TLR4 and AT1 receptor contribute to tuberculous pleural fibrosis through NOX4‐ERK‐ROS signal pathway

Abstract

Tuberculous pleurisy sometimes results in pleural fibrosis that could cause respiratory failure. Pleural mesothelial cells (PMC) play an important role in pleural fibrosis. Several studies suggest that reactive oxygen species (ROS) produced by NOXs have been shown to initiate lung fibrosis, but the detailed mechanisms about TB pleurisy-associated fibrosis remain to be not well understood. We aimed to investigate whether activation of TLR4 and renin angiotensin system (RAS) contributes to NOX4-ROS signaling in tuberculous pleural fibrosis. In vitro human PMC experiments were performed to assess the role of NOX4 -ROS associated signaling in heat-killed mycobacterium tuberculosis (HKMT) induced pleural fibrosis. We found that HKMT induces collagen I synthesis and NOX4-ROS expression in pleural mesothelial cells and NOX4 mediates HKMT-induced collagen -1 synthesis and epithelial-mesenchymal transition (EMT) via activation ERK signaling We also observed that the inhibition of TLR4 and AT1 receptor reduce HKMT-induced NOX4 – ROS production and collagen synthesis. In pleural mesothelial cells, HKMT upregulated Angiotensin Converting Enzyme (ACE) levels and TLR4 inhibitor pretreatment reduced ACE levels. These results suggest crosstalk between TLR4 and AT1 in tuberculous pleural fibrosis. In conclusion, these results suggest that NOX4-ERK-ROS mediates HKMT induced pleural fibrosis and EMT via TLR4 receptor and AT1 receptor. TLR4-NOX4-ROS signal pathway may a novel therapeutic target for intervention in tuberculous pleural fibrosis. Support or Funding Information This work was supported by National research Foundatin of Korea (NRF) grant funded by the Korea government (NRF-2017R1C1B501789, NRF-2017M3A9E8033225). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.