Exosome protease-mediated inflammation, tissue damage and cellular senescence in pathogen-induced lung disease

Proteases bound to exosomes, released from inflammatory cells, are thought to drive lung damage in diseases such as chronic obstructive pulmonary disease. We now wish to evaluate the contribution of a wide range of proteases to exosome-mediated lung inflammation, damage and senescence in pathogen- driven (bacterial and viral) lung disease.

Lung diseases such as chronic obstructive pulmonary disease (COPD) contribute to alarmingly high levels of death and morbidity and are driven by viral and bacterial pathogens. We know that that these respiratory pathogens can induce the release of proteases from inflammatory cells and airway epithelium, which may in turn, contribute to lung inflammation, lung damage and senescence. Recent data have shown that some of these proteases may remain attached to cells or exosomes following activation in the diseased lung. These surface- bound proteases may be more difficult to inhibit as they are bound to exosomes or the cell surface and may explain, in part, the lack of efficacy of protease inhibitors in clinical trials. In this study, we will evaluate the contribution of proteases bound to exosomes isolated from the lungs of patients with COPD to features of airway senescence, inflammation and tissue damage. We will utilise novel protease inhibitors to inhibit these exosome- bound proteases and evaluate the ability of protease inhibitors to reverse pathogen (bacterial and viral)-induced senescence, ameliorate inflammation and reduce the tissue damage associated with COPD.