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

Spring 4-21-2023

Document Type




Persistent identifier


Committee members

Torry Tucker, Ph.D., Vijaya Lella, Ph.D., Vijay Boggaram Ph.D., Hua Tang, Ph.D.


master of science in biotechnology