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Tlr5 Protects from Pulmonary Fibrosis by Promoting Epithelial Survival After Injury: Interaction with the Microbiome
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A1061 - Tlr5 Protects from Pulmonary Fibrosis by Promoting Epithelial Survival After Injury: Interaction with the Microbiome
Author Block: S. Hussain1, C. C. G. Johnson1, M. Xiaoling1, C. Trempus2, A. Rice3, A. Gudkov4, I. V. Yang5, D. A. Schwartz6, Y. Zhang7, S. Garantziotis8; 1NIEHS, Research Triangle Park, NC, United States, 2IIDL, NIH/NIEHS, Research Triangle Park, NC, United States, 3National Institute of Environmental Health, Research Triangle Park, NC, United States, 4Rosewell Park, Buffalo, NY, United States, 5Ivana Yang PhD, Univ of Colorado Denver, Aurora, CO, United States, 6Dept of Med, Univ of Colorado, Aurora, CO, United States, 7University of Pittsburgh, Pittsburgh, PA, United States, 8NIEHS, Natl Inst of Environmental Hlth Sciences, Research Triangle Park, NC, United States.
Epithelial damage is thought to be a crucial upstream factor in the pathogeneiss of idiopathic pulmonary fibrosis. Microbiome interaction with the innate immune receptor tlr5, which recognizes the bacterial protein flagellin, promotes epithelial integrity in the gut. We hypothesized that tlr5 may protect the lung from epithelial injury and fibrosis through interactions with the microbiome. We found that tlr5-deficient mice have increased epithelial injury after ozone exposure, and epithelial cell death and lung fibrosis after bleomycin exposure. We observed that microbiome significantly impacts tlr5 expression in the lungs. Treatment with antibiotics modulated the effect of tlr5 in epithelial cell death after bleomycin. Activation of tlr5 by a flagellin analogue ameliorated epithelial cell death and fibrosis after bleomycin in mice. Human carriers of a dominant-negative tlr5 allele were more susceptible to epithelial injury after ozone exposure, and showed increased serum markers of epithelial injury if they smoked, even if they had no clinical lung disease. Finally, tlr5 deficiency in humans was associated with the presence of IPF (OR=1.4, p=0.005, 497 IPF patients compared to 3309 controls). Our results suggest that tlr5 interactions with the microbiome contribute to epithelial homeostasis and protection from the development of fibrosis in the lung.
Author Block: S. Hussain1, C. C. G. Johnson1, M. Xiaoling1, C. Trempus2, A. Rice3, A. Gudkov4, I. V. Yang5, D. A. Schwartz6, Y. Zhang7, S. Garantziotis8; 1NIEHS, Research Triangle Park, NC, United States, 2IIDL, NIH/NIEHS, Research Triangle Park, NC, United States, 3National Institute of Environmental Health, Research Triangle Park, NC, United States, 4Rosewell Park, Buffalo, NY, United States, 5Ivana Yang PhD, Univ of Colorado Denver, Aurora, CO, United States, 6Dept of Med, Univ of Colorado, Aurora, CO, United States, 7University of Pittsburgh, Pittsburgh, PA, United States, 8NIEHS, Natl Inst of Environmental Hlth Sciences, Research Triangle Park, NC, United States.
Epithelial damage is thought to be a crucial upstream factor in the pathogeneiss of idiopathic pulmonary fibrosis. Microbiome interaction with the innate immune receptor tlr5, which recognizes the bacterial protein flagellin, promotes epithelial integrity in the gut. We hypothesized that tlr5 may protect the lung from epithelial injury and fibrosis through interactions with the microbiome. We found that tlr5-deficient mice have increased epithelial injury after ozone exposure, and epithelial cell death and lung fibrosis after bleomycin exposure. We observed that microbiome significantly impacts tlr5 expression in the lungs. Treatment with antibiotics modulated the effect of tlr5 in epithelial cell death after bleomycin. Activation of tlr5 by a flagellin analogue ameliorated epithelial cell death and fibrosis after bleomycin in mice. Human carriers of a dominant-negative tlr5 allele were more susceptible to epithelial injury after ozone exposure, and showed increased serum markers of epithelial injury if they smoked, even if they had no clinical lung disease. Finally, tlr5 deficiency in humans was associated with the presence of IPF (OR=1.4, p=0.005, 497 IPF patients compared to 3309 controls). Our results suggest that tlr5 interactions with the microbiome contribute to epithelial homeostasis and protection from the development of fibrosis in the lung.
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