title: Glucocorticoid effects in an endotoxin-induced rat pulmonary inflammation model: differential effects on neutrophil influx, integrin expression, and inflammatory mediators.
abstract: To understand the basis for the refractory nature of acute respiratory distress syndrome (ARDS) to glucocorticoids, the effects of dexamethasone pretreatment (DEX, 2 mg/kg, intraperitoneally) on the kinetics of airway tumor necrosis factor-alpha (TNF alpha) and macrophage inflammatory protein 2 (MIP-2) production, and polymorphonuclear leukocyte (PMN) influx after intratracheal lipopolysaccharide (LPS) (1 mg/kg) in rats were investigated. In the absence of exogenous glucocorticoids, TNF alpha and MIP-2 levels in bronchoalveolar lavage (BAL) fluid peaked at 21 and 300 ng, respectively, by 3 h. DEX pretreatment resulted in a 74% reduction in BAL TNF alpha, yet MIP-2 accumulation was unchanged. In addition, DEX reduced PMN influx at 5 h by 58.4% to 4.1 +/- 0.7 x 10(6) PMN (n = 5). DEX, however, did not mitigate the 3-fold increase in total BAL protein observed at 5 h, attributable to albumin influx. The effects of subacute DEX treatment (3.8 mg/kg per day, for 3 days) on cell-surface expression of the adhesion molecules CD11a, CD11b, and L-selectin were determined by flow cytometric analysis of peripheral blood and autologous BAL PMN. Compared with peripheral blood PMN, exudative PMN had 4-fold greater CD11b expression, no change in CD11a, and loss of L-selectin immunoreactivity 5 h after LPS challenge. The upregulation of CD11b on exudative PMN was insensitive to DEX pretreatment, which, together with a failure to suppress MIP-2 levels, provides a possible explanation for the lack of efficacy of steroids in the management of ARDS.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: O'Leary
authors.forename: P
authors.initials: P
authors.lastname: Marder
authors.forename: S H
authors.initials: SH
authors.lastname: Zuckerman
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D018949:Antigens, CD1 / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000187:drug effects; D054426:Chemokine CXCL2; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D004731:Endotoxins; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000032:analysis*; D016023:Integrins / Q000096:biosynthesis*; D007700:Kinetics; D019041:L-Selectin / Q000276:immunology / Q000378:metabolism; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D008297:Male; D015846:Monokines / Q000096:biosynthesis / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects
chemical_list: D018949:Antigens, CD1; D015815:Cell Adhesion Molecules; D054426:Chemokine CXCL2; D004731:Endotoxins; D005938:Glucocorticoids; D018836:Inflammation Mediators; D016023:Integrins; D008070:Lipopolysaccharides; D015846:Monokines; D014409:Tumor Necrosis Factor-alpha; D019041:L-Selectin; D003907:Dexamethasone; D010196:Pancreatic Elastase