Update on Novel Targeted Therapy for Pleural Organization and Fibrosis

Abstract

Pleural injury and subsequent loculation is characterized by acute injury, sustained inflammation and, when severe, pathologic tissue reorganization. While fibrin deposition is a normal part of the injury response, disordered fibrin turnover can promote pleural loculation and, when unresolved, fibrosis of the affected area. Within this review, we present a brief discussion of the current IPFT therapies, including scuPA, for the treatment of pathologic fibrin deposition and empyema. We also discuss endogenously expressed PAI-1 and how it may affect the efficacy of IPFT therapies. We further delineate the role of pleural mesothelial cells in the progression of pleural injury and subsequent pleural remodeling resulting from matrix deposition. We also describe how pleural mesothelial cells promote pleural fibrosis as myofibroblasts via mesomesenchymal transition. Finally, we discuss novel therapeutic targets which focus on blocking and/or reversing the myofibroblast differentiation of pleural mesothelial cells for the treatment of pleural fibrosis.

Keywords: fibrinous neomatrices; intrapleural fibrinolytic therapy (IPFT); mesomesenchymal transition (MesoMT); organization and scarification; pleural injury; pleural loculation and fibrothorax; pleural mesothelial cells.

Figure 1

Induction of MesoMT and Extracellular Matrix Deposition. In response to local injury, the pleural space demonstrates enhanced fibrin deposition via increased local procoagulant activity resulting from increased tissue factor, Factor Xa and thrombin and decreased fibrinolysis via increased PAI-1 expression [1,12,42]. As injury progresses, increases in TGF-β and other profibrogenic mediators promote pleural mesothelial cell transition to a profibrotic phenotype (myofibroblasts) via mesomesenchymal transition (MesoMT) [25,27,28,29,37,43]. These newly transitioned myofibroblasts expand due to increased profibrotic signaling, proliferation and resistance to apoptosis. Mesothelial cell-derived myofibroblast promote pleural thickening via enhanced expression of extracellular matrix proteins including collagen and fibronectin. TGF-β and other mediators of MesoMT activate PI3K/Akt, NFκB and GSK-3β prosurvival signaling pathways. These pathways have also been shown to be critical for the induction of MesoMT [37,43]. The therapeutic targeting of these and other pathways represent the most promising targets for the treatment of PF. Created using BioRender.