Pleural fibrosis can occur after empyema or complicated parapneumonic effusion as a result of tissue remodeling and excessive expression and deposition of extracellular matrix proteins. Pleural mesothelial cells transition into mesenchymal cells and acquire a profibrotic phenotype. This pathologic transition occurs through a process termed MesoMT and directly contributes to pleural fibrosis. MesoMT is regulated by diverse signaling pathways, including PI3K/AKT, which lie upstream of mTOR. However, the role of mTOR signaling in MesoMT is unknown. Using several mTOR inhibitors, we showed that inhibition of mTORC1/2 with INK128 and AZD8055 blocked and reversed TGF-β induced MesoMT. Targeted knockdown studies showed that mTORC2/Rictor pathway is indispensable for the Induction of MesoMT. Conversely, mTORC1/Raptor knockdown had no appreciable effect on MesoMT. Our in vivo analyses showed that INK128 treatment could attenuate pleural thickening injury and subsequent pleural fibrosis. Biomarkers of MesoMT, α-SMA and collagen were likewise reduced in INK128 treated mice compared to vehicle-treated mice. These studies suggest that mTORC2 may be an important therapeutic target for the treatment of PF.
Date of publication
Torry Tucker, Ph.D., Vijaya Lella, Ph.D., Vijay Boggaram Ph.D., Hua Tang, Ph.D.
master of science in biotechnology
Kyei, Perpetual S., "THE ROLE OF MTORC2 IN MESOMESENCHYMAL TRANSITIONING IN HUMAN PLEURAL MESOTHELIAL CELLS" (2023). Biotechnology Theses. Paper 13.