Evaluation of Protease Inhibitors and an Antioxidant for Treatment of Sulfur Mustard-Induced Toxic Lung Injury

摘要

Sulfur mustard (SM)-induced lung injury has been associated with protease activation, oxidative injury and inflammatory response culminating in tissue necrosis. The protease inhibitors aprotinin and ilomastat and the antioxidant trolox were evaluated for efficacy in ameliorating SM-induced lung injury. Anesthetized spontaneously breathing rats (N= 6-8/group) were intratracheally intubated and exposed to 1.4 mg/kg SM (0.35mg SM in 0.1 ml of ethanol) or ethanol alone by vapor inhalation for 50 min. At 1 min before the exposure rats were treated with one of the following: intravenous aprotinin, 4.4 mg/kg; intraperitoneal (ip) ilomastat, 25 mg/kg; or ip trolox, 500 micrograms/kg. Aprotinin-treated animals received supplemental 2.2 mg/kg doses at 1 min and 6 h post-exposure (PE). A whole body plethysmograph system was used to monitor pulmonary function (PF) parameters for 1 h before exposure (baseline), and from 5-6 and 23-24 hpost-exposure. SMinhalation caused significant increases in several PF parameters, including tidal volume, peak inspiratory flow, peak expiratory flow, end expiratory pause and enhanced pause. Consistent with the reported development of SM-induced pathology, these changes were minimal at the 5-6-h time and significant at the 23-24-h timepoint. At the later time it is known from previous work that airways are becoming obstructed with loose cellular debris, damaged cells and exudate, which contributed to the changes in PF parameters. Treatment with aprotinin or ilomastat eliminated these PF changes, yielding results comparable with controls for each of these parameters. Lung lavage fluid analysis showed that SM caused a significant increase in total protein (TP) and in the cytokines IL- 1alpha and IL-13.