KINETIC EXPRESSION OF ENDOTHELIAL ADHESION MOLECULES AND RELATIONSHIPTO LEUKOCYTE RECRUITMENT IN 2 CUTANEOUS MODELS OF INFLAMMATION

BACKGROUND: Adhesive interactions between circulating leukocytes and e ndothelium is requisite for subsequent leukocyte extravasation at infl ammatory sites. These adhesive events are mediated by a repertoire of proteins and carbohydrate moieties on both leukocyte and endothelial m embranes. Understanding the kinetic expression of these adhesion molec ules during an inflammatory cascade in vivo is important for the desig n and testing of rational therapeutic approaches directed at the block ade of adhesion molecule function in inflammatory disease. EXPERIMENTA L DESIGN: Two cutaneous inflammatory models were examined using health y rhesus monkeys. Acute cutaneous injury was studied during a 72-hour period by intradermal injection of endotoxin (lipopolysaccharide) and subsequent biopsy. These tissues were then compared with those obtaine d from a cutaneous delayed-type hypersensitivity reaction (DHR), elici ted by intradermal injections of mammalian tuberculin in sensitized an imals and followed for up to 11 days. Expression of E-selectin, P-sele ctin, VCAM-1, and ICAM-1 was assessed using immunohistochemistry and c ompared with leukocyte localization and immunohistochemical expression of interleukin (IL) 1, IL-8 and tumor necrosis factor-alpha (TNF-alph a). Finally, relevant adhesion ligands on leukocytes were assessed usi ng flow cytometry. RESULTS: The lipopolysaccharide model was character ized by early (0.5 hours) and sustained (up to 72 hours) expression of E-selectin on the superficial dermal vasculature, with maximal expres sion by 8 hours. The expression of VCAM-1 was either not detected or m inimal. Neutrophil localization, as detected by elastase immunoreactiv ity, paralleled E-selectin expression with a 4- to 12-hour lag phase, being maximal by 24 hours. In contrast, DHR was characterized by the d ual asynchronous expression of both E-selectin and VCAM-1. Localizatio n of CD2(+) lymphocytes, representing the predominant cell type recrui ted, kinetically followed the expression of E-selectin and VCAM-1, bei ng maximal in number at approximately 48 hours after peak expression o f both of these endothelial proteins. Neutrophil recruitment in lipopo lysaccharide-induced injury was associated with immunohistochemical lo calization of TNF-alpha, IL-1, and IL-8, whereas only TNF-alpha was co nsistently detected in DHR. During DHR, blood lymphocyte expression of L-selectin, VLA-4 (CD49d; alpha chain), and lymphocyte function-assoc iated antigen 1 (both CD11a (alpha chain) and CD18 (beta chain)) did n ot change. CONCLUSIONS: The results from this study demonstrate that c utaneous inflammatory infiltrates of varying cellular compositions are associated temporally and spatially with unique patterns of endotheli al adhesion molecule and cytokine expression.