Catalase attenuates pulmonary fibrosis while increasing pro-inflammatory cytokines

Shi, Lei. "Catalase attenuates pulmonary fibrosis while increasing pro-inflammatory cytokines." MS (Master of Science) thesis, ii ACKNOWLEDGMENTS I owe a debt of gratitude to Dr. Brent Carter, my thesis supervisor, for his advice and patience to an old and stubborn student. guidance and encouragement, I could not have gone so far. And thanks to Shubha, Alan, Heather and Chao, for a wonderful research team and my last two happy years in this beautiful country. Finally, to my son, wife and mom: you are the reason. iii ABSTRACT Pulmonary fibrosis is an aberrant transformation of injured lung tissue. It is characterized by irreversible accumulation of extracellular matrix produced by fibroblasts and myofibroblasts during tissue remodeling, resulting in destruction and dysfunction of the lung. Asbestos is an important cause of pulmonary fibrosis. In response to asbestos exposure, alveolar macrophages and recruited monocytes generate reactive oxygen species (ROS), especially hydrogen peroxide (H 2 O 2), pro-inflammatory cytokines, such as TNF-α and IL-1β, and induce subsequent collagen deposition in the lung. We have found that increased H 2 O 2 levels are linked to the development of pulmonary fibrosis. Catalase converts H 2 O 2 into water and oxygen, so we hypothesized that catalase may attenuate the development of pulmonary fibrosis. Interestingly, previous studies from our lab have demonstrated that decreased H 2 O 2 levels are associated not only with a decrease in fibrosis but also an increase in pro-inflammatory cytokines. In these current studies, we demonstrate that in the presence of asbestos, catalase increases TNF-α and IL-1β in macrophages while decreasing collagen production in fibroblasts. This is reversed when TNF-α receptor-1 is knocked down, suggesting that TNF-α may play a role in fibrosis development. To investigate these finding in vivo, catalase-treated mice showed decreased fibrosis histologically, decreased in collagen levels in BAL, and decreased hydroxyproline in lung tissue. The major finding of my study is that catalase attenuates asbestos-induced fibrosis while increasing pro-inflammatory cytokines. This is contrary to the typical thought that pro-inflammatory states are associated with the fibrotic phenotype. The studies in this iv thesis may uncover a therapeutic target to attenuate the progression and/or development of pulmonary fibrosis.