Crosstalk between pleural mesothelial cell and lung fibroblast contributes to pulmonary fibrosis

Pulmonary fibrosis is a kind of interstitial lung disease with progressive pulmonary scar formation, leading to irreversible loss of lung functions. The TGF-β1/Smad signaling pathway plays a key role in fibrogenic processes. It is associated with the increased synthesis of extracellular matrix, enhanced proliferation of fibroblasts, and transformation of alveolar epithelial cells into interstitial cells. We investigated P-Rex1, a PIP3-Gβγ–dependent guanine nucleotide exchange factor (GEF) for Rac, for its potential role in TGF-β1–induced pulmonary fibrosis. A high expression level of P-Rex1 was identified in the lung tissue of patients with pulmonary fibrosis than that from healthy donors. Using the P-Rex1 knockdown and overexpression system, we established a novel player of P-Rex1 in mouse lung fibroblast migration. P-Rex1 contributed to fibrogenic processes in lung fibroblasts by targeting the TGF-β type Ⅱ receptor (TGFβR2). The RNA-seq analysis for expression profiling confirmed the modulation of P-Rex1 in cell migration and the involvement of P-Rex1 in TGF-β1 signaling. These results identified P-Rex1 as a signaling molecule involved in TGF-β1–induced pulmonary fibrosis, suggesting that P-Rex1 may be a potential target for pulmonary fibrosis treatment.

Download Full-text

Idiopathic Pulmonary Fibrosis: Pathogenesis and the Emerging Role of Long Non-Coding RNAs

International Journal of Molecular Sciences ◽

10.3390/ijms21020524 ◽

2020 ◽

Vol 21 (2) ◽

pp. 524 ◽

Cited By ~ 2

Author(s):

Marina R. Hadjicharalambous ◽

Mark A. Lindsay

Keyword(s):

Chronic Disease ◽

Epithelial Cell ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Cell Activation ◽

Lung Fibroblast ◽

Biological Processes ◽

Aberrant Expression ◽

Non Coding Rnas

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disease characterized by excessing scarring of the lungs leading to irreversible decline in lung function. The aetiology and pathogenesis of the disease are still unclear, although lung fibroblast and epithelial cell activation, as well as the secretion of fibrotic and inflammatory mediators, have been strongly associated with the development and progression of IPF. Significantly, long non-coding RNAs (lncRNAs) are emerging as modulators of multiple biological processes, although their function and mechanism of action in IPF is poorly understood. LncRNAs have been shown to be important regulators of several diseases and their aberrant expression has been linked to the pathophysiology of fibrosis including IPF. This review will provide an overview of this emerging role of lncRNAs in the development of IPF.

Download Full-text

Pleural Mesothelial Cell Activation in Idiopathic Pulmonary Fibrosis

CHEST Journal ◽

10.1378/chest.1387544 ◽

2012 ◽

Vol 142 (4) ◽

pp. 953A

Author(s):

Jason Zolak ◽

Rajesh Jagirdar ◽

Ranu Surolia ◽

Octavio Oliva ◽

Suman Karki ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Cell Activation ◽

Mesothelial Cell

Download Full-text

Altered intercellular communication in lung fibroblast cultures from patients with idiopathic pulmonary fibrosis

Respiratory Research ◽

10.1186/1465-9921-7-122 ◽

2006 ◽

Vol 7 (1) ◽

Cited By ~ 30

Author(s):

Angela Trovato-Salinaro ◽

Elisa Trovato-Salinaro ◽

Marco Failla ◽

Claudio Mastruzzo ◽

Valerio Tomaselli ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Intercellular Communication ◽

Lung Fibroblast ◽

Fibroblast Cultures

Download Full-text

Effect of heparin and related glycosaminoglycan on PDGF-induced lung fibroblast proliferation, chemotactic response and matrix metalloproteinases activity

Mediators of Inflammation ◽

10.1080/096293500411541 ◽

2000 ◽

Vol 9 (2) ◽

pp. 85-91 ◽

Cited By ~ 16

Author(s):

Masahiro Sasaki ◽

Masayuki Kashima ◽

Takefumi Ito ◽

Akiko Watanabe ◽

Masaaki Sano ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Human Lung ◽

Heparan Sulphate ◽

Inhibitory Effect ◽

Lung Fibroblast ◽

Chemotactic Response ◽

Fibroblast Proliferation ◽

Human Lung Fibroblast ◽

Fibroblast Migration

Fibroblast migration, proliferation, extacellular matrix protein synthesis and degradation are the key events in various biological and pathological processes in pulmonary fibrosis. In addition, biopsy specimens from the lungs of patients with plumomary fibrosis show increased numbers of mast cells which have metachromatic granules containing heparin, histamin and proteases. Little is known about how these products influence pulmonary fibrosis. In the present study, we investigated the effect of heparin and related glycosaminoglycans on PDGF-induced lung fibroblast proliferation and chemotactic responsein vitro. In addition, we examined the effect of heparin on both the induction of matorix metalloproteinases (MMPs) and MMPs activity in lung fibroblastsin vitro.Heparin, de-N-sulphated heparin but not heparan sulphate inhibited PDGF-induced lung fibroblast proliferation. In contrast, only heparin inhibited PDGF-stimulated human lung fibroblast chemotaxis. Negatively charged poly-L-gultamic acid had no effect on either fibroblast proliferation or chemotaxis. Thus the negative charge alone cannot account for the ant-proliferative and anti-chemotactic effects of heparin.Furthermore, heparin and heparan sulphate also had no inhibitory effect on induction of MMPs, including MMP-1 (interstitial collagenase), MMP-2 (gelatinase A) and MMP-9 (gelatinase B). Only heparin inhibited both MMP-1 and MMP-2/MMP-9 activity. Additionally, tissue inhibitor of metalloproteinase type 1 (TIMP-1) and type 2 (TIMP-2) inhibited PDGF-stimulated human lung fibroblast chemotaxis. The ability of heparin to inhibit fibroblast chemotaxis may account for the inhibitory effect of heparin on MMP activity.The above results suggested that heparin and related glycosaminoglycans differentially regulate PDGF-induced lung fibroblast proliferation, chemotaxis and MMPs activity and further that these effects may have a key role in extracellular matrix remodeling in inflammatory lung disease.

Download Full-text

Loss of Fas-signaling in pro-fibrotic fibroblasts impairs homeostatic fibrosis resolution and promotes persistent pulmonary fibrosis

10.1101/2020.08.18.255869 ◽

2020 ◽

Author(s):

Elizabeth F. Redente ◽

Sangeeta Chakraborty ◽

Satria Sajuthi ◽

Bart P. Black ◽

Benjamin L. Edelman ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Lung Fibroblast ◽

Lung Fibroblasts ◽

Normal Lung ◽

Loss Of Function ◽

Fas Signaling ◽

Distal Lung ◽

Induced Apoptosis

ABSTRACTIdiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the accumulation and persistence of fibroblasts and myofibroblasts and continued production of collagen and other extracellular matrix (ECM) components. Prior in vitro studies have led to the hypothesis that the development of resistance to Fas-induced apoptosis by lung fibroblasts and myofibroblasts contibributes to their accumulation in the distal lung tissues of IPF patients. Here, we test this hypothesis in vivo in the resolving model of bleomycin-induced pulmonary fibrosis in mice. Using genetic loss-of-function approaches to inhibit Fas signaling in fibroblasts, novel flow cytometry strategies to quantify lung fibroblast subsets and transcriptional profiling of lung fibroblasts by bulk and single cell RNA-sequencing, we show that Fas is necessary for lung fibroblast apoptosis during homeostatic resolution of bleomycin-induced pulmonary fibrosis in vivo. Furthermore, we show that loss of Fas signaling leads to the persistence and continued pro-fibrotic functions of lung fibroblasts. Our studies provide novel insights into the mechanisms that contribute to fibroblast survival, persistence and continued ECM deposition in the context of IPF and how failure to undergo Fas-induced apoptosis prevents fibrosis resolution.

Download Full-text

HYAL1 Is Downregulated in Idiopathic Pulmonary Fibrosis and Inhibits HFL-1 Fibroblast Proliferation When Upregulated

BioMed Research International ◽

10.1155/2020/3659451 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15 ◽

Cited By ~ 1

Author(s):

Dong Leng ◽

Xiaoxi Huang ◽

Jiawen Yi ◽

Hongying Zhao ◽

Yuhui Zhang

Keyword(s):

Data Mining ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Western Blot ◽

Microarray Data ◽

Blot Analysis ◽

Western Blot Analysis ◽

Lung Fibroblast ◽

Fibroblast Proliferation ◽

Qrt Pcr

Background. Idiopathic pulmonary fibrosis (IPF), the most common interstitial lung disease, arises from transforming growth factor beta 1- (TGFβ1-) induced aberrant fibroproliferation in response to epithelial injury. The TGFβ1 antagonists—hyaluronidases (HYALs)—have been used to clinically treat pulmonary fibrosis. This study focused on characterizing the effect of HYAL1, the main enzyme in hyaluronan degradation, on human lung fibroblast proliferation and apoptosis, and elucidating its potential underlying mechanism of action. Methods. We first performed microarray data mining of previously published gene expression datasets to identify key gene signatures in IPF lung tissues. HYAL1 expression levels in IPF and normal lung tissues were then characterized using immunohistochemistry followed by real-time quantitative reverse transcription-PCR (qRT-PCR) and western blot analysis on isolated fibroblasts from fresh lung tissues of IPF and healthy donors. A human fetal lung fibroblast HFL-1 cell line, which was used in place of primary lung fibroblasts, was used to assess the proliferative or apoptotic effects associated with lentiviral-induced HYAL1 overexpression using CCK-8 cell proliferation assay and Annexin V-APC staining. The identification of potentially associated molecular pathways was performed using microarray analysis followed by qRT-PCR and western blot analysis. Results. Lung tissue microarray data mining and immunohistochemistry revealed significantly downregulation of HYAL1 in IPF lung tissue. However, HYAL1 expression level in IPF fibroblasts was significantly upregulated at the mRNA level, but not altered at the protein level. HYAL1 overexpression in HFL-1 fibroblasts reduced fibroproliferation modestly but did not promote apoptosis. In addition, HYAL1 overexpression led to concomitant transcription factor downregulation, bone morphogenetic protein receptor 2 (BMPR2) signaling activation, but had no effect on TGFβ receptor 2 (TGFβR2) signaling. Conclusions. We showed that HYAL1 overexpression could prevent HFL-1 fibroproliferation. Furthermore, our findings suggest that transcriptional regulators and BMP receptor signaling may be involved in HYAL1 modulation in IPF therapy.

Download Full-text