Monocyte chemoattractant protein 1 in a rat model of pulmonary granulomatosis

Abstract

Monocyte chemoattractant protein 1 (MCP1), also known as monocyte chemotactic and activating factor, possesses potent chemotactic activity for monocytes and can augment monocyte tumoristatic activity against some tumor cell lines. While these activities suggest a role in inflammatory and immunologic processes, the biologic role of MCP1 has not been studied in vivo. Glucan-induced pulmonary granulomatosis in the rat is an ideal model in which to study the role of MCP1 because the granulomas are monocyte/macrophage rich. Intravenous infusion of particulate yeast cell wall glucan resulted in the synchronous development of angiocentric pulmonary granulomas. Early lesions (6 hours) were characterized by intravascular glucan aggregates surrounded by neutrophils and foci of alveolar hemorrhage while later appearing granulomatous lesions (48 to 96 hours) were dominated by monocytes and macrophages. Granuloma formation was paralleled by a peripheral blood monocytosis. Analysis of bronchoalveolar lavage (BAL) fluid revealed an early, transient rise in tumor necrosis factor activity followed by a marked rise in monocyte-specific chemotactic activity. The rise in BAL fluid monocyte chemotactic activity, which coincided with the development of the monocyte/macrophage-rich granulomas, was preceded by a marked increase in whole lung MCP1 mRNA expression. BAL fluid monocyte chemotactic activity could be nearly completely neutralized with antibody directed against rat MCP1. These studies demonstrate that MCP1 mRNA expression is upregulated in glucan-induced pulmonary granulomatosis and that MCP1 is present in BAL fluid. Intrapulmonary granulomatosis may be important in the pathogenesis of granuloma formation.