The primary goal of my research is to understand the molecular mechanisms that modulate the development of lung injury and pulmonary fibrosis from occupational and environmental exposures. Specifically, my laboratory focuses on the role of macrophage-derived oxidant production and signaling in the…
more pathogenesis of pulmonary fibrosis. Investigations include basic in vitro studies to uncover mechanisms using a genetic approach in order to manipulate the oxidant signaling. The in vitro studies are translated in vivo in a murine model using transgenic animals. Finally, the observations are then verified in alveolar macrophages from patients with asbestos-induced pulmonary fibrosis. The small GTPase, Rac1, and the antioxidant enzyme, Cu,Zn-SOD, mediate macrophage-derived H2O2 lung injury. Recently we discovered that mitochondria are the primary source of reactive oxygen species in alveolar macrophages exposed to environmental toxins, such as asbestos. The mitochondrial translocation of these effector molecules, Rac1 and Cu,Zn-SOD, generates H2O2, which provides a novel mechanism for release of oxidants after asbestos exposure. We have found that expression of mutant Rac1 and/or Cu,Zn-SOD inhibits mitochondrial oxidative stress. Furthermore, the generation of H2O2 is indispensable for the fibrotic response in lung injury because abrogating mitochondrial oxidant stress attenuates pulmonary fibrosis in mice. Our overall goal is to understand the molecular mechanisms that modulate mitochondrial oxidant levels in alveolar macrophages as it may provide a direct therapeutic target to prevent the development of pulmonary fibrosis.
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