinyl LT. Relative synthesis of these subclasses of LT, each with different proinflammatory properties, depends on the expression and subsequent activity of LTA4 hydrolase and LTC4 synthase, respectively. LTA4 hydrolase differs from other proteins required for LT synthesis because it is expressed ubiquitously. Also, in vitro studies indicate that it possesses an aminopeptidase activity. Introduction of cysteinyl LT and LTB4 into animals has shown LTB4 is a potent chemoattractant, while the cysteinyl LT alter vascular permeability and smooth muscle tone. It has been impossible to determine the relative contributions of these two classes of LT to inflammatory responses in vivo or to define possible synergy resulting from the synthesis of both classes of mediators. To address this question, we have generated LTA4 hydrolase-deficient mice. These mice develop normally and are healthy. Using these animals, we show that LTA4 hydrolase is required for the production of LTB4 in an in vivo inflammatory response. We show that LTB4 is responsible for the characteristic influx of neutrophils accompanying topical arachidonic acid and that it contributes to the vascular changes seen in this model. In contrast, LTB4 influences only the cellular component of zymosan A-induced peritonitis. Furthermore, LTA4 hydrolase-deficient mice are resistant to platelet-activating factor, identifying LTB4 as one mediator of the physiological changes seen in systemic shock. We do not identify an in vivo role for the aminopeptidase activity of LTA4 hydrolase.

Topics: Acute Disease; Anaphylaxis; Animals; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Cell Movement; Crosses, Genetic; Cysteine; Dermatitis, Contact; Ear; Epoxide Hydrolases; Fluorescein-5-isothiocyanate; Immunoglobulin E; Inflammation Mediators; Leukotriene B4; Leukotrienes; Lipopolysaccharides; Mice; Mice, Knockout; Neutrophils; Peritonitis; Platelet Activating Factor

Patients with homozygous (PiZ) alpha(1)-antitrypsin (AAT) deficiency have not only low baseline serum AAT levels (approximately 10 to 15% normal) but also an attenuated acute phase response. They are susceptible to the development of premature emphysema but may also be particularly susceptible to lung damage during bacterial exacerbations when there will be a significant neutrophil influx. The purposes of the present study were to assess the inflammatory nature of acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD) in subjects with AAT deficiency, to compare this with COPD patients without deficiency, and to monitor the inflammatory process and its resolution following appropriate antibacterial therapy. At the start of the exacerbation, patients with AAT deficiency had lower sputum AAT (p < 0.001) and secretory leukoprotease inhibitor (SLPI; p = 0.02) with higher elastase activity (p = 0.02) compared with COPD patients without deficiency. Both groups had a comparable acute phase response as assessed by C-reactive protein (CRP) but the AAT-deficient patients had a minimal rise in serum AAT (to < 6 microM). After treatment with antibiotics, in patients with AAT deficiency, there were significant changes in many sputum proteins including a rise in SLPI levels, and a reduction in myeloperoxidase (MPO) and elastase activity (p < 0. 005 for all measures); the sputum chemoattractants interleukin-8 (IL-8) and leukotriene B(4) (LTB(4)) fell (p < 0.01), and protein leak (sputum/serum albumin ratio) became lower (p < 0.01). The changes were rapid and within 3 d of the commencement of antibiotic therapy the biochemical markers had decreased significantly, but took a variable time thereafter to return to baseline values. In conclusion, patients with AAT deficiency had evidence of increased elastase activity at the start of the exacerbation when compared with nondeficient COPD patients which probably reflects a deficient antiproteinase screen (lower sputum AAT and SLPI). The increased bronchial inflammation at presentation resolved rapidly with 14 d of antibiotic therapy.

Topics: Acute Disease; Acute-Phase Reaction; Aged; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Bacterial Infections; Bronchi; C-Reactive Protein; Female; Humans; Inflammation Mediators; Interleukin-8; Leukotriene B4; Lung Diseases, Obstructive; Male; Middle Aged; Pancreatic Elastase; Peroxidase; Phenotype; Proteinase Inhibitory Proteins, Secretory; Proteins; Respiratory Tract Infections; Secretory Leukocyte Peptidase Inhibitor; Serine Proteinase Inhibitors; Serum Albumin; Sputum

Topics: Acute Disease; Animals; Blood Platelets; Disease Models, Animal; In Vitro Techniques; Inflammation; Kinetics; Leukocyte Count; Leukocytes, Mononuclear; Leukotriene B4; Leukotriene E4; Male; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Platelet Count; Rabbits

The role of 5-lipoxygenase metabolites of arachidonic acid in the inflammatory response associated with experimental acute pancreatitis has been evaluated. For this purpose, an experimental necrohemorrhagic pancreatitis was induced in rats by intraductal administration of 5% sodium taurocholate. Neutrophil infiltration was detected in pancreas at 1 and 3 h after the induction of pancreatitis. This was concomitant with increased levels of leukotriene B4 and peptide leukotrienes (C4, D4 and E4). In lung, similar increases in neutrophil infiltration were detected but only 3 h after acute pancreatitis induction, and no changes in leukotriene B4 nor peptide leukotrienes were apparent at this time. These results suggest that after induction of acute pancreatitis, 5-lipoxygenase metabolites could play a role in the inflammatory response in the pancreas, but they are not involved in the inflammatory response in lung.

Topics: Acute Disease; Animals; Disease Models, Animal; Leukotriene B4; Leukotrienes; Lipase; Lung; Male; Neutrophils; Pancreas; Pancreatitis; Peroxidase; Rats; Rats, Wistar; Taurocholic Acid

Persistent polymorphonuclear neutrophil (PMN) recruitment to airway is thought to be an important component of continuing inflammation and progression of chronic destructive lung diseases. Although chemoattractants are required for the PMN to migrate, the nature of the chemoattractants in the airways has not yet been clarified. We therefore investigated the contribution of interleukin-8 (IL-8) and leukotriene-B4 (LTB4) to the chemotactic activity of lung secretions by inhibiting their activity using a monoclonal antibody to IL-8 and an LTB4 receptor antagonist (LY293111 sodium). Fifty-nine sputum samples obtained from 19 patients with bronchiectasis were studied. In preliminary studies the chemotactic responses to IL-8 and LTB4 were found to be additive, and we were able to remove their contribution independently with the appropriate antibody and antagonist. The chemotactic activity of the secretions was related to the macroscopic appearance (mucoid, mucopurulent, and purulent), and this appeared to be related to an increase in IL-8 contribution. Chemotactic activity was reduced by antibiotic therapy and again that seemed to relate to a reduction in the IL-8 contribution. The contributions of LTB4 were similar among the three types of sputum in varying clinical states. These data suggest that LTB4 and IL-8 are important chemotactic factors in lung secretions from such patients, although IL-8 appears to play a more important role during acute exacerbations. These results may be useful in determining therapeutic strategies for chronic destructive lung diseases in the future.

Topics: Acute Disease; Anti-Bacterial Agents; Antibodies, Monoclonal; Benzoates; Bronchiectasis; Bronchitis; Cell Movement; Chemotactic Factors; Chemotaxis, Leukocyte; Chronic Disease; Disease Progression; Female; Humans; Interleukin-8; Leukotriene B4; Male; Middle Aged; Mucus; Neutrophils; Receptors, Leukotriene B4; Reproducibility of Results; Sputum; Suppuration

Neutrophils have been implicated as major contributors to tissue injury in inflammatory bowel disease. In this study, we have assessed the effects of an inhibitor of neutrophil activation and adherence, NPC-18915 (4-¿2-[2-(2-benzofuranyl)phenyl]-(E)-ethenyl¿benzoic acid sodium salt), in models of both acute and reactivated colitis. Acute colitis was induced by intracolonic administration of a hapten. In other rats, colitis was reactivated 6 wk after a bout of acute colitis by subcutaneous administration of the hapten. NPC-18915 given during the first 4 days after induction of acute colitis significantly reduced tissue injury and the incidence of diarrhea and adhesions. When treatment of NPC-18915 was initiated after colitis was firmly established (48 h posthapten), it did not produce a significant effect. NPC-18915 was effective at significantly reducing colonic injury and granulocyte infiltration in the reactivated colitis model, and a similar effect could be observed in rats treated with antineutrophil serum. These results demonstrate that an inhibitor of neutrophil activation is effective in both acute and reactivated colitis, although in the former case, effectiveness is only seen when the drug is given before full establishment of colitis. These results also suggest that neutrophils, are a critical effector cell of hapten-induced colitis in the rat, particularly in the case of reactivated colitis.

Topics: Acute Disease; Animals; Benzoates; Benzofurans; Colitis; Colon; Ferric Compounds; Immunization, Passive; Leukocyte Count; Leukotriene B4; Male; Neutrophils; Rats; Rats, Wistar; Recurrence; Regional Blood Flow

Contact lens induced acute red eye (CLARE) and contact lens induced peripheral ulcer (CLPU) are among the most common contact lens induced inflammatory reactions. Both CLARE and CLPU are characterized by corneal infiltration which indicates the presence of chemoattractants and other inflammatory mediators. The aim of this study was to characterize the cytokine and chemotactic lipid inflammatory mediator profile in the tears of people experiencing CLARE or CLPU. Cytokines IL-1 beta, IL-6, IL-8, GM-CSF and LTB4 in tears were measured by antibody sandwich and competition inhibition enzyme-linked immunosorbent assays (ELISA). Platelet activating factor-like activity was measured by a degranulation assay by measuring the release of labelled serotonin from platelets. The functional role GM-CSF and chemoattractants were determined by flow cytometry and chemotaxis. Increased levels of cytokines and chemoattractants were detected in both CLARE and CLPU tears. CLPU tears showed increased levels of LTB4 (P = 0.002) and PAF-like activity (P = 0.047) whereas CLARE tears showed increased levels of GM-CSF (P = 0.002). IL-8 (P < 0.05). LTB4 (P = 0.002) and PAF-like activity (P = 0.047) compared to control tears. Flow cytometric analysis revealed that incubation of PMN with CLARE tears increased the number of IgA receptors indicating that the GM-CSF in CLARE tears was active. Combinations of suboptimal concentrations (which were found in CLARE and CLPU tears) of IL-8 with either LTB4 or PAF significantly (P < 0.0001) enhanced the chemotactic activity for PMN compared to their individual effects. Our data highlight the possible pathophysiological roles of these inflammatory mediators in leukocyte recruitment and activation during ocular inflammatory responses. The results suggests that GM-CSF, IL-8 and LTB4 are active during corneal pathology and LTB4 or IL-8 may maintain the contact lens induced PMN response in vivo.

Topics: Acute Disease; Analysis of Variance; Cells, Cultured; Contact Lenses; Corneal Ulcer; Cytokines; Dose-Response Relationship, Drug; Flow Cytometry; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Inflammation Mediators; Interleukin-8; Keratitis; Leukotriene B4; Lipids; Neutrophil Activation; Neutrophils; Platelet Activating Factor; Receptors, Fc; Tears

Interleukin-10 (IL-10) is an anti-inflammatory cytokine that downregulates the secretion of pro-inflammatory cytokines and additionally induces the secretion of anti-inflammatory cytokines, thus possibly leading to reduction of chronic inflammation in inflammatory bowel disease. In this study we evaluated the anti-inflammatory effect of IL-10 in a model of acute colitis in rabbits.. Colitis was induced by rectal instillation of formalin, 0.65%, followed by intravenous infusion of 0.85 ml heat-aggregated rabbit immunoglobulin. Rabbits were treated with an intravenous bolus of recombinant human IL-10 (SCH52000), 100 microg/kg (n=14) or 500 microg/kg (n=14), 1 h before induction of colitis (control group, n=12).. High-dose IL-10 improved macroscopic scores of inflammation and decreased tissue myeloperoxidase levels and leukotriene B4 levels in dialysate fluid. Thromboxane B2 and prostaglandin E2 levels remained unaffected.. IL-10 ameliorates acute colitis in this model. Consequently, this anti-inflammatory cytokine may have a role in the therapy of acute inflammatory bowel disease.

Topics: Acute Disease; Animals; Antigen-Antibody Complex; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Enterocolitis; Interleukin-10; Intestinal Mucosa; Leukotriene B4; Male; Rabbits; Random Allocation; Reference Values

The flavonoid morin was tested for anti-inflammatory activity in trinitrobenzenesulfonic acid (TNBS)-induced rat colitis. Rats were pretreated orally with several doses of the flavonoid (5, 10, 25, 100 and 200 mg/kg) 48, 24 and 1 h before and 24 h after colitis induction and examined for colonic damage 48 h after colitis induction. Colonic inflammation was characterized by diffuse hemorrhagic necrosis of the mucosa, bowel wall thickening, impairment of fluid absorption, increase in myeloperoxidase (MPO) activity, enhanced leukotriene B4 (LTB4) synthesis, glutathione depletion and increased levels of malonyldialdehyde (MDA). Morin treatment, at doses ranging from 10 to 200 mg/kg, significantly reduced colonic macroscopic damage. This beneficial effect was also confirmed by inhibition of colonic MPO activity. Several mechanisms may contribute to the protective effect exerted by morin. First, inhibition of colonic LTB4 synthesis is a common feature for all the active doses of the flavonoid. Second, the antioxidant properties of morin, which partially prevented colonic glutathione depletion (at doses of 10 and 25 mg/kg) or inhibited colonic MDA production (at doses of 100 and 200 mg/kg), can collaborate in preventing TNBS-induced inflammation.

Topics: Acute Disease; Administration, Oral; Animals; Antioxidants; Colitis; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Flavonoids; Leukotriene B4; Malondialdehyde; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid

Mac-1 (alphambeta2), a leukocyte adhesion receptor, has been shown in vitro to functionally interact with Fcgamma receptors to facilitate immune complex (IC)-stimulated polymorphonuclear neutrophil (PMN) functions. To investigate the relevance of Mac-1-FcgammaR interactions in IC-mediated injury in vivo, we induced a model of Fc-dependent anti-glomerular basement membrane (GBM) nephritis in wild-type and Mac-1-deficient mice by the intravenous injection of anti-GBM antibody. The initial glomerular PMN accumulation was equivalent in Mac-1 null and wild-type mice, but thereafter increased in wild-type and decreased in mutant mice. The absence of Mac-1 interactions with obvious ligands, intercellular adhesion molecule 1 (ICAM-1), and C3 complement, is not responsible for the decrease in neutrophil accumulation in Mac-1- deficient mice since glomerular PMN accumulation in mice deficient in these ligands was comparable to those in wild-type mice. In vitro studies showed that spreading of Mac-1-null PMNs to IC-coated dishes was equivalent to that of wild-type PMNs at 5-12 min but was markedly reduced thereafter, and was associated with an inability of mutant neutrophils to redistribute filamentous actin. This suggests that in vivo, Mac-1 is not required for the initiation of Fc-mediated PMN recruitment but that Mac-1-FcgammaR interactions are required for filamentous actin reorganization leading to sustained PMN adhesion, and this represents the first demonstration of the relevance of Mac-1-FcgammaR interactions in vivo. PMN-dependent proteinuria, maximal in wild-type mice at 8 h, was absent in Mac-1 mutant mice at all time points. Complement C3-deficient mice also had significantly decreased proteinuria compared to wild-type mice. Since Mac-1 on PMNs is the principal ligand for ic3b, an absence of Mac-1 interaction with C3 probably contributed to the abrogation of proteinuria in Mac-1-null mice.

Topics: Actins; Acute Disease; Animals; Anti-Glomerular Basement Membrane Disease; Basement Membrane; Capillary Permeability; Cell Adhesion; Complement C3b; Complement System Proteins; Endothelium, Vascular; Female; Immune Complex Diseases; Intercellular Adhesion Molecule-1; Isoantibodies; Kidney Glomerulus; Leukotriene B4; Macrophage-1 Antigen; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Immunological; Neutrophils; Proteinuria; Receptors, IgG

The local and systemic release of thromboxane A2, prostaglandin I2, leukotriene B4 (LTB4), tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and interleukin-8 (IL-8) were studied before and after operation in 29 patients with acute and 22 with chronic posttraumatic osteomyelitis. Twenty patients without osteomyelitis, who underwent operations for fractures of the lower extremities, served as controls. Blood and tissue samples from the osteomyelitic and control groups were collected under defined conditions and mediators were determined by radioimmunoassay (thromboxane B2, 6-keto-prostaglandin F1 alpha, LTB4) or by enzyme-linked immunosorbent assay (TNF-alpha, IL-1 beta, and IL-8). In addition, common parameters (leukocyte count, C-reactive protein, temperature) were measured. The best correlation with acute disease activity was given by TNF-alpha, IL-6, IL-8, and LTB4. Plasma levels of these mediators in acute osteomyelitis were significantly increased compared to chronic osteomyelitis and to controls, respectively. Tissue samples from osteomyelitic focus showed significantly increased levels for IL-8, IL-6, TNF-alpha, IL-1 beta, and LTB4 in acute osteomyelitis, whereas the values for TxB2 and 6-keto-prostaglandin F1 alpha were only slightly increased compared to the chronic osteomyelitis group. This study describes the local and systemic liberation of various mediators in acute and chronic posttraumatic osteomyelitis in detail for the first time and provides data for pre- and postoperative monitoring of disease activity and demonstrates new pathogenetic and therapeutic aspects of bone modulation in osteomyelitis.

Topics: Acute Disease; Adult; Case-Control Studies; Chronic Disease; Cytokines; Eicosanoids; Epoprostenol; Female; Fractures, Bone; Humans; Interleukin-6; Interleukin-8; Leukotriene B4; Male; Middle Aged; Osteomyelitis; Thromboxane A2

Laboratory animal models and clinical studies suggest that dietary n-3 fatty acids are beneficial in diseases with an inflammatory component such as rheumatoid arthritis or psoriasis. In the present study we investigated the effect of purified docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on phorbol ester (TPA)-induced acute inflammation. Mice were fed for 6 weeks a diet containing 5% corn oil enriched with either 1% DHA or 1% EPA and compared with a group receiving 6% corn oil only. The dietary treatment with DHA or EPA elevated the n-3 polyunsaturated fatty acids as expected in the spleen and ear phospholipids, associated with a reduction in arachidonic acid levels. The degree of ear inflammation was quantified by measuring the four parameters including (1) edema as the increase in ear biopsy weight, (2) polymorphonuclear cell infiltration as myeloperoxidase activity (MPO) at the site of inflammation, (3) prostaglandin E2 (PGE2) and (4) leukotriene B4 (LTB4) concentrations in ear edema. The addition of DHA to the diet reduced significantly the edema formation and the MPO activity 24 h after TPA challenge. Both DHA and EPA significantly reduced the PGE2 and LTB4 levels compared with animals fed corn oil. This result suggests that DHA rather than EPA may be useful in the adjuvant treatment of diseases where acute inflammatory processes play a role.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Dermatitis; Dinoprostone; Disease Models, Animal; Docosahexaenoic Acids; Ear, External; Edema; Eicosapentaenoic Acid; Leukotriene B4; Male; Mice; Mice, Inbred BALB C; Neutrophils; Peroxidase; Steroids; Tetradecanoylphorbol Acetate

The role of nitric oxide in lipoxygenase metabolism after a process of ischemia-reperfusion in pancreas transplantation has been evaluated in this study. Sprague-Dawley rats were randomized into three groups, as follows: Group I--Control animals not surgically manipulated; Group II.--Pancreas transplantation, after 12 h of organ preservation; Group III.--Same as II but with administration of NG-nitro-L-arginine methyl esther (a nitric oxide synthase inhibitor) (10 mg/Kg) prior to organ revascularization. The results show post-transplantation increases in leukotriene B4 and 12-hydroxyeicosatraenoic acid levels in pancreatic tissue. Nitric oxide synthase inhibition reversed the increases in 12-hydroxyeicosatetraenoic acid, but was unable to modify leukotriene B4 increases suggesting the existence of a direct effect of nitric oxide on the 12-lipoxygenase metabolism in pancreas transplantation.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Acute Disease; Animals; Arachidonate 12-Lipoxygenase; Enzyme Activation; Enzyme Inhibitors; Free Radicals; Gene Expression Regulation; Ischemia; Leukotriene B4; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Organ Preservation; Pancreas; Pancreas Transplantation; Pancreatitis; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Leukotrienes may mediate bronchoconstriction in asthma. Cysteinyl leukotriene production rises in vivo after allergen challenge, but few reports describe leukotriene concentrations in clinical asthma or in children. Using high performance liquid chromatography/radioimmunoassay, plasma and urinary leukotrienes in asthmatic children (aged 5-10 years) were measured during an acute exacerbation (peak expiratory flow (PEF) < 65%, n = 10) and one month later (PEF 74-169%, n = 9), and in non-atopic normal children (aged 1.3-13.2 years). In the asthmatics, geometric mean (95% confidence interval) plasma leukotriene B4 (LTB4) was 746 pg/ml (398 to 1403) acutely and 1026 pg/ml (662 to 1593) in remission, compared with 369 pg/ml (167 to 728) in the normal children (n = 14). Plasma cysteinyl leukotrienes were low or undetectable, but urinary leukotriene E4 (LTE4) was higher in the asthmatics during an acute episode (210 pmol/mmol creatinine, 101 to 454) and at follow up (179 pmol/mmol, 110 to 293), compared with the normal children (98 pmol/mmol, 81 to 118, n = 41). This persistent increase in plasma LTB4 and urinary LTE4 concentrations one month after a severe asthmatic episode suggests leukotriene production is related to chronic inflammation rather than to acute bronchoconstriction.

Topics: Acute Disease; Adolescent; Asthma; Child; Child, Preschool; Chromatography, High Pressure Liquid; Humans; Leukotriene B4; Leukotriene C4; Leukotriene E4; Radioimmunoassay

The changing levels of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) were compared over a period of 1 h to 15 days in two kinds of inflammatory responses induced in the rat air pouch by chemically similar polymers of peptidoglycan-polysaccharide (PG-PS) isolated from cell walls of group A streptococci. The smaller polymers (100 s, average mol. wt 5.3 x 10(6)) induced a more severe acute response over the first 24 h, whereas, from 3 to 15 days the larger polymers (10 p, average mol. wt 5 x 10(8)) induced greater chronic inflammation, as measured by pouch fluid volume, number of infiltrating cells and weight of granulation tissue. The most prominent difference between the two kinds of responses in the pattern of PGE2 and LTB4 were: (a) A shift between 1 to 6 h to much higher production of PGE2 in the exudate induced by large polymers. During this time the level of LTB4 also increased, but continued to be higher in the exudate induced by small polymers. (b) The sustained production of relatively high levels of LTB4 and PGE2 in the large polymer exudate at 15 days. Changes such as these indicate that this model is useful for analyzing mediators which regulate the evolution of acute into chronic inflammation.

Topics: Acute Disease; Animals; Cell Wall; Chronic Disease; Dinoprostone; Enzyme-Linked Immunosorbent Assay; Female; Granulation Tissue; Granuloma; Inflammation; Leukotriene B4; Molecular Weight; Peptidoglycan; Rats; Rats, Inbred Lew; Streptococcus pyogenes

A comparative study in horses of the pharmacokinetics (PK) and pharmacodynamics (PD) of 2 extensively used nonsteroidal anti-inflammatory drugs (NSAIDs), flunixin (FXN) and ketoprofen (KTP), was carried out applying PK/PD modelling. To evaluate the anti-inflammatory properties of these drugs a model of acute inflammation, comprising surgically implanted subcutaneous tissue cages stimulated by intracaveal injection of carrageenan, was used. FXN elimination half-life (T1/2 beta) in plasma was 3.37 +/- 1.09 h. However, in exudate a much longer T1/2 beta was obtained (15.99 +/- 3.80 h). Apparent volume of distribution (Vdarea) for FXN was 0.317 +/- 0.126 l/kg and body clearance (ClB) was 0.058 +/- 0.004 l/kg/h. KTP displayed enantioselective pharmacokinetics, the S(+) enantiomer being predominant in plasma, exudate and transudate. T1/2 beta values for R(-) and S(+)KTP were, respectively, 1.09 +/- 0.19 h and 1.51 +/- 0.45 h (plasma) and 19.73 +/- 2.72 h and 22.64 +/- 4.34 h (exudate), respectively. R(-)KTP was cleared more rapidly than the S(+) enantiomer. ClB values were 0.277 +/- 0.035 l/kg/h and 0.202 +/- 0.022 l/kg/h, respectively. FXN and KTP pharmacodynamics was evaluated by determining their inhibitory effects on serum thromboxane (Tx)B2, exudate prostaglandin (PG)E2, leukotriene (LT)B4 and beta-glucuronidase (beta-glu) and intradermal bradykinin-induced swelling. Both drugs produced marked inhibition of serum TxB2 synthesis for up to 24 h, with no significant differences between the drugs. FXN was a more potent inhibitor of exudate PGE2, the EC50 for FXN being lower (P < 0.01) than that for KTP (0.019 +/- 0.010 microgram/ml and 0.057 +/- 0.009 microgram/ml, respectively). Neither drug had any effect on exudate LTB4 concentration. Differences between the 2 drugs were observed for the inhibition of beta-glu, the Emax for KTP being higher (P < 0.01) than for FXN. However, no differences were observed in other PD parameters. Both FXN and KTP inhibited bradykinin-induced swelling. Differences between the drugs were obtained for Emax, which was greater for FXN (P < 0.01) than for KTP. Equilibration half-life (T1/2Ke0) also differed, being much longer (P < 0.01) for FXN than for KTP. PK/PD modelling proved to be a useful and novel analytical technique for studying the pharmacodynamics of NSAIDs, with the advantage over classical in vitro methods that it provides data in the whole animal. By quantifying action-concentration interrelationships through PK-PD mod

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Clonixin; Cross-Over Studies; Dinoprostone; Exudates and Transudates; Glucuronidase; Half-Life; Horses; Inflammation; Ketoprofen; Leukotriene B4; Male; Models, Biological; Thromboxane B2

Pancreatic production of lipid mediators of inflammation, including eicosanoids and platelet-activating factor (PAF), was examined in two models of pancreatitis in the rat. Chronic pancreatitis was induced by ligation of the pancreatic duct and acute pancreatitis by infusion of sodium taurocholate into the pancreatic duct. In the model of chronic pancreatitis, prostaglandin E2 (PGE2), PGD2, 6-keto PGF1 alpha, thromboxane B2 (TXB2), and PAF increased significantly in the pancreas in a similar fashion, whereas leukotriene B4 (LTB4) remained unchanged. BN52021, a PAF antagonist, reduced the accumulation of pancreatic TXB2, 6-keto PGF1 alpha, and PGD2, and did not affect PGE2. In the model of acute pancreatitis, LTB4 increased, whereas PGE2, TXB2, and 6-keto PGF1 alpha decreased significantly; PGD2 changed slightly; and PAF was undetectable. The present results indicate that mild chronic pancreatitis is accompanied by the production and accumulation of a wide spectrum of lipid mediators while LTB4 was the only lipid mediator detected at biologically active concentrations in the model of severe acute pancreatitis. It is suggested that various mediators are involved in establishing a balance between inflammation and the repair of the inflamed pancreatic tissue observed in mild chronic pancreatitis. While both eicosanoids and PAF are involved in such self-limiting responses to inflammatory challenge, PAF seems to play a central role in instigating the production of the various other mediators detected in the model of chronic pancreatitis. In the model of acute pancreatitis while the deficiency of various lipid mediators may render the pancreatic tissue more susceptible to acute damage, enhanced LTB4 appears to contribute to the destructive pathology observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Chronic Disease; Dinoprostone; Diterpenes; Eicosanoids; Ginkgolides; Lactones; Leukotriene B4; Ligation; Male; Masoprocol; Pancreatic Ducts; Pancreatitis; Platelet Activating Factor; Prostaglandin D2; Rats; Rats, Sprague-Dawley; Taurocholic Acid; Thromboxane B2

Several studies have reported that prostanoids are involved in many of the physiopathological mechanisms underlying acute pancreatitis but their precise role in this disease remains to be established. The objective of this work is to evaluate the variation of local tissue production of prostanoids and lipoxygenase metabolites of arachidonic acid in acute pancreas inflammation induced by intraductal administration of 3.5% sodium taurocholate (0.1 ml/100 mg body weight) in rats. Pancreatic tissue levels of leukotriene B4 (LTB4), 15 hydroxyeicosatetraenoic acid (15-HETE), 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha), thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) were determined by HPLC-RIA techniques at 5 and 60 minutes after induction of acute pancreatitis (AP). Prostanoids increased significantly at 5 minutes and LTB4 and 15-HETE at 60 minutes. These data confirm that the prostanoid imbalance could be considered as an early specific response of the pancreas to the inflammatory events characteristic of induced AP while the altered levels of the lipoxygenase products (LTB4 and 15-HETE) would be more of a nonspecific organ response associated to the high cellular infiltration rate and necrosis observed in the late phases of acute pancreatitis.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Dinoprostone; Hemorrhage; Hydroxyeicosatetraenoic Acids; Kinetics; Leukotriene B4; Lipoxygenase; Male; Pancreas; Pancreatitis; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Taurocholic Acid; Thromboxane B2

Arachidonate metabolism was examined in rats with experimentally induced acute and chronic liver injuries. Acute liver injury was induced by a single administration of D-galactosamine (D-Galn) and lipopolysaccharide (LPS) or carbon tetrachloride (CCl4). Chronic liver injury was produced by several administrations of CCl4 for 5 weeks. Non-parenchymal liver cells from rats with D-Galn/LPS-induced acute liver injury produced prominently leukotriene B4 and 5-hydroxy-arachidonic acid which were hardly synthesized by the normal rat liver. No apparent changes were observed in the arachidonate metabolism of the non-parenchymal cells of the acute CCl4-injured liver. In chronic liver injury, the production of 6-ketoprostaglandin F1 alpha, a stable metabolite of prostaglandin I2, by the non-parenchymal cell fraction was significantly enhanced in contrast with the fixed amount of the other arachidonate metabolites. These results suggested the arachidonate metabolism by non-parenchymal liver cells might change according to the pathogenesis of the liver disease.

Topics: Acute Disease; Animals; Arachidonic Acids; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Chronic Disease; Eicosanoids; Galactosamine; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipopolysaccharides; Liver; Liver Cirrhosis, Experimental; Liver Diseases; Male; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rats; Rats, Wistar

High-pressure liquid chromatography was used to measure the blood content of lipoxygenase metabolites (LM) of arachidonic acid: leukotriene B4 (LTB4) and hydroxyeicosatetraene acids (5 HETE, 12 HETE, 15 HETE) in 65 patients with acute pneumonia (AP) of mild gravity (group 1) and of medium gravity (group 2), in 23 patients with acute bronchitis (AB), and in 15 normal male persons aged 18 to 20 years. In all the examined, the zonal pulmonary blood flow was measured by regional rheopulmonography. External respiratory function (ERF) was also determined together with the recording of the flow-volume loop. At the height of AP and AB, all the patients demonstrated an increase of LM in the blood, with the maximum LM content being recorded in group 2. During convalescence, AB and AP patients of group 1 manifested normalization of the majority of the parameters. In group 2, they significantly exceeded the control level. 5 and 15 HETE had the closest correlations with the blood flow parameters, whereas LTB4 and 12 HETE had less intensive correlations. The influences of LM such as 5 and 15 HETE on the pulmonary blood flow were associated with deterioration of the blood content of the lungs and venous return, the action of LTB4 was coupled with venous congestion formation, that of 12 HETE with the rise of vascular resistance. Close negative correlations of LTB4 and 5 HETE with the majority of ERF parameters indicate that they are important factors in the pathogenesis of restrictive and obstructive ventilatory disorders.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adolescent; Adult; Arachidonic Acid; Arachidonic Acids; Bronchitis; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase; Male; Pneumonia; Pulmonary Circulation; Respiratory Mechanics

Spontaneous colitis in CTT's presents cytological characteristics similar to chronic ulcerative colitis in humans, e.g. inflammatory cell infiltrate and crypt abscesses. To better characterize CTT colitis as a potential model for human inflammatory bowel disease (IBD), inflammatory mediators identified in colonic tissue of human IBD patients and/or experimental colitis models were assayed. Inflammatory mediator changes in plasma and colon from tamarins with acute (n = 10) and chronic (n = 10) colitis (by mucosal biopsy) were assayed by RIAs. Similar inflammatory mediators were found in the CTT's with acute colitis. In the plasma, PAF and PGE2 levels were lower in acute colitis CTT's, no LTB4 was detected, and histamine levels were not different from chronic colitic animals. In the colon, myeloperoxidase and interleukin-1 beta were significantly higher in acute colitis, PGE2 and LTB4 were higher but not significantly, and PAF was not different from chronic CTT's. These data suggest that a combination of events are occurring in the pathogenesis of tamarin colitis that involves some of the same mediators that are found in the human disease and in other experimental models. The importance of these findings to human IBD remains for further investigation; however, the spontaneous primate model offers an exciting approximation of the disease development and merits further investigation for understanding the pathogenesis of human IBD as well as to aid in development of targeted therapeutics.

Topics: Acute Disease; Animals; Chronic Disease; Colitis; Dinoprostone; Disease Models, Animal; Histamine; Interleukin-1; Leukotriene B4; Peroxidase; Platelet Activating Factor; Saguinus

We have compared the early development (0-4h) of two acute non-specific inflammatory reactions induced by the intrapleural injection of isologous serum or a suspension of CaPP crystals. The intensity of the reactions was assessed in terms of the exudate volume, the number and ratio of pleural cells and different cell functions and secretions. The number of exudative cells elicited by isologous serum was higher than with CaPP but the PMN/Monocytes ratio was the same. The amount of protein in the serum-induced exudate was constant from 1 h to 4 h and was similar in the CaPP-induced pleural exudate at the latter time. The amount of complement increased similarly in the two models. The chemotactic potency of the exudates and cell supernatants following incubation showed similar values in the two models. Eicosanoid levels were higher in CaPP--than in isologous serum-induced exudates. Prostacyclin and peptidoleukotrienes were released in specially large amounts at the very outset of the inflammatory reactions.

Topics: Acute Disease; Animals; Calcium Phosphates; Cells, Cultured; Eicosanoids; Epoprostenol; Leukocytes, Mononuclear; Leukotriene B4; Male; N-Formylmethionine Leucyl-Phenylalanine; Pleurisy; Rats; Rats, Inbred Strains; SRS-A; Thromboxane B2

1. PAF and LTs may be mediators of the acute gastrointestinal mucosal damage due to endotoxic shock. 2. LTs may be mediators of the acute gastrointestinal mucosal damage due to PAF administration. 3. LMW heparin and unfractionated heparin prevented the increase of LTs due to endotoxin and PAF administration.

Topics: Acute Disease; Animals; Benzoquinones; Dogs; Gastric Mucosa; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Intestinal Mucosa; Leukotriene B4; Lipoxygenase Inhibitors; Necrosis; Phospholipid Ethers; Platelet Activating Factor; Shock, Septic

We hypothesized that leukotrienes might contribute to the pathophysiology of acute lung injury induced by oleic acid. Oleic acid (2-20 mg.kg-1.h-1), LY171883 [leukotriene (LT) D4/LTE4 receptor antagonist, 10 mg/kg + 1 mg.kg-1.h-1] + oleic acid (10 mg.kg-1. h-1), or triolein (20 mg.kg-1.h-1) were infused intravenously into anesthetized pigs. Treatment with the cyclooxygenase inhibitor was designed to possibly enhance LT release. Bronchoalveolar lavage fluid concentrations of LTB4, LTC4, LTD4, and LTE4 were measured by reverse-phase high-performance liquid chromatography and radioimmunoassay. Oleic acid caused dose-related hypoxemia and pulmonary hypertension and increased pulmonary vascular resistance, lung water, and alveolar-capillary membrane permeability. Bronchoalveolar lavage fluid levels of LTB4, LTC4, LTD4, and LTE4 showed no significant changes in oleic acid- or indomethacin + oleic acid-treated pigs, compared with triolein-treated controls. Indomethacin modestly attenuated the oleic acid-induced hypoxemia and the early increases (i.e., 0-0.5 h) in mean pulmonary arterial pressure and pulmonary vascular resistance. In contrast, LY171883 provided no protection against any oleic acid-induced cardiopulmonary effect (measured or calculated). We conclude that LTs are not likely to be important mediators of oleic acid-induced lung injury in the pig.

Topics: Acetophenones; Acute Disease; Animals; Autacoids; Blood Pressure; Bronchoalveolar Lavage Fluid; Indomethacin; Leukotriene B4; Leukotriene E4; Leukotrienes; Lung; Oleic Acid; Oleic Acids; Respiratory Insufficiency; SRS-A; Swine; Tetrazoles; Triolein; Vascular Resistance

Concentrations of leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) in peritoneal fluid were measured in 19 women with suspected acute pelvic inflammatory disease. Acute salpingitis was verified by laparoscopy in 16 cases; 11 of them had isolation of microbes from the peritoneal cavity. Means (+/- SD) levels of peritoneal fluid LTB4 and PGE2 in acute salpingitis were 506 +/- 288 and 378 +/- 330 pg/ml, respectively, and higher (p less than 0.001) than the levels in the peritoneal fluid of 20 healthy controls: LTB4 44 +/- 57, PGE2 11 +/- 2 pg/ml, respectively. An inflammatory cytologic pattern was found in the peritoneal fluid in all the cases with acute salpingitis, neutrophils being the prominent cells. These chemical mediators of inflammation in peritoneal fluid may have a role in the development of scarring and peritubal adhesions found after acute salpingitis.

Topics: Acute Disease; Adult; Ascitic Fluid; Dinoprostone; Female; Humans; Leukotriene B4; Neutrophils; Salpingitis

Dietary polyunsaturated fatty acid modulation has been used as an anti-inflammatory strategy in experimental models of disease as well as in clinical trials. To elucidate the mechanisms underlying the anti-inflammatory effects of manipulating dietary polyunsaturated fatty acids, the in vivo effects of essential fatty acid (EFA) deficiency and (n-3) fatty acid supplementation were contrasted using a model of acute inflammation induced by the i.p. injection of zymosan into mice. Both diets led to a substantial decrease in tissue (n-6) fatty acid content. EFA deficiency was also characterized by the accumulation of (n-9) fatty acids, particularly 20:3 (n-9), the fatty acid that uniquely characterizes the deficiency state. Dietary (n-3) fatty acid supplementation led instead to marked increases in (n-3) fatty acids, especially 20:5 (n-3). With respect to the antiinflammatory effects of the two diets, EFA deficiency, but not (n-3) fatty acid supplementation, depleted levels of resident peritoneal macrophages. EFA deficiency was also more effective than (n-3) fatty acid supplementation in inhibiting the influx of polymorphonuclear neutrophils in response to zymosan. The effect of the two diets on the in vivo generation of leukotriene(LT)B also differed markedly. EFA deficiency completely inhibited the synthesis of LTB. Dietary (n-3) fatty acid supplementation, in contrast, reduced the production of LTB4 by only 50%. With (n-3) fatty acid supplementation LTB5 was produced. The more modest effect of (n-3) fatty acid supplementation in decreasing LTB4 generation was not due to blockade of the cyclooxygenase pathway. EFA deficiency, but not (n-3) fatty acid supplementation, was associated with the decreased synthesis of thromboxane. Although dietary fatty acid modulation has been shown to diminish platelet activating factor (PAF) synthesis, studies using the PAF receptor blocker, L659989, established that PAF was not a significant factor in the elicitation of leukocytes in this model of inflammation. In summary, the anti-inflammatory effect of EFA deficiency was more marked that that of dietary (n-3) fatty acid supplementation in acute inflammation. This difference in anti-inflammatory potential appeared to be due to either the greater effect of EFA deficiency in decreasing levels of resident peritoneal macrophages or in suppressing the in vivo generation of LTB4.

Topics: Acute Disease; Animals; Dietary Fats; Eicosanoids; Fatty Acids, Essential; Fatty Acids, Unsaturated; Furans; Inflammation; Leukotriene B4; Liver; Macrophages; Mice; Mice, Inbred C57BL; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Receptors, G-Protein-Coupled

Acute non-specific inflammation was induced in rats by injection of isologous serum into the pleural cavity. Pleural and peritoneal cells were collected at various times after pleurisy induction and tested for production of leukotriene B4 (LTB4), prostaglandin E2 (PGE2) and prostacyclin (PGI2) after in-vitro stimulation with calcium ionophore A23187. Cells obtained by lavage of pleural and peritoneal cavities of normal rats were used as controls. Increased production of LTB4, PGE2 and PGI2 by pleural cells was observed 3 days after pleurisy induction, but with a significant depression of PGI2 release at 3 h. As the relative proportions of polymorphonuclear cells (PMN) and macrophages in the inflammatory exudate varied during the development of inflammation, these cells were examined separately for LTB4 production. PMN and macrophages contributed equally to the liberation of this mediator in normal and inflamed rats. Similar qualitative and quantitative changes in LTB4 production by pleural cells were observed, irrespective of the type of irritant used (isologous serum, dextran, carrageenan, microcrystals). In contrast, intrapleural injection of saline had no significant effect. In order to determine whether local inflammation may influence mediator release by phagocytic cells at remote sites, peritoneal cells were collected 3 or 72 after pleurisy induction. The production of LTB4, PGE2 and PGI2 was increased at 72 h. Mediator production by peritoneal macrophages was observed in both normal and inflamed rats. In conclusion, acute non-specific inflammation provoked increased arachidonic acid metabolite generation by phagocytes both locally and at a distance: this occurred more than 24 h after pleurisy resolution.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Cells, Cultured; Dinoprostone; Eicosanoids; Epoprostenol; Leukotriene B4; Macrophages; Male; Neutrophils; Pleurisy; Rats; Rats, Inbred Strains; Tuftsin

The biochemical changes underlying the clinical manifestations of psoriasis are unknown. Certain chemotactic eicosanoids derived from arachidonic acid metabolism have been suggested to play important roles in psoriasis, because of their presence in lesional psoriatic skin and their ability to elicit skin inflammation and to stimulate epidermal proliferation. The purpose of the present study was to elucidate which eicosanoids might be involved in the early phases of the inflammatory processes of psoriasis. Eicosanoids were analyzed in scale and in lesional skin without scale both in acute guttate and chronic plaque psoriatic lesions. Methods for identification of eicosanoids included reversed-phase high-performance liquid chromatography combined with radioimmunoassay. Leukotriene B4 was present in both acute guttate and chronic plaque skin lesions in biologically active amounts (acute guttate lesions: 18.7 +/- 7.1 ng/g wet tissue in scale and 3.2 +/- 1.5 ng/g wet tissue in lesional skin without scale; chronic plaque lesions: 33.1 +/- 9.7 ng/g wet tissue in scale and 5.3 +/- 2.0 ng/g wet tissue in lesional skin without scale). 12- and 15-hydroxy-eicosatetraenoic acid (HETE) reached biologically active concentrations only in scale of chronic plaque lesions (1,512 +/- 282 and 1,441 +/- 411 ng/g wet tissue, respectively). The level of prostaglandin E2 in chronic plaque lesions was similar to the level in normal skin, while the level in acute guttate lesions was increased twofold (71.0 +/- 14.8 ng/g wet tissue). These results demonstrate that leukotriene B4, but not 12-HETE, is present in acute guttate psoriatic skin lesions in concentrations able to exert biologic effects. Leukotriene B4 may therefore participate in inflammatory changes of acute psoriasis.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Acute Disease; Chromatography, High Pressure Liquid; Chronic Disease; Dinoprostone; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Psoriasis; Radioimmunoassay; Skin

A study was conducted to investigate production rate of leukotriene B4 (LTB4) in parenchymal and sinusoidal liver cells of rats with acute hepatic failure (AHF). AHF was induced by simultaneous administration of D-galactosamine (GalN) and endotoxin (LPS), and parenchymal as well as sinusoidal liver cells were isolated by collagenase perfusion method. Following preincubation for 15 min, isolated cellular fractions were incubated with Ca-ionophore (2 microM) for 5 min, and levels of LTB4 in culture media before and 5 min after addition of Ca-ionophore were analyzed by HPLC. Following results were obtained: The production rate of LTB4 was found to be the highest in Kupffer cells (7.2ng/10(6) cells/5 min), followed by endothelial cells (1.1), stellate cells (0.2) and parenchymal cells (not detectable). The production rate of LTB4 in both Kupffer cells and endothelial cells was found to reach a maximum in the fraction isolated 60 min after administration of GalN and LPS. Treatment with AA861, one of the selective inhibitors of 5-lipoxygenase, was shown to reduce the production of LTB4 in Kupffer cells to 53% at 10(-7)M and above 99% at higher than 10(-5)M. In conclusion, the majority of LTB4 generated in the liver of rats with AHF was found to be synthesized in Kupffer cells and, to a lesser extent, in endothelial cells, and the enhanced production of LTB4 was found to be greatly inhibited by treatment with AA861.

Topics: Acute Disease; Animals; Chemical and Drug Induced Liver Injury; Endotoxins; Galactosamine; Leukotriene B4; Lipopolysaccharides; Liver; Liver Diseases; Male; Rats; Salmonella enteritidis

Topics: Acute Disease; Enzyme Precursors; Humans; Leukocytes; Leukotriene B4; Pancreas; Pancreatic Elastase; Pancreatitis; Tumor Necrosis Factor-alpha

1. Two selective inhibitors of arachidonate 5-lipoxygenase, BW A4C and BW A797C, have been studied for their effects on acute inflammatory responses following oral administration to rats and mice. 2. The concentrations of the lipoxygenase product leukotriene B4 (LTB4) in 6 h inflammatory exudates, induced in rats by the subcutaneous implantation of carrageenin-soaked polyester sponges, were reduced dose-dependently by BW A4C (ED50 = 2.6 mg kg-1) or BW A797C (ED50 = 14.3 mg kg-1). 3. BW A4C and BW A797C had little or no effect on prostaglandin E2 (PGE2) concentrations in inflammatory exudates (ED50s greater than 100 mg kg-1). 4. Doses of up to 200 mg kg-1 of either BW A4C or BW A797C had no effect on carrageenin-induced oedema in rat paws. 5. BW A4C and BW A797C had little or no effect on carrageenin-induced hyperalgesia in rats or phenyl-benzoquinone-induced writhing in mice. 6. Yeast-induced pyrexia in rats was reduced by both BW A4C (ED50 = 32 mg kg-1) and BW A797C (ED50 = 23 mg kg-1). 7. The accumulation of leucocytes in sponge exudates was reduced dose-dependently by BW A4C (ED50 = 54 mg kg-1) and BW A797C (ED50 = 16.7 mg kg-1). 8. The selective lipoxygenase inhibitors BW A4C and BW A797C do not suppress inflammatory oedema or pain although they are anti-pyretic and they do inhibit leucocyte migration. There is not, however, a close agreement between these in vivo activities and their potencies as lipoxygenase inhibitors.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Acute Disease; Animals; Arachidonate Lipoxygenases; Dinoprostone; Female; Hydroxamic Acids; Inflammation; Leukocyte Count; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mice; Mice, Inbred Strains; Prostaglandins E; Pyrazoles; Rats; Rats, Inbred Strains

Prostaglandins are important regulators of inflammatory responses. The rat subcutaneous air pouch, a model for synovial inflammation, was used to study the effect of systemic injections of prostaglandin E1 (PGE1) and its stable analog 15S,15 methyl prostaglandin E1 (15M PGE1) on nonimmunologically induced acute inflammation. The 15M PGE1 analog was a more effective longer-lasting antiinflammatory agent. Acute inflammatory responses were induced with three diverse stimuli including monosodium urate crystals, leukotriene B4 and formylmethionylleucyl-phenylalanine. Animals were treated with 15 M PGE1 for 2 days before induction of inflammation. Analysis of pouch fluid 6 hours after injection of the inflammatory stimulus indicates that 15M PGE1 treatment suppressed exudate volume and protein concentration, polymorphonuclear leucocyte accumulation and activity of the lysosomal enzyme beta-galactosidase. Treatment with 15M PGE1 was least effective in preventing the fluid phase of inflammation (exudate volume and protein concentration) when leukotriene B4 was used to induce inflammation. Direct observation (dissecting microscope) of pouch lining vessels indicated that 15M PGE1 reduced markedly the intense vascular reactivity (increased number of dilated vessels and filamentous, corkscrew-shaped vessels) usually seen in an acute inflammatory response. The antiinflammatory effect of 15M PGE1 was also documented by histopathology of pouch lining tissue. Treatment with 15M PGE1 reduced substantially the invasion of pouch tissue by polymorphonuclear leucocytes which was induced by all three stimuli of inflammation. Results of these experiments show that systemic administration of 15M PGE1 is capable of suppressing acute inflammation induced by monosodium urate crystals, by the potent soluble naturally occurring mediator of inflammation leukotriene B4, and by the synthetic chemotactic peptide, formylmethionylleucylphenylalanine.

Topics: Acute Disease; Alprostadil; Animals; Inflammation; Leukotriene B4; Male; N-Formylmethionine Leucyl-Phenylalanine; Rats; Rats, Inbred Strains; Uric Acid

The sulfidopeptide leukotrienes (LT) C4 and D4 have been reported to promote the formation of pulmonary edema when administered into the pulmonary circulation of laboratory animals. As a first step in the evaluation of the hypothesis that these leukotrienes participate in the edema formation of the adult respiratory distress syndrome (ARDS), we investigated whether LTC4 and LTD4 were present in the bronchoalveolar lavage (BAL) fluid of patients with ARDS compared to nonsmoker control subjects and to patients with acute respiratory failure exhibiting no radiographic evidence of widespread pulmonary infiltrates but having a clinical predisposition for developing ARDS, i.e., the "at risk" group. Bronchoscopic lavage was performed with sterile 0.9% NaCl on 32 control subjects, nine patients with ARDS, and nine patients "at risk" for ARDS. Leukotrienes were measured in BAL fluid by radioimmunoassay after methanol extraction and HPLC purification of a 20-ml aliquot of the BAL sample. LTC4 and LTD4 (mean +/- SE) increased from 1.1 +/- 0.2 and 1.2 +/- 0.5 ng/lavage in the BAL fluid of control subjects to 6.3 +/- 2.3 and 20.1 +/- 5.9 ng/lavage in patients "at risk" for ARDS and to 12.5 +/- 3.0 and 30.5 +/- 7.8 ng/lavage in patients with ARDS, respectively. The sulfidopeptide LTs correlated with BAL fluid protein content. These results suggest that increased amounts of LTs in BAL fluid are a general finding in patients with ARDS and those "at risk" for ARDS.

Topics: Acute Disease; Bronchoalveolar Lavage Fluid; Humans; Leukotriene B4; Pulmonary Edema; Radioimmunoassay; Respiratory Distress Syndrome; Respiratory Insufficiency; Risk Factors; SRS-A

Topics: Acute Disease; Animals; Cheek; Cricetinae; Inflammation; Leukotriene B4; Mesocricetus; Mouth Mucosa; Muscles; Platelet Activating Factor; Rabbits; Substance P

The migration of leucocytes to sites of acute and chronic inflammation is an event of central importance to the maintenance of inflammatory processes; extravascular leucocytes are responsible for generating chemical mediators of inflammation and the phagocytosis of particulate matter. They may also be involved in the conversion of acute to chronic inflammatory lesions. Leucocytes are attracted to sites of tissue injury by a range of chemoattractants. This paper describes the development of a method for separating on Percoll gradients purified populations of equine polymorphonuclear and mononuclear leucocytes and use of the isolated cells in vitro studies. Two independent assay methods, the agarose microdroplet and the Boyden chamber microfilter techniques, were used. The assays were utilised in three ways: (a) to investigate the sensitivity of polymorphonuclear and mononuclear leucocytes to two standard chemoattractants, zymosan activated plasma and n-formyl-methionyl-leucyl phenylalanine; (b) to study the chemoattractant properties of leukotriene B4 and prostaglandin E2 for equine leucocytes; and (c) to investigate the inhibitory actions of several nonsteroidal anti-inflammatory drugs (NSAIDs) on equine leucocyte movement.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Migration Inhibition; Centrifugation, Density Gradient; Chemotaxis, Leukocyte; Chronic Disease; Dinoprostone; Horse Diseases; Horses; Immunity, Cellular; Inflammation; Leukocytes; Leukocytes, Mononuclear; Leukotriene B4; Neutrophils; Phagocytosis; Prostaglandins E

Carrageenin pleurisy was induced in adrenalectomised (ADX) and sham-operated (SHO) rats. The magnitude and duration of inflammation, as estimated by fluid exudation and cell migration, was greatly increased (approximately doubled) in ADX rats compared with that in their SHO controls. The content of eicosanoids (6-keto-prostaglandin F1 alpha (6-keto-PGF 1 alpha), thromboxane B2 (TXB2), and leukotriene B4 (LTB4] in inflammatory exudates from ADX rats was significantly (2-4 fold) greater than that of their SHO controls. Resident macrophages obtained from ADX rats produced more eicosanoids per cell per unit time when stimulated in vitro with zymosan, than did cells from the SHO controls. Administration of glucocorticoids blocked the inflammatory response and reduced the release of eicosanoids both in vitro and in vivo in both groups of rats. These data are consistent with the notion that physiological amounts of glucocorticoids exert a tonic inhibitory action on phospholipase activity in normal animals and that the increased secretion of these hormones during the inflammatory response serves to check and control the development of inflammation.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Adrenalectomy; Animals; Annexins; Carrageenan; Glucocorticoids; Glycoproteins; In Vitro Techniques; Inflammation; Leukotriene B4; Phospholipases A; Pleurisy; Rats; Thromboxane B2

The subcutaneous sponge implant model of acute inflammation in the rat has been evaluated as a suitable test system for evaluating the potential anti-inflammatory efficacy of 5-lipoxygenase inhibitors. The inflammatory parameters measured were exudate volume and leukocyte recruitment. Specific radioimmunoassays were used to measure (1) 5-lipoxygenase (LPO) and cyclo-oxygenase (CO) activity in exudate leukocytes stimulated ex vivo with A23187, and (2) the LTB4 and PGE2 content of inflammatory exudate. The NSAIDs flurbiprofen and indomethacin inhibited cell recruitment, exudate volume and CO activity with ED50S of approximately 1 mg per kg p.o. but failed to inhibit LPO activity at 10 mg per kg p.o. Nafazatrom (Bayer 6575), quercetin and NDGA, which inhibit LPO activity in vitro, were inactive against all parameters when dosed at 100 mg per kg p.o. The "mixed inhibitors" BW755C and phenidone were approximately equipotent inhibitors of LPO activity but BW755C was 10 times more potent than phenidone against CO activity. BW755C was also greater than 10 times more potent at inhibiting cell recruitment and exudate volume than phenidone suggesting that the anti-inflammatory efficacy of the mixed inhibitors reflect their potency against CO rather than LPO activity. Time course studies demonstrated that the inhibitor effects of BW755C and phenidone on leukocyte recruitment reflected a reduction in the PGE2 but not the LTB4 content of the inflammatory exudate. Polyester sponges soaked in high concentrations of LTB4 caused only a modest (2-fold) increase in leukocyte recruitment whilst physiological levels were inactive. The results taken together suggest that CO products make a major contribution to leukocyte recruitment in this model whilst the LPO product LTB4 has little role. This model therefore is of little value for evaluating the anti-inflammatory efficacy of 5-lipoxygenase inhibitors. Moreover, the rat would appear to be unsuitable for evaluating the role of LTB4 in acute inflammation.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Acute Disease; Animals; Blood Proteins; Calcimycin; Chemotaxis, Leukocyte; Cyclooxygenase Inhibitors; Dinoprostone; Dose-Response Relationship, Drug; Flurbiprofen; Indomethacin; Inflammation; Leukocytes; Leukotriene B4; Lipoxygenase Inhibitors; Male; Prostaglandins E; Pyrazoles; Pyrazolones; Rats; Rats, Inbred Strains; Skin

Desensitization of the neutrophil inflammatory response to intracutaneous injection of chemotaxins and endotoxin was studied in rabbits. When restimulated 6 hr later with the same agent, inflammatory lesions initiated with platelet-activating factor (PAF), leukotriene B4 (LTB4), or endotoxin supported a diminished influx of neutrophils compared with responses in normal skin. In contrast, repeated stimulation of lesions with alpha-casein failed to lead to desensitization. The specificity of desensitization was investigated, and it was found that lesions initiated with formylmethionyl-leucyl-phenylalanine (FMLP) supported a normal response when restimulated with PAF, alpha-casein, or endotoxin. Initiation of lesions with LTB4, however, diminished the subsequent response to zymosan-activated plasma and PAF, but not endotoxin, alpha-casein, or FMLP. This result indicates that LTB4 is not a final common mediator of neutrophil infiltration of acute inflammatory lesions. Desensitization was detected irrespective of the concentration of chemotaxin used to investigate the response. Repeated stimulation of lesions with FMLP abolished the accumulation of neutrophils after the final stimulus, indicating that complete desensitization can occur and the presence of a chemotaxin within an inflammatory lesion is not sufficient stimulus for neutrophil infiltration of the site to proceed. Lesions initiated with endotoxin supported comparable responses when restimulated with a mixture of FMLP and endotoxin or FMLP alone, despite 93% inhibition of the response to restimulation with endotoxin alone. This indicates that a cell-directed inhibitor of neutrophil migration, such as lipomodulin or neutrophil-immobilizing factor, does not produce the diminished responses in desensitized lesions. It is proposed that desensitization occurs due to down-regulation of a receptor-coupled pathway that permits or facilitates neutrophil extravasation in acute inflammatory lesions. The chemotaxin receptors regulating neutrophil extravasation are probably located on endothelial cells of post-capillary venules.

Topics: Acute Disease; Animals; Caseins; Chemotactic Factors; Desensitization, Immunologic; Dose-Response Relationship, Immunologic; Endotoxins; Female; Inflammation; Leukotriene B4; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Platelet Activating Factor; Rabbits; Zymosan

Leukotriene B4 (LTB4), a metabolite of arachidonic acid and a potent cytotaxin, is generated by human peripheral polymorphonuclear leucocytes (PMNs) exposed to monosodium urate crystals (MSU). The leukotriene is present in gouty effusions in concentrations significantly greater than those found in synovial fluid from patients with active rheumatoid arthritis or osteoarthritis. Further metabolism and biological deactivation of LTB4 by PMNs are partly inhibited by MSU. It is concluded that LTB4 is an important chemical mediator in an acute gouty attack.

Topics: Acute Disease; Adult; Aged; Chemotactic Factors; Crystallization; Gout; Humans; Leukotriene B4; Male; Middle Aged; Neutrophils; Synovial Fluid; Uric Acid