VERY EARLY CHANGES IN PULMONARY PROTEIN KINASE-C-ALPHA AND CALPAIN-IICONTENTS FOLLOWING INJECTION OF BUTYLATED HYDROXYTOLUENE (BHT) INTO MICE

Butylated hydroxytoluene (BHT)-induced lung damage in mice is an excel lent model system for studying mechanisms of chemically-induced, rever sible alveolar injury. Changes in the pulmonary contents of protein ki nase C (PKC) and the calcium-dependent protease, calpain, were previou sly noted during the repair phase following BHT-induced pneumotoxicity . Calpain is believed to initiate PKC down-regulation. PKC-alpha is th e major PKC isozyme and calpain II the major calpain isozyme in mouse lung. We have now studied the time course of these enzymatic changes i n detail. Pulmonary PKC-alpha concentrations decreased as early as 45 min after an i.p. injection of 200 mg/kg BHT. Calpain If levels rose w ithin the first 40 min after BHT injection, and then declined below co ntrol levels. The rapidity of these changes implies a role of these en zymes in mediating the onset of injury. Lung damage and repair, as est imated by measuring the lung weight/body weight ratio, is maximal 6 da ys after administration of this dose of BHT. The extent of the decreas ed PKC-alpha and calpain II concentrations at this time was linearly r elated to the estimated degree of injury based on increased lung weigh t. This correlation suggests the value of monitoring these enzymes as putative early biomarkers of alveolar injury.