Administration of α₁-Proteinase Inhibitor Ameliorates Bleomycin-induced Pulmonary Fibrosis in Hamsters

Abstract

The effect of alpha 1-proteinase inhibitor (alpha 1Pi) administration on the acute lung injury and subsequent fibrosis induced by bleomycin (BLM) was examined in hamsters. Pulmonary lesions were quantitatively reduced in alpha 1Pi-administered BLM-treated (BLM-alpha 1Pi) animals compared with animals treated by BLM alone (BLM-control) at both 7 days (acute stage) and 30 days (fibrotic stage) after BLM treatment. Analysis of intraalveolar cells from bronchoalveolar lavage (BAL) fluid revealed that neutrophils and lymphocytes were significantly decreased in the BLM-alpha 1Pi animals at 7 days after BLM treatment and that 30 days after BLM treatment macrophages as well as neutrophils and lymphocytes were remarkably decreased in the BLM-alpha 1Pi animals. The elastase activity in supernatants of BAL fluid during 7 days following BLM treatment was detected, but there was no difference between the two groups. In vitro studies on neutrophil responsiveness to stimulation of BAL fluid at 3 days after BLM treatment revealed noticeable chemotaxis and generation of superoxide anion of isolated neutrophils, but alpha 1Pi did not show any inhibitory effects on neutrophil responsiveness. We suggest that alpha 1Pi administration ameliorates pulmonary fibrosis preceded by acute lung injury induced by BLM treatment in hamsters and that the inhibitory effects of alpha 1Pi on lung injury may not be brought about by altered elastase activity, chemotaxis, or superoxide generation in neutrophils. Alternative mechanisms are discussed.

Effects of alpha 1-antitrypsin on endotoxin-induced lung inflammation in vivo

“…Today it is well known that AAT exhibits various anti-inflammatory characteristics when administrated systemically or locally in vivo and in cell models in vitro [3,4,[6][7][8][9][10][11]. Several in vitro and in vivo studies exist in which prior initiation of an acutephase response or administration of a specific APP was shown to limit the severity of inflammation or to protect against the lethal effects of toxic stimuli [29][30][31][32]. AAT was also found to inhibit the lethal responses in mice when injected 2 h before TNFa or LPS [6].…”

C-type natriuretic peptide attenuates bleomycin-induced pulmonary fibrosis in mice

“…Considering that IL-1␤ is mainly produced by activated alveolar macrophages, it is interesting to speculate that CNP inhibits IL-1␤ production via inactivation of macrophages. Neutrophils have been shown to induce lung parenchymal injury by producing toxic radical oxygen species and a variety of proteolytic enzymes in BLM-induced fibrosis (12,13,26). The recruitment of lymphocytes has been shown to precede the development of pulmonary fibrosis (10).…”

Neutrophil activation in fibrosing alveolitis: a comparison of lone cryptogenic fibrosing alveolitis and systemic sclerosis

“…Indirect evidence that augmentation of the action of enzyme inhibitors may have a beneficial effect comes from animal models. In the hamster, infused alpha 1 -antitrypsin significantly attenuates the development of bleomycin-induced lung fibrosis, but the mechanism of this effect is unclear [34]. Possible therapeutic roles for other inhibitors of neutrophil enzymes, such as the tissue inhibitors of metaloproteases, are yet to be elucidated.…”