Granzyme activity in the inflamed lung is not controlled by endogenous serine proteinase inhibitors

Numerous lung diseases, such as hypersensitivity pneumonitis (HP), are char acterized by the presence of activated alveolar CTL and NK cells. Since the se cells produce granzymes, granzyme A and B levels in bronchoalveolar lava ge (BAL) fluids from 14 normal subjects and 12 patients with HP were measur ed by ELISA, Median (range) BAL granzyme A and B levels were 4 (0-37) and 0 (0-6) pg/ml in normal subjects. BAL granzyme levels were significantly hig her in HP patients, being at 74 (0-1889) and 10 (0-78) pg/ml for granzymes A and B, respectively. In vitro, neither of the three main serine protease inhibitors of the lung, namely alpha(1)-antitrypsin, secretory leukocyte pr otease inhibitor,and elafin,showed any effect on granzyme A or B activity. In addition, granzyme a was shown to be fully active in BAL fluids. Hence, these data show that granzyme activity may be poorly controlled by protease inhibitors in inflamed tissues. Thus, granzymes could contribute to tissue remodeling and inflammation characterizing HP.