PULMONARY GRANULOMA-FORMATION IN THE RAT IS PARTIALLY DEPENDENT ON MONOCYTE CHEMOATTRACTANT PROTEIN-1

BACKGROUND: We have examined the role of MCP-1 (monocyte chemoattracta nt protein 1; also known a's monocyte chemotactic and activating facto r or the murine JE gene product) in the pathogenesis of glucan-induced granulomatous vasculitis in the rat. While in vitro studies indicate that MCP-1 possesses monocyte chemotactic and activating activities, l ittle is known about its biologic role in pathologic processes. Glucan -induced pulmonary granulomatous vasculitis is an ideal model in which to study the role of MCP-1, because the granulomas develop rapidly an d synchronously and are monocyte/macrophage-rich. EXPERIMENTAL DESIGN: The purpose of this study was to define the topographic distribution and temporal pattern of MCP-1 expression in the lungs of rats with evo lving glucan-induced granulomatous vasculitis and to determine the eff ect of neutralization of MCP-1 activity on granuloma formation. Glucan -induced pulmonary granulomatous vasculitis was induced in rats by the intravenous infusion of yeast cell wall glucan. At the indicated time points after glucan infusion, rats were sacrificed and the lungs proc essed for Northern, immunohistochemical and in situ hybridization anal yses of MCP-I production. Morphometric analysis was used to quantify t he effect of neutralization of MCP-I activity on granuloma formation. RESULTS: Granuloma formation was accompanied by a biphasic increase in steady-state whole lung MCP-1 mRNA levels that peaked at 1 and 6 to 2 4 hours. In situ hybridization and immunohistochemical analyses reveal ed that components of the bronchial and vascular walls are responsible for the early rise (1 hour) in MCP-1 mRNA and protein expression, whe reas granuloma-associated alveolar macrophages are the predominant sou rce of MCP-1 later (6 to 24 hours) in the evolution of these lesions. Intravenous infusion and/or intratracheal instillation of neutralizing concentrations of anti-rat MCP-1 antibody raised against recombinant rat MCP-1 resulted in a dramatic decrease in the number and size of gl ucan-induced granulomas as well as in the numbers of mononuclear phago cytes retrieved in bronchoalveolar lavage fluid. CONCLUSIONS: These st udies demonstrate that glucan-induced granulomatous vasculitis is acco mpanied by increased local expression of MCP-1 mRNA and protein, that there is a coordinated production of MCP-1 by different cell types wit hin the lung during evolving glucan-induced pulmonary vasculitis, and that MCP-1 plays a requisite role in pulmonary granuloma formation.