ROLE OF PROTEASE IN INFECTION & INFLAMMATION OF COPD

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DESCRIPTION (adapted from the applicants' abstract) The project will analyze the role of the neutrophil/monocyte serine proteases, elastase, cathepsin-G and proteinase-3, and their specific inhibitors, alpha- 1-antitrypsin and especially MNEI (monocyte/neutrophil elastase inhibitor), in infection and inflammation of COPD. The hypothesis to be evaluated is that excess of the proteases in inflammatory lung fluids contributes to disease progression, not only by inducing inflammation and injury, but also importantly by targeting and destroying innate anti-microbial pulmonary defense molecules. Based largely on the investigators recent findings, the investigators hypothesize that an important innate defense molecule targeted by the proteases, and protected by MNEI, is surfactant protein-A (SP-A), an opsonin and activating agent, known to enhance uptake and clearance of microbes by resident pulmonary macrophages. Studies are proposed in a mouse model of excess neutrophil/monocyte protease activity, which the investigators will generate by targeting the mnei gene. Mnei-A def deficient mice will be compared to wildtype mice for their ability to clear pulmonary infections with Streptococcus pneumoniae and nontypeable Haemophilus influenzae, significant infectious agents in chronic bronchitits. Inflammatory parameters (neutrophil influx, free protease, SP-A levels, cytokines, chemokines) will also be compared. Using a complementary human in vitro system, the investigators will compare inflammatory lung fluids (BAL supernatants) of COPD patients with lung fluids of normal healthy non-smokers and smokers, for their ability to enhance uptake of S. pneumoniae and H. influenzae by normal macrophages. The investigators will examine also the effect of exogenous protease on bacterial uptake enhancing activity (including SP-A). Clarifying the role of elastase, cathepsin-G and proteinase-3 in disease progression of COPD is important, among other reasons, because therapeutic modalities are now feasible and could be delivered to the patients if the underlying pathological processes were understood.