POLYMERIZATION OF FIBRINOGEN IN MURINE BLEOMYCIN-INDUCED LUNG INJURY

Bleomycin lung injury in mice leads to an acute alveolitis followed by a fibroproliferative response characterized by the accumulation of ex tracellular matrix. Because distinct regions of the fibrin(ogen) molec ule have unique in vitro biological effects on cells, we quantified, l ocalized, and biochemically characterized the molecular form of extrav ascular fibrin(ogen) in methoxyflurane anesthetized, bleomycin-injured mice. Bleomycin or saline (controls) was administered intratracheally , and lung tissue was harvested and analyzed at several times thereaft er. Immunoreactive fibrin tissue content increased to a maximal 50-fol d over controls in a temporal and spatial pattern paralleling that of alveolitis and maximal fibroproliferation. The generation of gamma-gam ma-chain dimers and alpha-chain polymers, together with the loss of fr ee alpha- and gamma-chains, indicates that the fibrin is predominantly covalently cross-linked. In fibroproliferative phase lungs, the fibri n fibrils are branched and colocalize with those of collagen at the el ectron microscopic level. These observations strongly suggest that fib rin is a significant molecular effector of the in vivo fibroproliferat ive response after lung injury.