Regulatory effects of endogenous protease inhibitors in acute lung inflammatory injury

Inflammatory lung injury is probably regulated by the balance between prote ases and protease inhibitors together with oxidants and antioxidants, and p roinflammatory and anti-inflammatory cytokines, Rat tissue inhibitor of met alloprotease-2 (TIMP-2) and secreted leukoprotease inhibitor (SLPI) were cl oned, expressed, and shown to be up-regulated at the levels of mRNA and pro tein during lung inflammation in rats induced by deposition of IgG immune c omplexes. Using immunoaffinity techniques, endogenous TIMP-2 in the inflame d lung was shown to exist as a complex with 72- and 92-kDa metalloproteinas es (MMP-2 and MMP-9), In inflamed lung both TIMP-2 and SLPI appeared to exi st as enzyme inhibitor complexes, Lung expression of both TIMP-2 and SLPI a ppeared to involve endothelial and epithelial cells as well as macrophages, To assess how these endogenous inhibitors might affect the lung inflammato ry response, animals were treated with polyclonal rabbit Abs to rat TIMP-2 or SLPI, This intervention resulted in significant intensification of lung injury las revealed by extravascular leak of albumin) and substantially inc reased neutrophil accumulation, as determined by cell content in bronchoalv eolar lavage (BAL) fluids. These events were correlated with increased leve ls of C5a-related chemotactic activity in BAL fluids, while BAL levels of T NF-alpha and chemokines were not affected by treatment with anti-TIMP-2 or anti-SLPI, The data suggest that endogenous TIMP-2 and SLPI dynamically reg ulate the intensity of lung inflammatory injury, doing so at least in part by affecting the generation of the inflammatory mediator, C5a.