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

BACKGROUND: Adhesive interactions between circulating leukocytes and endothelium is requisite for subsequent leukocyte extravasation at inflammatory sites. These adhesive events are mediated by a repertoire of proteins and carbohydrate moieties on both leukocyte and endothelial membranes. Understanding the kinetic expression of these adhesion molecules during an inflammatory cascade in vivo is important for the design and testing of rational therapeutic approaches directed at the blockade of adhesion molecule function in inflammatory disease. EXPERIMENTAL DESIGN: Two cutaneous inflammatory models were examined using healthy 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 obtained from a cutaneous delayed-type hypersensitivity reaction (DHR), elicited by intradermal injections of mammalian tuberculin in sensitized animals and followed for up to 11 days. Expression of E-selectin, P-selectin, VCAM-1, and ICAM-1 was assessed using immunohistochemistry and compared with leukocyte localization and immunohistochemical expression of interleukin (IL) 1, IL-8 and tumor necrosis factor-alpha (TNF-alpha). Finally, relevant adhesion ligands on leukocytes were assessed using flow cytometry. RESULTS: The lipopolysaccharide model was characterized by early (0.5 hours) and sustained (up to 72 hours) expression of E-selectin on the superficial dermal vasculature, with maximal expression by 8 hours. The expression of VCAM-1 was either not detected or minimal. Neutrophil localization, as detected by elastase immunoreactivity, paralleled E-selectin expression with a 4- to 12-hour lag phase, being maximal by 24 hours. In contrast, DHR was characterized by the dual asynchronous expression of both E-selectin and VCAM-1. Localization of CD2(+) lymphocytes, representing the predominant cell type recruited, kinetically followed the expression of E-selectin and VCAM-1, being maximal in number at approximately 48 hours after peak expression of both of these endothelial proteins. Neutrophil recruitment in lipopolysaccharide-induced injury was associated with immunohistochemical localization of TNF-alpha, IL-1, and IL-8, whereas only TNF-alpha was consistently detected in DHR. During DHR, blood lymphocyte expression of L-selectin, VLA-4 (CD49d; alpha chain), and lymphocyte function-associated antigen 1 (both CD11a (alpha chain) and CD18 (beta chain)) did not change. CONCLUSIONS: The results from this study demonstrate that cutaneous inflammatory infiltrates of varying cellular compositions are associated temporally and spatially with unique patterns of endothelial adhesion molecule and cytokine expression.