Journal
JOURNAL OF CLINICAL MEDICINE
Volume 8, Issue 1, Pages -Publisher
MDPI
DOI: 10.3390/jcm8010116
Keywords
tuberculosis; fibrosis; NADPH oxidase
Categories
Funding
- Bio & Medical Technology Development Program of the National Research Foundation (NRF) - Korean government (MSIT) [NRF-2017M3A9E8033225]
- National Research Foundation of Korea - Korean Government [NRF 2017R1C1B5017879]
- National Research Foundation of Korea [2017M3A9E8033225] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [NOX] enzymes serve several hemostatic and host defense functions in various lung diseases, but the role of NOX4 signaling in tuberculous pleurisy is not well understood. The role of NOX4 signaling in tuberculous pleural fibrosis was studied using invitro pleural mesothelial cell (PMC) experiments and a murine model of Mycobacterium bovis bacillus Calmette-Guerin (BCG) pleural infection. The production of NOX4 reactive oxygen species (NOX4-ROS) and the epithelial mesenchymal transition (EMT) in PMCs were both induced by heat-killed mycobacterium tuberculosis (HKMT). In cultured PMCs, HKMT-induced collagen-1 synthesis and EMT were blocked by pretreatment with small interfering RNA (siRNA) NOX4. Moreover, NOX4-ROS production and subsequent fibrosis were reduced by treatment with losartan and the toll-like receptor 4 (TLR4) inhibitor TAK-242. The HKMT-induced EMT and intracellular ROS production were mediated by NOX4 via the activation of extracellular signal-regulated kinase (ERK) signaling. Finally, in a BCG-induced pleurisy model, recruitment of inflammatory pleural cells, release of inflammatory cytokines, and thickened mesothelial fibrosis were attenuated by SiNOX4 compared to SiCon. Our study identified that HKMT-induced pleural fibrosis is mediated by NOX4-ERK-ROS via TLR4 and Angiotensin II receptor type1 (AT1R). There results suggest that NOX4 may be a novel therapeutic target for intervention in tuberculous pleural fibrosis.
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