Update on Novel Targeted Therapy for Pleural Organization and Fibrosis.

Torry A Tucker,Steven Idell

doi:10.3390/ijms23031587

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.

Highlights

Pleural injury can develop as a result of underlying infection, collagen vascular disease or other insults and when severe can progress to local organization and fibrosis [1]
This study showed that the fibrinolytic activity of scuPA was durable in infectious pleural injury as it evaded inhibition by plasminogen activator inhibitor (PAI)-1 via complex with α2 macroglobulin
We found that TNF-α and IL-1β reduced the expression of the endocytic receptor lowdensity lipoprotein receptor-related protein 1 (LRP1) in Pleural mesothelial cell (PMC), increasing the half-life of uPAR at the cell surface, increasing uPA enzymatic durability, and increasing HPMC migration

Summary

Introduction

Pleural injury can develop as a result of underlying infection, collagen vascular disease or other insults and when severe can progress to local organization and fibrosis [1]. Enhanced vascular permeability resulting from this inflammation causes fibrinogen-rich plasma-like fluid to leak into the inflamed pleural space This fibrinogen is converted to fibrin by the local expression of soluble and cell-associated tissue factor (TF) and subsequent activation of the extrinsic coagulation pathway. This study showed that the fibrinolytic activity of scuPA was durable in infectious pleural injury as it evaded inhibition by PAI-1 via complex with α2 macroglobulin In this trial, the use of scuPA in doses from 50,000 to 800,000 IU was found to be safe when delivered by tube thoracostomy in patients with pleural infection, loculation and failed pleural drainage. These findings enabled the conduct of a phase 2 trial of scuPA in patients with empyema and failed pleural drainage, which is currently underway (ClinicalTrials.gov: NCT04159831) These studies suggest that PAI-1 may represent a previously unrecognized target for the treatment of pleural loculation

Mesothelial Cells

MesoMT

Novel Targets for Interventional Therapy

Conclusions