Mechanisms of neutrophil accumulation in the lungs of patients with idiopathic pulmonary fibrosis

Abstract

Neutrophils are a characteristic feature of the alveolitis of idiopathic pulmonary fibrosis (IPF), a chronic disorder limited to lung. One mechanism by which neutrophils may be selectively attracted to lung and not other tissues is via the secretion of a neutrophil-specific chemotactic factor by alveolar macrophages. To evaluate the role of alveolar macrophages in modulating the migration of neutrophils to the lung in IPF, alveolar macrophages, obtained by bronchoalveolar lavage of patients with IPF, were evaluated for their ability to release a chemotactic factor for neutrophils. Unstimulated alveolar macrophages from normal individuals did not release the factor. In patients with IPF, there was a significant correlation between the proportions of neutrophils in lavage fluid and the release of a chemotactic factor for neutrophils by alveolar macrophages (P < 0.001). The chemotactic factor released by IPF alveolar macrophages was of low molecular weight (400-600), at least partially lipid in nature, and preferentially attracted neutrophils compared with monocytes. Several lines of evidence suggested that immune complexes in the lung stimulated alveolar macrophages of patients with IPF to release the chemotactic factor. First, immune complexes stimulated normal macrophages to release the factor. Second, there was a significant correlation between the release of the chemotactic factor by IPF alveolar macrophages and the levels of immune complexes in bronchoalveolar lavage fluid. Third, bronchoalveolar lavage fluid containing immune complexes stimulated normal macrophages to release the factor. Fourth, IPF alveolar macrophages that released large amounts of the chemotactic factor had an apparent suppression of their immunoglobulin (Ig)G Fc receptor function, suggesting that immune complexes were bound to their surface. In contrast, the IgG Fc receptor function of IPF alveolar macrophages that released only small amounts of the factor was similar to that of normal macrophages. These studies suggest that neutrophils are attracted to the lung in patients with IPF by a potent chemotactic factor released by alveolar macrophages that have been stimulated, in vivo, via their IgG Fc receptor by immune complexes.