ROLE OF MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA (MIP-1-ALPHA) IN ACUTE LUNG INJURY IN RATS

The role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in t he pathogenesis of acute lung injury in rats after intrapulmonary depo sition of IgG immune complexes or intratracheal administration of LPS has been assessed. Critical to these studies was the cloning and funct ional expression of rat MIP-1 alpha. The resulting product shared 92% and 90% homology with the known murine sequence at the cDNA level and protein level, respectively. Recombinant rat MIP-1 alpha exhibited dos e-dependent chemotactic activity for both rat and human monocytes and neutrophils, which could be blocked by anti-murine MIP-1 alpha Ab. Rat MIP-1 alpha mRNA and protein expression were determined as a function of time in both injury models. A time-dependent increase in MIP-1 alp ha mRNA in lung extracts was observed in both models. In the LPS model , MIP-1 alpha protein could also be detected in bronchoalveolar lavage (BAL) fluids by Western blot analysis. Anti-MIP-1 alpha administered at commencement of Ige immune complex- or LPS-induced injury resulted in significant reductions in BAL neutrophils as well as in injury as m easured by pulmonary vascular permeability. Under such conditions, in both models TNF-alpha content in BAL fluids was substantially reduced as compared with BAL fluids from positive control animals. These findi ngs suggest that rat MIP-1 alpha plays an important role in the develo pment of lung injury in these neutrophil-dependent models. The role of MIP-1 alpha seems to be related to production of TNF-alpha, which in turn up-regulates vascular adhesion molecules required for neutrophil influx.