Administration of a synthetic antiprotease reduces smoke-induced lung injury

Our previous studies suggest that a neutrophil-mediated inflammatory injury causes a major fraction of the pulmonary edema that occurs after smoke inhalation. Because activated neutrophils extrude cytotoxic proteases, the current study was conducted to evaluate the role of proteases in the pulmonary microvascular injury. Twelve sheep, instrumented for collection of lung lymph, were insufflated with cotton smoke. The sheep were treated 30 min after smoke inhalation with either gabexate mesilate (an inhibition of serine proteases) or vehicle. Smoke inhalation resulted in an increased protease activity in the lung interstitium, as evidenced by decreases in both antiprotease activity and immunoreactive α₂-macroglobulin. Intravenous infusion of gabexate mesilate prevented the decrease in antiprotease activity. The protease inhibitor significantly attenuated the smoke-induced increase in transvascular fluid and protein flux, with untreated animals exhibiting 460% increases in flux compared with 180% in the inhibitor treated sheep. The protease inhibitor also eliminated the functional degradation in gas exchange that was observed in the untreated sheep. These studies strongly suggest that an increase in pulmonary proteolytic enzyme activity is responsible for a significant fraction of the degradation in microvascular integrity and gas exchange that is associated with smoke inhalation injury.