Abstract

Neutrophil elastase (NE) activity is increased in lung diseases such as alpha-1-antitrypsin (A1AT) deficiency and pneumonia. We have recently demonstrated that NE can induce expression of cathepsin B and MMP 2 in vitro and in a mouse model. We postulated that increased Cathepsin B and MMP-2 in acute and chronic lung diseases are due to the presence of high levels of extracellular NE and that expression of these proteases could be inhibited by A1AT augmentation therapy. Cathepsin and MMP activities were assessed in bronchoalveolar lavage fluid (BAL) from A1AT deficient, pneumonia and control patients. Macrophages were exposed to BAL rich in free NE from pneumonia patients, following pre-treatment with A1AT. MMP-2, Cathepsin B, SLPI and lactoferrin levels were determined in BAL from A1AT deficient patients pre and post aerosolization of A1AT. BAL from both pneumonia and A1AT deficient patients, containing free neutrophil elastase, had increased cathepsin B and MMP-2 activities compared to BAL from healthy volunteers. Addition of A1AT to pneumonia BAL greatly reduced NE-induced cathepsin B and MMP-2 expression in macrophages in vitro. A1AT augmentation therapy to A1AT deficient individuals also reduced cathepsin B and MMP-2 activity in BAL in vivo. Furthermore, A1AT deficient patients had higher levels of SLPI and lactoferrin post A1AT augmentation therapy. This study describes a novel role for A1AT - inhibition of neutrophil elastase-induced up-regulation of expression of MMPs and cathepsins both in vitro and in vivo.