Emphysema is an age-related and chronic inflammatory disease that is largely associated with exposure to cigarette smoke and caused by a protease/antiprotease imbalance in the lungs. The identification of the cellular origin of the inflammatory mediators and the mechanisms underlying their expression and function is fundamental for gaining insight into the link between chronic inflammation and age-related lung disease. Senescent cells are characterized by irreversible cell cycle arrest. They remain metabolically active and are capable of secreting mediators of inflammation in vitro. Chronic exposure to cigarette smoke induces senescence of fibroblasts and hallmarks of senescence are found in lung fibroblasts of emphysema patients. Interestingly, our published data show that caveolin-1 promotes chronic cigarette smoke-induced senescence of lung fibroblasts in mice. To determine whether a causal relationship exists between caveolin-1-mediated senescence of lung fibroblasts and development of emphysema, we propose to test the novel paradigm that caveolin-1-mediated inhibition of autophagy promotes smoke-induced autophagy-to-senescence transition (AST) of lung fibroblasts, which become a chronic source of pro-inflammatory chemokines that stimulate the release of proteases by inflammatory cells, therefore contributing to the development of pulmonary emphysema. This central hypothesis will be tested by pursuing three specific aims:
Aim 1 : Determine the molecular mechanism of autophagy-to-senescence transition in lung fibroblasts. Hypothesis: caveolin-1 is a novel beclin-1-interacting protein. Caveolin-1 promotes cigarette smoke-induced AST of lung fibroblasts by inhibiting autophagy through disruption of the beclin-1/Vps34 complex.
Aim 2 : Identify the molecular mechanism and functional significance of the cigarette smoke-induced and caveolin-1-mediated chronic release of mediators of inflammation by senescent fibroblasts. Hypothesis: caveolin-1, through inhibition of eNOS activity, promotes the NF-kB-mediated sustained expression and secretion of chemokines by senescent fibroblasts that underwent AST, which stimulate the release of proteases by inflammatory cells.
Aim 3 : Determine if caveolin-1-mediated senescence of lung fibroblasts promotes chronic lung inflammation and emphysema in vivo. Hypothesis: chronic exposure to cigarette smoke induces senescence of lung fibroblasts, which promote chronic lung inflammation and contribute to the pathogenesis of emphysema in a caveolin-1-dependent fashion in vivo. These investigations will identify the caveolin-1-mediated switch from autophagic to senescent signaling as a novel biological process that is relevant to chronic lung inflammation and the pathogenesis of emphysema. Novel cellular and molecular mechanisms will be determined that have the potential to directly impact the future development of novel therapeutic interventions for the treatment of age-related lung disease.
Chronic inflammation is associated with age-related diseases, such as pulmonary emphysema. Pulmonary emphysema is a fatal lung disease that occurs after chronic exposure to cigarette smoking. Although we know that chronic inflammation promoted by cigarette smoking plays a crucial role in the pathogenesis of pulmonary emphysema, the cellular origin of the mediators of inflammation that cause emphysema and the molecular mechanisms through which they act remain to be fully identified. This research proposal seeks to understand at the molecular, cellular and animal levels how senescence of lung fibroblasts is functionally associated with chronic inflammation and pulmonary emphysema. New information that will be obtained from our studies has the potential to directly impact the future development of novel therapeutic interventions for the treatment of age-related lung disease.