Evaluation of ilomastat, a matrix metalloprotease inhibitor, as a treatment for sulfur mustard (SM) inhalation injury

Abstract

The broad spectrum matrix metalloprotease inhibitor Ilomastat was evaluated for its ability to ameliorate SM-induced lung injury. Anesthetized rats were tracheally intubated and exposed to 1.4 mg/kg SM by vapor inhalation. Ilomastat (100 mg/kg in phosphate buffered saline) was administered intraperitoneally 2 min prior to exposure. At 24 hr post-exposure, a blood sample was taken, rats were euthanized and the lungs lavaged with saline (3 five ml washes). The recovered bronchoalveolar lavage fluid (BALF) was evaluated for biochemical indicators of SM-induced lung injury. Lung weight/body weight ratios (LW/BW) showed that SM-exposed rats had higher (p<0.05) LW/BW compared with controls, indicating lung injury. Cytological analysis of lavage fluid showed significantly higher neutrophil counts for the SM-exposed groups vs controls, indicative of an inflammatory response. Neither of these parameters was affected by Ilomastat treatment. Analysis of recovered bronchoalveolar lavage fluid (BALF) showed that SM caused significant increases (>20 fold) in the levels of the cytokines IL-1alpha, IL1beta, and IL-2, as well as interferon-gamma. These changes were eliminated or reduced with Ilomastat treatment. Also in BALF, we observed SM-induced changes in clinical chemistries such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK) and lactate dehydrogenase (LDH), which were reduced in the Ilomastat-treated animals. These early results indicate that Ilomastat treatment reduces some of the inflammatory response and damage associated with SM-induced lung injury.