Calponin 1 contributes to myofibroblast differentiation of human pleural mesothelial cells

Pleural mesothelial cells (PMCs) can become myofibroblasts via mesothelial-mesenchymal transition (MesoMT) and contribute to pleural organization, fibrosis, and rind formation. However, how these transformed mesothelial cells contribute to lung fibrosis remains unclear. Here, we investigated the mechanism of contractile myofibroblast differentiation of PMCs. TGF-b induced marked upregulation of calponin 1 expression, which was correlated with notable cytoskeletal rearrangement in human PMCs (HPMCs) to produce stress fibers. Downregulation of calponin 1 expression reduced stress fiber formation. Interestingly, induced stress fibers predominantly contain αSMA associated with calponin 1 but not b-actin. Calponin 1 associated stress fibers also contained myosin II and α-actinin. Further, focal adhesions were aligned with the produced stress fibers. These results suggest that calponin 1 facilitates formation of stress fibers that resemble contractile myofibrils. Supporting this notion, TGF-b significantly increased the contractile activity of HPMCs, an effect that was abolished by downregulation of calponin 1 expression. We infer that differentiation of HPMCs to contractile myofibroblasts facilitates stiffness of scar tissue in pleura to promote pleural fibrosis and that upregulation of calponin 1 plays a central role in this process.

TGF-β regulation of the uPA/uPAR axis modulates mesothelial-mesenchymal transition (MesoMT)

Pleural fibrosis (PF) is a chronic and progressive lung disease which affects approximately 30,000 people per year in the United States. Injury and sustained inflammation of the pleural space can result in PF, restricting lung expansion and impairing oxygen exchange. During the progression of pleural injury, normal pleural mesothelial cells (PMCs) undergo a transition, termed mesothelial mesenchymal transition (MesoMT). While multiple components of the fibrinolytic pathway have been investigated in pleural remodeling and PF, the role of the urokinase type plasminogen activator receptor (uPAR) is unknown. We found that uPAR is robustly expressed by pleural mesothelial cells in PF. Downregulation of uPAR by siRNA blocked TGF-β mediated MesoMT. TGF-β was also found to significantly induce uPA expression in PMCs undergoing MesoMT. Like uPAR, uPA downregulation blocked TGF-β mediated MesoMT. Further, uPAR is critical for uPA mediated MesoMT. LRP1 downregulation likewise blunted TGF-β mediated MesoMT. These findings are consistent with in vivo analyses, which showed that uPAR knockout mice were protected from S. pneumoniae-mediated decrements in lung function and restriction. Histological assessments of pleural fibrosis including pleural thickening and α-SMA expression were likewise reduced in uPAR knockout mice compared to WT mice. These studies strongly support the concept that uPAR targeting strategies could be beneficial for the treatment of PF.

Challenges in Image-Guided Drainage of Infected Pleural Collections: A Review

Infected pleural fluid collections (IPFCs) commonly occur as a part of bacterial, fungal, or tubercular pneumonia or due to involvement of pleura through hematogenous route. Management requires early initiation of therapeutic drugs, as well as complete drainage of the fluid, to relieve patients’ symptoms and prevent pleural fibrosis. Image-guided drainage plays an important role in achieving these goals and improving outcomes. Intrapleural fibrinolytic therapy (IPFT) is also a vital component of the management. The concepts of image-guided drainage procedures, IPFT, and nonexpanding lung are discussed in this review.

HDAC Inhibitor Abrogates LTA−Induced PAI-1 Expression in Pleural Mesothelial Cells and Attenuates Experimental Pleural Fibrosis

Lipoteichoic acid (LTA) stimulates pleural mesothelial cell (PMC) to overproduce plasminogen activator inhibitor-1 (PAI-1), and thus may promote pleural fibrosis in Gram-positive bacteria (GPB) parapneumonic effusion (PPE). Histone deacetylase inhibitor (HDACi) was found to possess anti-fibrotic properties. However, the effects of HDACi on pleural fibrosis remain unclear. The effusion PAI-1 was measured among 64 patients with GPB PPE. Pleural fibrosis was measured as radiographical residual pleural thickening (RPT) and opacity at a 12-month follow-up. The LTA−stimulated human PMCs and intrapleural doxycycline−injected rats were pretreated with or without the pan-HDACi, m-carboxycinnamic acid bis-hydroxamide (CBHA), then PAI-1 and collagen expression and activated signalings in PMCs, and morphologic pleural changes in rats were measured. Effusion PAI-1 levels were significantly higher in GPB PPE patients with RPT > 10 mm (n = 26) than those without (n = 38), and had positive correlation with pleural fibrosis shadowing. CBHA significantly reduced LTA−induced PAI-1 and collagen expression via inhibition of JNK, and decreased PAI-1 promoter activity and mRNA levels in PMCs. Furthermore, in doxycycline−treated rats, CBHA substantially repressed PAI-1 and collagen synthesis in pleural mesothelium and minimized pleural fibrosis. Conclusively, CBHA abrogates LTA−induced PAI-1 and collagen expression in PMCs and attenuates experimental pleural fibrosis. PAI-1 inhibition by HDACi may confer potential therapy for pleural fibrosis.

Imaging diagnosis of classical and new pneumoconiosis: predominant reticular HRCT pattern

Our understanding of the manifestations of pneumoconioses is evolving in recent years. Associations between novel exposures and diffuse interstitial lung disease have been newly recognized. In advanced asbestosis, two types of fibrosis are seen, probably related to dose of exposure, existence of pleural fibrosis, and the host factor status of the individual. In pneumoconiosis of predominant reticular type, nodular opacities are often seen in the early phase. The nodular pattern is centrilobular, although some in metal lung show perilymphatic distribution, mimicking sarcoidosis. High-resolution computed tomography enables a more comprehensive correlation between the pathologic findings and clinically relevant imaging findings. The clinician must understand the spectrum of characteristic imaging features related to both known dust exposures and to historically recent new dust exposures.