Mast cell tryptase stimulates human lung fibroblast proliferation via protease-activated receptor-2

2000 ◽  
Vol 278 (1) ◽  
pp. L193-L201 ◽  
Author(s):  
Ian A. Akers ◽  
Maddy Parsons ◽  
Michael R. Hill ◽  
Morley D. Hollenberg ◽  
Shahin Sanjar ◽  
...  
Keyword(s):  
Mast Cells ◽  
Dermal Fibroblast ◽  
Fetal Lung ◽  
Dermal Fibroblasts ◽  
Lung Fibroblasts ◽  
Chronic Obstructive ◽  
Fibroblast Proliferation ◽  
Obstructive Pulmonary Disease ◽  
Human Lung Fibroblast ◽  
Protease Activated Receptor 2

Mast cells play a potentially important role in fibroproliferative diseases, releasing mediators including tryptase that are capable of stimulating fibroblast proliferation and procollagen synthesis. The mechanism by which tryptase stimulates fibroblast proliferation is unclear, although recent studies suggest it can activate protease-activated receptor (PAR)-2. We therefore investigated the role of PAR-2 in tryptase-induced proliferation of human fetal lung and adult lung parenchymal and airway fibroblasts and, for comparative purposes, adult dermal fibroblasts. Tryptase (0.7–70 mU/ml) induced concentration-dependent increases in proliferation of all fibroblasts studied. Antipain, bis(5-amidino-2-benzimidazolyl)methane, and benzamidine inhibited tryptase-induced fibroblast proliferation, demonstrating that proteolytic activity is required for the proliferative effects of tryptase. RT-PCR demonstrated the presence of PAR-2 mRNA, and immunohistochemical staining localized PAR-2 to the cell surface of lung fibroblasts. In addition , specific PAR-2 activating peptides, SLIGKV and SLIGRL, mimicked the proliferative effects of tryptase. In contrast, human dermal fibroblasts only weakly stained with the PAR-2 antibody, PAR-2 mRNA was almost undetectable, and fibroblasts did not respond to PAR-2 activating peptides. These results suggest that tryptase induces lung, but not dermal, fibroblast proliferation via activation of PAR-2 and are consistent with the hypothesis that the release of tryptase from activated mast cells may play an important role in the fibroproliferative response observed in asthma, chronic obstructive pulmonary disease, and patients with pulmonary fibrosis.

scholarly journals Interleukin-1α drives the dysfunctional cross-talk of the airway epithelium and lung fibroblasts in COPD

2016 ◽  
Vol 48 (2) ◽  
pp. 359-369 ◽  
Author(s):  
Emmanuel T. Osei ◽  
Jacobien A. Noordhoek ◽  
Tillie L. Hackett ◽  
Anita I.R. Spanjer ◽  
Dirkje S. Postma ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Airway Epithelium ◽  
Fetal Lung ◽  
Bronchial Epithelial Cell ◽  
Airway Epithelial Cells ◽  
Lung Fibroblast ◽  
Lung Fibroblasts ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
And Control

Chronic obstructive pulmonary disease (COPD) has been associated with aberrant epithelial–mesenchymal interactions resulting in inflammatory and remodelling processes. We developed a co-culture model using COPD and control-derived airway epithelial cells (AECs) and lung fibroblasts to understand the mediators that are involved in remodelling and inflammation in COPD.AECs and fibroblasts obtained from COPD and control lung tissue were grown in co-culture with fetal lung fibroblast or human bronchial epithelial cell lines. mRNA and protein expression of inflammatory mediators, pro-fibrotic molecules and extracellular matrix (ECM) proteins were assessed.Co-culture resulted in the release of pro-inflammatory mediators interleukin (IL)-8/CXCL8 and heat shock protein (Hsp70) from lung fibroblasts, and decreased expression of ECM molecules (e.g. collagen, decorin) that was not different between control and COPD-derived primary cells. This pro-inflammatory effect was mediated by epithelial-derived IL-1α and increased upon epithelial exposure to cigarette smoke extract (CSE). When exposed to CSE, COPD-derived AECs elicited a stronger IL-1α response compared with control-derived airway epithelium and this corresponded with a significantly enhanced IL-8 release from lung fibroblasts.We demonstrate that, through IL-1α production, AECs induce a pro-inflammatory lung fibroblast phenotype that is further enhanced with CSE exposure in COPD, suggesting an aberrant epithelial–fibroblast interaction in COPD.

scholarly journals Cigarette smoke induction of S100A9 contributes to chronic obstructive pulmonary disease

2020 ◽  
Vol 319 (6) ◽  
pp. L1021-L1035
Author(s):  
Christopher Railwah ◽  
Alnardo Lora ◽  
Kanza Zahid ◽  
Hannah Goldenberg ◽  
Michael Campos ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Extracellular Matrix ◽  
Lung Function ◽  
Matrix Metalloproteinase ◽  
Pulmonary Disease ◽  
Cigarette Smoke ◽  
Lung Fibroblasts ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Acute And Chronic Exposure

S100 calcium-binding protein A9 (S100A9) is elevated in plasma and bronchoalveolar lavage fluid (BALF) of patients with chronic obstructive pulmonary disease (COPD), and aging enhances S100A9 expression in several tissues. Currently, the direct impact of S100A9-mediated signaling on lung function and within the aging lung is unknown. Here, we observed that elevated S100A9 levels in human BALF correlated with age. Elevated lung levels of S100A9 were higher in older mice compared with in young animals and coincided with pulmonary function changes. Both acute and chronic exposure to cigarette smoke enhanced S100A9 levels in age-matched mice. To examine the direct role of S100A9 on the development of COPD, S100a9−/− mice or mice administered paquinimod were exposed to chronic cigarette smoke. S100A9 depletion and inhibition attenuated the loss of lung function, pressure-volume loops, airway inflammation, lung compliance, and forced expiratory volume in 0.05 s/forced vital capacity, compared with age-matched wild-type or vehicle-administered animals. Loss of S100a9 signaling reduced cigarette smoke-induced airspace enlargement, alveolar remodeling, lung destruction, ERK and c-RAF phosphorylation, matrix metalloproteinase-3 (MMP-3), matrix metalloproteinase-9 (MMP-9), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and keratinocyte-derived chemokine (KC) release into the airways. Paquinimod administered to nonsmoked, aged animals reduced age-associated loss of lung function. Since fibroblasts play a major role in the production and maintenance of extracellular matrix in emphysema, primary lung fibroblasts were treated with the ERK inhibitor LY3214996 or the c-RAF inhibitor GW5074, resulting in less S100A9-induced MMP-3, MMP-9, MCP-1, IL-6, and IL-8. Silencing Toll-like receptor 4 (TLR4), receptor for advanced glycation endproducts (RAGE), or extracellular matrix metalloproteinase inducer (EMMPRIN) prevented S100A9-induced phosphorylation of ERK and c-RAF. Our data suggest that S100A9 signaling contributes to the progression of smoke-induced and age-related COPD.

scholarly journals Mast cells and mast cell tryptase enhance migration of human lung fibroblasts through protease-activated receptor 2

2018 ◽  
Vol 16 (1) ◽  
Author(s):  
Mariam Bagher ◽  
Anna-Karin Larsson-Callerfelt ◽  
Oskar Rosmark ◽  
Oskar Hallgren ◽  
Leif Bjermer ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Human Lung ◽  
Lung Fibroblasts ◽  
Mast Cell Tryptase ◽  
Human Lung Fibroblasts ◽  
Protease Activated Receptor 2

scholarly journals miR-146a-5p plays an essential role in the aberrant epithelial–fibroblast cross-talk in COPD

2017 ◽  
Vol 49 (5) ◽  
pp. 1602538 ◽  
Author(s):  
Emmanuel T. Osei ◽  
Laura Florez-Sampedro ◽  
Hataitip Tasena ◽  
Alen Faiz ◽  
Jacobien A. Noordhoek ◽  
...  
Keyword(s):  
Airway Epithelial Cells ◽  
Lung Fibroblasts ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Single Nucleotide ◽  
Obstructive Pulmonary Disease ◽  
Bronchial Epithelial ◽  
Lung Epithelial ◽  
Inflammatory Phenotype

We previously reported that epithelial-derived interleukin (IL)-1α drives fibroblast-derived inflammation in the lung epithelial–mesenchymal trophic unit. Since miR-146a-5p has been shown to negatively regulate IL-1 signalling, we investigated the role of miR-146a-5p in the regulation of IL-1α-driven inflammation in chronic obstructive pulmonary disease (COPD).Human bronchial epithelial (16HBE14o-) cells were co-cultured with control and COPD-derived primary human lung fibroblasts (PHLFs), and miR-146a-5p expression was assessed with and without IL-1α neutralising antibody. Genomic DNA was assessed for the presence of the single nucleotide polymorphism (SNP) rs2910164. miR-146a-5p mimics were used for overexpression studies to assess IL-1α-induced signalling and IL-8 production by PHLFs.Co-culture of PHLFs with airway epithelial cells significantly increased the expression of miR-146a-5p and this induction was dependent on epithelial-derived IL-1α. miR-146a-5p overexpression decreased IL-1α-induced IL-8 secretion in PHLFs via downregulation of IL-1 receptor-associated kinase-1. In COPD PHLFs, the induction of miR-146a-5p was significantly less compared with controls and was associated with the SNP rs2910164 (GG allele) in the miR-146a-5p gene.Our results suggest that induction of miR-146a-5p is involved in epithelial–fibroblast communication in the lungs and negatively regulates epithelial-derived IL-1α induction of IL-8 by fibroblasts. The decreased levels of miR-146a-5p in COPD fibroblasts may induce a more pro-inflammatory phenotype, contributing to chronic inflammation in COPD.

Fibroblasts that resist cigarette smoke-induced senescence acquire profibrotic phenotypes

2014 ◽  
Vol 307 (5) ◽  
pp. L364-L373 ◽  
Author(s):  
Nobuhiro Kanaji ◽  
Hesham Basma ◽  
Amy Nelson ◽  
Maha Farid ◽  
Tadashi Sato ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Tissue Repair ◽  
Lung Fibroblasts ◽  
Chronic Obstructive ◽  
Receptor Kinase ◽  
Collagen Gels ◽  
Obstructive Pulmonary Disease ◽  
Adult Lung ◽  
Β Receptor ◽  
Extended Exposure

This study assessed the effect of extended exposure to cigarette smoke extract (CSE) on tissue repair functions in lung fibroblasts. Human fetal (HFL-1) and adult lung fibroblasts were exposed to CSE for 14 days. Senescence-associated β-galactosidase (SA β-gal) expression, cell proliferation, and tissue repair functions including chemotaxis and gel contraction were assessed. HFL-1 proliferation was inhibited by CSE and nearly half of the CSE-exposed cells were SA β-gal positive after 14 days exposure, whereas 33% of adult lung fibroblasts were SA β-gal positive in response to 10% CSE exposure. The SA β-gal-positive cells did not proliferate as indicated by bromodeoxyuridine incorporation. In contrast, cells negative for SA β-gal after CSE exposure proliferated faster than cells never exposed to CSE. These nonsenescent cells migrated more and contracted collagen gels more than control cells. CSE exposure stimulated TGF-β1 production, and both inhibition of TGF-β receptor kinase and TGF-β1 siRNA blocked CSE modulation of fibroblast function. Extended exposure to CSE might induce two different fibroblast phenotypes, a senescent and a profibrotic phenotype. The fibroblasts that resist CSE-induced cellular senescence may contribute to the pathogenesis of idiopathic pulmonary fibrosis and could contribute to fibrotic lesions in chronic obstructive pulmonary disease acting through a TGF-β1-mediated pathway. In contrast, the senescent cells may contribute to the pathogenesis of emphysema.

scholarly journals WNT5a-ROR Signaling Is Essential for Alveologenesis

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 384 ◽  
Author(s):  
Changgong Li ◽  
Susan M Smith ◽  
Neil Peinado ◽  
Feng Gao ◽  
Wei Li ◽  
...  
Keyword(s):  
Lung Development ◽  
Lung Fibroblasts ◽  
Chronic Obstructive ◽  
Type I ◽  
Loss Of Function ◽  
Obstructive Pulmonary Disease ◽  
Alveolar Epithelial ◽  
Isolated Lung ◽  
And Migration

WNT5a is a mainly “non-canonical” WNT ligand whose dysregulation is observed in lung diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma. Germline deletion of Wnt5a disrupts embryonic lung development. However, the temporal-specific function of WNT5a remains unknown. In this study, we generated a conditional loss-of-function mouse model (Wnt5aCAG) and examined the specific role of Wnt5a during the saccular and alveolar phases of lung development. The lack of Wnt5a in the saccular phase blocked distal airway expansion and attenuated differentiation of endothelial and alveolar epithelial type I (AT1) cells and myofibroblasts. Postnatal Wnt5a inactivation disrupted alveologenesis, producing a phenotype resembling human bronchopulmonary dysplasia (BPD). Mutant lungs showed hypoalveolization, but endothelial and epithelial differentiation was unaffected. The major impact of Wnt5a inactivation on alveologenesis was on myofibroblast differentiation and migration, with reduced expression of key regulatory genes. These findings were validated in vitro using isolated lung fibroblasts. Conditional inactivation of the WNT5a receptors Ror1 and Ror2 in alveolar myofibroblasts recapitulated the Wnt5aCAG phenotype, demonstrating that myofibroblast defects are the major cause of arrested alveologenesis in Wnt5aCAG lungs. Finally, we show that WNT5a is reduced in human BPD lung samples, indicating the clinical relevance and potential role for WNT5a in pathogenesis of BPD.

Hyperoxia inhibits fetal rat lung fibroblast proliferation and expression of procollagens

1997 ◽  
Vol 273 (4) ◽  
pp. L726-L732 ◽  
Author(s):  
Naveed Hussain ◽  
Fengying Wu ◽  
Constance Christian ◽  
Mitchell J. Kresch
Keyword(s):  
Steady State ◽  
Fetal Lung ◽  
Lung Fibroblasts ◽  
Type I ◽  
Fibroblast Proliferation ◽  
Rat Lung ◽  
Collagen Production ◽  
Fetal Rat ◽  
Fetal Rat Lung ◽  
Steady State Levels

The direct effects of hyperoxia on collagen production by fetal lung fibroblasts are unknown and would be important to the understanding of the molecular mechanisms involved in bronchopulmonary dysplasia in premature infants. We studied the effect of hyperoxia on 1) proliferation, 2) mRNA levels for type I and III procollagens, and 3) net collagen production in primary cultures of fetal rat lung fibroblasts. Fibroblasts from 19-day-old rat fetuses (term is 22 days) were obtained. Test plates were incubated in hyperoxia and controls in room air for varying time periods. Cell viability in both conditions was >97% as determined by trypan blue exclusion. Fibroblast proliferation in nonconfluent cultures was found to be significantly reduced with exposure to hyperoxia ( P< 0.001). Steady-state levels of type I and III procollagen mRNAs, analyzed on Northern blots hybridized to [32P]cDNA probes, were significantly decreased in hyperoxia ( P < 0.01). This effect was noted as early as 4 h of exposure to hyperoxia and persisted for 5 days. There was a significant inverse correlation between duration of exposure to O2 and steady-state levels of mRNA for α1(I)-procollagen ( r = −0.904) and α1(III)-procollagen ( r = −0.971). There were no significant changes in steady-state levels of β-actin mRNA. We also found a significant decrease in collagen synthesis in hyperoxia-exposed fibroblasts ( P < 0.05). We conclude that hyperoxia directly effects a reduction in fetal lung fibroblast proliferation and net collagen production at a pretranslational level.

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