Enhanced ROCK1 dependent contractility in fibroblast from chronic obstructive pulmonary disease patients

Hällgren, Oskar; Rolandsson, Sara; Andersson-Sjöland, Annika; Nihlberg, Kristian; Wieslander, Elisabet; Kvist-Reimer, Martina; Dahlbäck, Magnus; Eriksson, Leif; Bjermer, Leif; Erjefält, Jonas; Löfdahl, Claes‐Göran; Westergren‐Thorsson, Gunilla

doi:10.1186/1479-5876-10-171

Cited by 24 publications

(31 citation statements)

References 34 publications

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“…The present data implicate an important issue that severe COPD patients may have a reduced repair mechanism in the ECM structure of the collagen network in the distal lung. Previous studies support our findings that changes in ECM synthesis are involved in pathologic conditions of COPD [17] and that fibroblasts from COPD patients may have a reduced or defective capacity of tissue repair [17,18,28]. Conversely, in this study, fibroblasts from COPD patients showed not only an altered production of prostacyclin and proteoglycans, but also a general decrease in proliferative rate and migratory capacity and an increased contractile phenotype compared to fibroblasts from control subjects.…”

Section: Discussionsupporting

confidence: 90%

“…Unfortunately, we could not detect any MMP-9 synthesis in the present study. Importantly, distally-derived fibroblasts from severe COPD patients demonstrated a more contractile phenotype in this study, probably due to enhanced ROCK1 activity [18], than fibroblasts from control subjects, and treatment with iloprost attenuated the contractile capacity to the same level as fibroblasts from control subjects in the present study. The inhibitory effect of prostacyclin analogs on fibroblast gel contractions has previously been shown in healthy lung fibroblasts and the response was mediated through cAMP activation of PKA [48].…”

Section: Discussionmentioning

confidence: 50%

“…Control subjects were recruited from two different sources. First, lung explants from healthy donors (n = 4) with no history of lung disease [18] could be included in this study as no matched recipients were available. Second, non-smokers (n = 5) with no history of smoking or other lung diseases were included in the study [19] (Table 1) .…”

Section: Methodsmentioning

confidence: 99%

“…Control lung fibroblasts were isolated from lung explants from donors after lung transplantation [18] and from transbronchial biopsy samples from control subjects as previously described [19]. Importantly, alveolar parenchymal specimens from lung explants were collected 2-3 cm from the pleura in the lower lobes, equivalent to the location where the transbronchial biopsies were obtained.…”

Section: Methodsmentioning

confidence: 99%

“…The gels were prepared as previously described [18] using a modified form of a previous protocol [27]. Briefly, 96-well cell culture plates (Cellstar, Monroe, NC) were coated with 1% BSA overnight and were then washed with PBS.…”

Section: Methodsmentioning

confidence: 99%

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Defective alterations in the collagen network to prostacyclin in COPD lung fibroblasts

Larsson‐Callerfelt

Hällgren

Andersson-Sjöland

et al. 2013

Respiratory Research

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BackgroundProstacyclin analogs are potent vasodilators and possess anti-inflammatory properties. However, the effect of prostacyclin on extracellular matrix (ECM) in COPD is not well known. Collagen fibrils and proteoglycans are essential ECM components in the lung and fibroblasts are key players in regulating the homeostasis of ECM proteins. The aim was to study the synthesis of prostacyclin and its effect on fibroblast activity and ECM production, and in particular collagen I and the collagen-associated proteoglycans biglycan and decorin.MethodsParenchymal lung fibroblasts were isolated from lungs from COPD patients (GOLD stage IV) and from lungs and transbronchial biopsies from control subjects. The prostacyclin analog iloprost was used to study the effect of prostacyclin on ECM protein synthesis, migration, proliferation and contractile capacity of fibroblasts.ResultsTGF-β1 stimulation significantly increased prostacyclin synthesis in fibroblasts from COPD patients (p < 0.01), but showed no effect on fibroblasts from control subjects. Collagen I synthesis was decreased by iloprost in both control and COPD fibroblasts (p < 0.05). Conversely, iloprost significantly altered biglycan and decorin synthesis in control fibroblasts, but iloprost displayed no effect on these proteoglycans in COPD fibroblasts. Proliferation rate was reduced (p < 0.05) and contractile capacity was increased in COPD fibroblasts (p < 0.05) compared to control fibroblasts. Iloprost decreased proliferative rate in control fibroblasts (p < 0.05), whereas iloprost attenuated contraction capacity in both COPD (p < 0.01) and control fibroblasts (p < 0.05).ConclusionsIloprost reduced collagen I synthesis and fibroblast contractility but did not affect the collagen-associated proteoglycans or proliferation rate in fibroblasts from COPD patients. Enhanced prostacyclin production could lead to improper collagen network fibrillogenesis and a more emphysematous lung structure in severe COPD patients.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 50%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Defective alterations in the collagen network to prostacyclin in COPD lung fibroblasts

Larsson‐Callerfelt

Hällgren

Andersson-Sjöland

et al. 2013

Respiratory Research

Self Cite

View full text Add to dashboard Cite

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Gene expression analysis of membrane transporters and drug‐metabolizing enzymes in the lung of healthy and COPD subjects

Berg

Myrbäck

Olsson

et al. 2014

Pharmacology Res & Perspec

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This study describes for the first time the expression levels of genes encoding membrane transporters and drug-metabolizing enzymes in the lungs of ex-smoking patients with chronic obstructive pulmonary disease (COPD). Membrane transporters and drug-metabolizing enzymes are key determinants of drug uptake, metabolism, and elimination for systemically administered as well as inhaled drugs, with consequent influence on clinical efficacy and patient safety. In this study, while no difference in gene expression was found between healthy and COPD subjects, we identified a significant regional difference in mRNA expression of both membrane transporters and drug-metabolizing enzymes between central and peripheral tissue in both healthy and COPD subjects. The majority of the differentially expressed genes were higher expressed in the central airways such as the transporters SLC2A1 (GLUT1), SLC28A3 (CNT3), and SLC22A4 (OCTN1) and the drug-metabolizing enzymes GSTZ1, GSTO2, and CYP2F1. Together, this increased knowledge of local pharmacokinetics in diseased and normal lung may improve modeling of clinical outcomes of new chemical entities intended for inhalation therapy delivered to COPD patients. In addition, based on the similarities between COPD and healthy subjects regarding gene expression of membrane transporters and drug-metabolizing enzymes, our results suggest that clinical pharmacological studies in healthy volunteers could be a valid model of COPD patients regarding drug disposition of inhaled drugs in terms of drug metabolism and drug transporters.

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Basic fibroblast growth factor activates β-catenin/RhoA signaling in pulmonary fibroblasts with chronic obstructive pulmonary disease in rats

Zhou

Yang

et al. 2016

Mol Cell Biochem

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Chronic obstructive pulmonary disease (COPD) is featured by aberrant extracellular matrix (ECM) deposition. Trigger of the β-catenin/RhoA pathway has been involved in aberrant ECM deposition in several diseases. We investigated WNT signaling activation in primary pulmonary fibroblasts of rats with and without COPD and the function of WNT signaling in pulmonary fibroblast. We evaluated the expression of WNT signaling and the role of β-catenin, using MRC-5 fibroblasts and primary lung fibroblasts of rats with and without COPD. Lung fibroblasts highly expressed mRNA of genes associated with WNT signaling. Treatment of MRC-5 fibroblasts using basic fibroblast growth factor (bFGF), a composition of the mucus in COPD patients, enhanced β-catenin, Wnt5a and RhoA expression. The expression in β-catenin, Wnt5a and RhoA induced by bFGF was higher in fibroblasts of rats with COPD than without COPD, whereas the basal expression was similar. bFGF also activated transcriptionally active and increased total β-catenin protein expression. Moreover, bFGF enhanced the expression of α-sm-actin and fibronectin, which was abrogated by β-catenin, Wnt5a and RhoA-specific adenovirus siRNA. The induction of active β-catenin and then fibronectin turnover in response to bFGF were markedly increased in pulmonary fibroblasts from rat with COPD. β-Catenin/RhoA pathway results in ECM deposition in lung fibroblasts and myofibroblasts differentiation. β-catenin/RhoA signaling induced by bFGF is promoted in lung fibroblasts from rats with COPD. The study indicated a crucial role of the WNT signaling in mediating fibroblast morphology and function in COPD.

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Enhanced ROCK1 dependent contractility in fibroblast from chronic obstructive pulmonary disease patients

Cited by 24 publications

References 34 publications

Defective alterations in the collagen network to prostacyclin in COPD lung fibroblasts

Defective alterations in the collagen network to prostacyclin in COPD lung fibroblasts

Gene expression analysis of membrane transporters and drug‐metabolizing enzymes in the lung of healthy and COPD subjects

Basic fibroblast growth factor activates β-catenin/RhoA signaling in pulmonary fibroblasts with chronic obstructive pulmonary disease in rats

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