Enzymes and inhibitors in Lung Disease

Enzymes and inhibitors in lung disease

Neutrophils (neutrophilic granulocytes) and killer cells form a first line of defense against invading bacteria and viruses and are equipped with a large arsenal of lethal destructive weapons, of which serine proteases are most prominent. The traditional opinion of proteases being destructive scissors for the purpose of degradation and elimination of microbes and tissues has been complemented by new perspectives on their role in regulating cellular processes, innate immune responses and tissue remodelling.

We are particularly interested in the functions and target substrates of neutrophil serine proteases, their role in immune defense, cell migration and cellular activation. Apart from the three known serine proteases of primary granules, elastase, cathepsin G and proteinase 3, a fourth member, NSP4, which was discovered by us very recently, is being characterized at the biochemical and functional levels both in vitro and in vivo. Using genetically modified mice, that lack one or a combination of these protease genes, we are able to analyze the molecular defects and alterations in neutrophil-mediated responses, in cell migration and in clinical disease models after elimination of these proteases.

As these four serine proteases appear to mediate diverse proinflammatory effects in preclinical mouse models of lung diseases, their specific inhibition should ameliorate a number of chronic disease conditions. Moreover, specific autoantibodies to endogenous neutrophil proteins develop in certain chronic inflammatory diseases with aggravating consequences. In particular, autoantibodies to proteinase 3 and myeloperoxidase are specific and diagnostically useful for systemic vasculitides and trigger disease relapses and lung injury in patients.