Calcitonin gene-related peptide down-regulates bleomycin-induced pulmonary fibrosis

Li, Xianwei; Li, Xiaohui; Du, Jie; Li, Dai; Li, Yuan‐Jian; Hu, Chang-Ping

doi:10.1139/cjpp-2015-0602

Cited by 19 publications

(16 citation statements)

References 32 publications

(16 reference statements)

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“…Many studies report that when A549 cells are stimulated with TGF-β, the cells begin to produce mesenchymal cell proteins such as vimentin, desmin, N-cadherin, α-SMA, fibronectin and collagen instead of epithelial cell markers such as Ecadherin, cytokeratin and zonula okludens-1. In other words, they convert their epithelial phenotype into mesenchymal phenotype [25,28,29]. In the present study, GRP did not stimulate the differentiation of A549 cells into myofibroblasts via EMT, whereas it was able to differentiate MRC5 fibroblast into myofibroblasts.…”

Section: Discussioncontrasting

confidence: 62%

“…The most important contribution of TGF-β signalling to the pathogenesis of pulmonary fibrosis is the stimulation of myofibroblast differentiation. The increased TGF-β1 signalling in the lungs enables the differentiation of various cell types, particularly fibroblasts and type 2 pneumocytes, into myofibroblasts [29,35]. Unlike normal lungs, TGF-β1 expression is increased in lung tissue of IPF patients [36].…”

Section: Discussionmentioning

confidence: 99%

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Gastrin-releasing peptide induces fibrotic response in MRC5s and proliferation in A549s

2020

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Idiopathic pulmonary fibrosis (IPF) is a complex lung disease, whose build-up scar tissue is induced by several molecules. Gastrin-releasing peptide (GRP) is released from pulmonary neuroendocrine cells, alveolar macrophages, and some nerve endings in the lung. A possible role of GRP in IPF is unclear. We aimed to investigate the fibrotic response to GRP, at the cellular level in MRC5 and A549 cell lines. The proliferative and fibrotic effects of GRP on these cells were evaluated by using BrdU, immunoblotting, immunofluorescence and qRT-PCR for molecules associated with myofibroblast differentiation, TGF-β and Wnt signalling. All doses of GRP increased the amount of BrdU incorporation in A549 cells. In contrast, the amount of BrdU increased in MRC5 cells in the first 24 h, though progressively decreased by 72 h. GRP did not stimulate epithelial-mesenchymal transition in A549 cells, rather, it stimulated the differentiation of MRC5 cells into myofibroblasts. Furthermore, GRP induced gene and protein expressions of p-Smad2/3 and Smad4, and reduced the levels of Smad7 in MRC5 cells. In addition, GRP decreased Wnt5a protein levels and stimulated β-catenin activation by increasing Wnt4, Wnt7a and β-catenin protein levels. GRP caused myofibroblast differentiation by inducing TGF-βand Wnt pathways via paracrine and autocrine signalling in MRC5 cells. In conclusion, GRP may lead to pulmonary fibrosis due to its proliferative and fibrotic effects on lung fibroblasts. The abrogation of GRP-mediated signal activation might be considered as a treatment modality for fibrotic lung diseases.

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Section: Discussioncontrasting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Gastrin-releasing peptide induces fibrotic response in MRC5s and proliferation in A549s

2020

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“…This study provides the information about the contribution of α-CGRP on liver fibrosis and cellular senescence during cholestatic liver injury. However, other studies have demonstrated that α-CGRP plays an anti-fibrotic role in pulmonary fibrosis 38 and in liver fibrosis due to hepatitis induced by repeated administration of concanavalin A 39 . This discrepant role of α-CGRP-regulated in fibrosis may be due to mediators of different organs and different animal models of liver injury used.…”

Section: Discussionmentioning

confidence: 95%

Knockout of α-calcitonin gene-related peptide attenuates cholestatic liver injury by differentially regulating cellular senescence of hepatic stellate cells and cholangiocytes

Wan

Ceci

et al. 2019

Laboratory Investigation

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Background: α-Calcitonin gene-related peptide (α-CGRP) is a 37-amino acid neuropeptide involved in several pathophysiological processes. α-CGRP is involved in the regulation of cholangiocyte proliferation during cholestasis. In this study, we aimed to evaluate if α-CGRP regulates bile duct ligation (BDL)-induced liver fibrosis by using a α-CGRP knockout (α-CGRP −/− ) mouse model. Methods: α-CGRP −/− and wild-type (WT) mice were subjected to sham surgery or BDL for 7 days. Then, liver fibrosis and cellular senescence as well as the expression of kinase such as p38 and C-Jun N-terminal protein kinase (JNK) in mitogen-activated protein kinases (MAPK) signaling pathway were evaluated in total liver, together with measurement of cellular senescence in cholangiocytes or hepatic stellate cells (HSCs). Results: There was enhanced hepatic expression of Calca (coding α-CGRP) and the CGRP-receptor components (CRLR, RAMP-1 and RCP) in BDL and in both WT α-CGRP −/− and BDL α-CGRP −/− mice, respectively. Moreover, there was increased CGRP serum levels and hepatic mRNA expression of CALCA and CGRP receptor components in late-stage PSC samples compared to healthy control samples. Depletion of α-CGRP reduced liver injury and fibrosis in BDL mice that was associated with enhanced cellular senescence of hepatic stellate cells and reduced senescence of cholangiocytes as well as decreased activation of p38 and JNK MAPK signaling pathway. Cholangiocyte supernatant from BDL α-CGRP −/− mice inhibited the activation and increased cellular senescence of cultured human HSCs (HHSCs) compared to HHSCs stimulated with BDL cholangiocyte supernatant. Taken together, endogenous α-CGRP promoted BDL-induced cholestatic liver fibrosis through differential changes in senescence of HSCs and cholangiocytes and activation of p38 and JNK signaling. Modulation of α-CGRP/CGRP receptor signaling may be key for the management of biliary senescence and liver fibrosis in cholangiopathies.

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“…Pulmonary fibrosis is often complicated by PAH, and it is implicated as a major participant in PAH and is currently being studied as a new therapeutic target [ 51 , 52 ]. The development of MCT-induced pulmonary fibrosis is characterized by an initial inflammatory process with upregulation of pro-fibrotic markers; it increases progressively in a time-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Betaine Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats via Inhibiting Inflammatory Response

et al. 2018

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Background: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance, leading to right ventricular failure and death. Recent studies have suggested that chronic inflammatory processes are involved in the pathogenesis of PAH. Several studies have demonstrated that betaine possesses outstanding anti-inflammatory effects. However, whether betaine exerts protective effects on PAH by inhibiting inflammatory responses in the lungs needs to be explored. To test our hypothesis, we aimed to investigate the effects of betaine on monocrotaline-induced PAH in rats and attempted to further clarify the possible mechanisms. Methods: PAH was induced by monocrotaline (50 mg/kg) and oral administration of betaine (100, 200, and 400 mg/kg/day). The mean pulmonary arterial pressure, right ventricular systolic pressure, and right ventricle hypertrophy index were used to evaluate the development of PAH. Hematoxylin and eosin staining and Masson staining were performed to measure the extents of vascular remodeling and proliferation in fibrous tissue. Monocyte chemoattractant protein-1 (MCP-1) and endothelin-1 (ET-1) were also detected by immunohistochemical staining. Nuclear factor-κB (NF-κB), tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β) were assessed by Western blot. Results: This study showed that betaine improved the abnormalities in right ventricular systolic pressure, mean pulmonary arterial pressure, right ventricle hypertrophy index, and pulmonary arterial remodeling induced by monocrotaline compared with the PAH group. The levels of MCP-1 and ET-1 also decreased. Western blot indicated that the protein expression levels of NF-κB, TNF-α, and IL-1β significantly decreased (p < 0.01). Conclusion: Our study demonstrated that betaine attenuated PAH through its anti-inflammatory effects. Hence, the present data may offer novel targets and promising pharmacological perspectives for treating monocrotaline-induced PAH.

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Calcitonin gene-related peptide down-regulates bleomycin-induced pulmonary fibrosis

Cited by 19 publications

References 32 publications

Gastrin-releasing peptide induces fibrotic response in MRC5s and proliferation in A549s

Gastrin-releasing peptide induces fibrotic response in MRC5s and proliferation in A549s

Knockout of α-calcitonin gene-related peptide attenuates cholestatic liver injury by differentially regulating cellular senescence of hepatic stellate cells and cholangiocytes

Betaine Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats via Inhibiting Inflammatory Response

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