Lipopolysaccharide-induced leukocyte rolling and adhesion in the rat mesenteric microcirculation: regulation by glucocorticoids and role of cytokines.
A common side effect of high dose glucocorticoid therapy is increased susceptibility to bacterial infection, an effect that is in part mediated through inhibition of leukocyte recruitment to infected areas. However, the sites at which glucocorticoids act to prevent the multistep process of leukocyte recruitment have not been fully established. In this study, the effects of the glucocorticoid dexamethasone (DEX) on leukocyte-endothelial interactions, in response to bacterial LPS, were examined utilizing a model of rat mesenteric intravital microscopy. Pretreatment of rats with DEX (0.5 mg/kg) for 18 h or 30 min before stimulation with LPS significantly inhibited LPS-induced leukocyte rolling and adhesion in mesenteric postcapillary venules. Pretreatment with DEX also inhibited LPS-induced changes in expression of L-selectin and a shared epitope of CD11b/c on circulating neutrophils. These effects of DEX may be due to DEX inhibition of IL-1, TNF, and cytokine-induced neutrophil chemoattractant-1 (CINC-1) generation, since antagonists to these mediators were able to mimic DEX effects on leukocyte-endothelial interactions and circulating leukocyte phenotype. These data indicate that inhibition of cytokine- and chemokine-induced leukocyte-endothelial interactions may be a primary mechanism by which glucocorticoids inhibit leukocyte recruitment to bacterial agents and thus increase susceptibility to infection.
Davenpeck
K L
KL
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
Zagorski
J
J
Schleimer
R P
RP
Bochner
B S
BS
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D018821:CD18 Antigens / Q000096:biosynthesis / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003864:Depression, Chemical; D003907:Dexamethasone / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000473:pathology; D019446:Endotoxemia / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006133:Growth Substances / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D019041:L-Selectin / Q000096:biosynthesis / Q000235:genetics; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016177:Macrophage-1 Antigen / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008642:Mesenteric Veins / Q000473:pathology*; D008833:Microcirculation; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology; D014699:Venules
D000893:Anti-Inflammatory Agents; D018821:CD18 Antigens; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C513297:Cxcl1 protein, rat; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016177:Macrophage-1 Antigen; D014409:Tumor Necrosis Factor-alpha; D019041:L-Selectin; D003907:Dexamethasone