Characterization of matrix metalloproteinases from the rat alveolar macrophage: Role in acute alveolitis in the rat.

Abstract

The matrix metalloproteinases (MMPs) are important proteolytic enzymes which have known roles in normal processes involving matrix turnover and tissue remodeling. MMPs have also been implicated in a diverse selection of pathologic processes. Recent studies from our laboratories have demonstrated a role for neutrophil MMPs in a neutrophil-dependent model of IgG immune complex-mediated acute lung inflammation in the rat. Alveolar macrophages have well-defined roles in the phagocytosis of inhaled irritants and the initiation of inflammation through the production of cytokines. There is also evidence of a role for alveolar macrophage-derived oxidants in acute inflammation, but the role of alveolar macrophage MMPs in acute lung inflammation is unknown. The purpose of these studies was to determine whether MMPs play a role in the progression of macrophage-dependent acute lung inflammation and, if so, to identify the specific proteinases involved and their source. To this end, two rat models of experimental acute alveolitis were studied: an IgA immune complex-induced model which is known to be macrophage-dependent and neutrophil-independent, and a lipopolysaccharide (LPS)-induced model which is known to be both macrophage and neutrophil dependent. The data from these studies show that both the IgA and the LPS injury models are inhibited by recombinant human tissue inhibitor of metalloproteinases-two (TIMP-2). Further, the component of LPS injury which remains after neutrophil-depletion is also inhibitable by TIMP-2. Bronchoalveolar lavage fluids from injured animals of both models show increased levels of MMPs. Analysis of MMP secretion by endothelial cells, fibroblasts, type II epithelial cells, neutrophils, and alveolar macrophages isolated from rat lungs shows that only the alveolar macrophages produce a spectrum of MMP secretion which matches that seen in BAL. Alveolar macrophages taken from injured lungs in both models show evidence of in vivo activation to produce this same spectrum of activities. In vitro characterization studies identify these activities as MMP-9, MMP-2, and MMP-12. Taken together the data show that MMPs are produced during macrophage-dependent acute lung injury, that these MMPs play a role in the progression of injury, and that the alveolar macrophage is the likely source of these matrix metalloproteinases.