ROLE OF INTERCELLULAR-ADHESION MOLECULE-1 IN GLUCAN-INDUCED PULMONARYGRANULOMATOSIS IN THE RAT

Glucan-induced pulmonary granulomatous vasculitis in the rat mimics se veral human lung diseases (e.g., Wegener's granulomatosis, intravenous talcosis). We sought to clarify the role of intercellular adhesion mo lecule-1 (ICAM-1) in the pathogenesis of glucan-induced granulomatous vasculitis. Immunohistochemical analysis of lung sections from rats wi th florid vasculitis (48 hours) revealed marked alveolar septal and le sional expression of ICAM-1. An ex vivo binding analysis with isotope- labeled antibodies and lung sections taken at various times up to 48 h ours after glucan infusion revealed a progressive increase in whole-lu ng ICAM-1 expression. In vivo measurements of vascular wall-associated ICAM-1 expression revealed an earlier rise that began less than 6 hou rs after glucan infusion, peaked at 24 to 48 hours, and then declined to near baseline during the ensuing 24 to 96 hours. To assess whether ICAM-1 expression both within blood vessel walls and within lesions pe r se is important in granuloma development, we carried out in vivo neu tralization experiments with several different routes of administratio n of antibody to ICAM-1. Monoclonal antibody to rat ICAM-1 was either infused intravenously at time 0 (when glucan was infused), infused int ravenously at time 0 and after 24 hours, instilled only intratracheall y 24 hours after glucan infusion, or given both intravenously (time=0 and 24 hours) and intratracheally (time=24 hours). Infusions of monocl onal antibody to rat ICAM-1 resulted in dose-dependent reductions in m ean granuloma number and cross-sectional area. Intrapulmonary instilla tion of antibody to rat ICAM-1 (via tracheostomy 24 hours after glucan infusion) resulted in a modest reduction in mean granuloma number and cross-sectional area. When antibody to ICAM-1 was both infused and in stilled via the trachea, we found an additive reduction in mean granul oma size and number. There was a 12-fold increase in adhesion of ED-1- positive peripheral blood mononuclear cells (monocytes) to granuloma-b earing frozen lung sections prepared 48 hours after glucan infusion. M oreover, 73% of the additional adherent monocytes were bound specifica lly to granulomas per se. The increase in ex vivo monocyte binding to lung sections prepared at 48 hours was reduced 62% when sections were incubated with monoclonal antibody to ICAM-1. Taken together, these da ta indicate that ICAM-1 expression in evolving glucan-induced granulom atous vasculitis occurs first within blood vessel walls and then withi n lesional cells per se. The in vivo blocking studies suggest that ICA M-1 expression in both anatomic sites is important in granuloma develo pment.