Bleomycin is an
antineoplastic drug commonly used for the treatment of many
carcinomas and
lymphomas. Its toxic side effect on lung tissue is a major limitation to its use, with approximately 3-5% of patients affected. Although the number of affected patients is small, the damage incurred by
bleomycin in these patients is often irreversible and, at times, fatal. A number of
therapies have been shown to be effective in animal studies to minimize damage, but to date no "magic bullet" has been identified. Many
proteins of the fibrinolytic system have been implicated as playing a role in the progression of the disease, one of which is
fibrinogen (Fg) acting in the context of a fibroproliferative agent. Its presence correlates with an upregulation of
plasminogen activator inhibitor-1 and
tissue factor in alveolar cells surrounding the lesion area. It is believed that Fg participates in the activation and migration of fibroblasts and provides a scaffold, in the form of
fibrin, for cell migration following induction of
acute lung injury. To further understand the mechanism of injury following
bleomycin treatment and the possible role of
fibrinogen therein, mice have been generated with a targeted deletion of the gamma-chain of Fg, which resulted in the absence of detectable circulating Fg. The offsprings of Fg heterozygous mice (FG+/-) mice follow Mendelian distributions indicating no embryonic lethality with this deletion. Approximately one-half of the Fg-deficient (FG-/-) neonates exhibited
bleeding episodes, approximately one-half of which were fatal. For the
pulmonary fibrosis study, FG-/- mice and wildtype littermates were administered a
bleomycin solution intratracheally and the disease was allowed to progress for two weeks. The mice were then sacrificed, the left lung was excised for
hydroxyproline analysis, the right lung was processed for histologic profiling. Examination of trichrome stained sections, surprisingly, revealed no qualitative difference between wildtype and FG-/- animals. The extent and pattern of the deposition of
collagen were also similar. These results were quantitatively confirmed by
hydroxyproline analysis, which revealed equivalent increases in
collagen content between wildtype and FG-/- animals when compared to appropriate saline controls. Analysis of the early acute inflammatory stage of the disease showed a difference in the neutrophil population between days three and five of the disease. These studies suggest that, although
fibrinogen is not required for
collagen deposition at the later stage of the disease, it may play a role in the early acute
inflammation stage.