Dataset Information

Lung fibroblast repair functions in patients with chronic obstructive pulmonary disease are altered by multiple mechanisms.

ABSTRACT:

Rationale

Fibroblasts are believed to be the major cells responsible for the production and maintenance of extracellular matrix. Alterations in fibroblast functional capacity, therefore, could play a role in the pathogenesis of pulmonary emphysema, which is characterized by inadequate maintenance of tissue structure.

Objectives

To evaluate the hypothesis that deficient fibroblast repair characterizes cells obtained from individuals with chronic obstructive pulmonary disease (COPD) compared with control subjects.

Methods

Fibroblasts were cultured from lung tissue obtained from individuals undergoing thoracotomy and were characterized in vitro.

Measurements and main results

Fibroblasts from individuals with COPD, defined by reduced FEV(1), manifested reduced chemotaxis toward fibronectin and reduced contraction of three-dimensional collagen gels, two bioassays associated with fibroblast repair function. At least two mechanisms appear to account for these differences. Prostaglandin E (PGE), a known inhibitor of fibroblast repair functions, was produced in increased amount by fibroblasts from subjects with COPD, which also expressed increased amounts of the receptors EP2 and EP4, both of which signal through cyclic AMP. Incubation of fibroblasts with indomethacin or with the PKA inhibitor KT-5720 partially restored COPD subject fibroblast function. In addition, fibroblasts from subjects with COPD produced more transforming growth factor (TGF)-beta1, but manifested reduced response to TGF-beta1. The functional alterations in fibroblasts correlated with both lung function assessed by FEV(1) and, for the data available, with severity of emphysema assessed by Dl(CO).

Conclusions

Fibroblasts from individuals with COPD have reduced capability to sustain tissue repair, which suggests that this may be one mechanism that contributes to the development of emphysema.

SUBMITTER: Togo S

PROVIDER: S-EPMC2542423 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Publications

Lung fibroblast repair functions in patients with chronic obstructive pulmonary disease are altered by multiple mechanisms.

Togo Shinsaku S Holz Olaf O Liu Xiangde X Sugiura Hisatoshi H Kamio Koichiro K Wang Xiangqi X Kawasaki Shin S Ahn Youngsoo Y Fredriksson Karin K Skold C Magnus CM Mueller Kai Christian KC Branscheid Detlef D Welker Lutz L Watz Henrik H Magnussen Helgo H Rennard Stephen I SI

American journal of respiratory and critical care medicine 20080508 3

<h4>Rationale</h4>Fibroblasts are believed to be the major cells responsible for the production and maintenance of extracellular matrix. Alterations in fibroblast functional capacity, therefore, could play a role in the pathogenesis of pulmonary emphysema, which is characterized by inadequate maintenance of tissue structure.<h4>Objectives</h4>To evaluate the hypothesis that deficient fibroblast repair characterizes cells obtained from individuals with chronic obstructive pulmonary disease (COPD) ...[more]

PMID: 18467512

Similar Datasets

Project description:Alterations in microRNA (miRNA) expression may contribute to COPD pathogenesis. In COPD, lung fibroblast repair functions are altered in multiple ways, including extracellular mediator release. Our prior study revealed miR-503 expression is decreased in COPD lung fibroblasts, although the exact role played by miR-503 is undetermined. The current study examined a role of miR-503 in cytokine, growth factor and fibronectin production by lung fibroblasts from patients with and without COPD. Primary adult lung fibroblasts were isolated from patients with or without COPD. MiR-503 expression and interleukin (IL)-6, -8, PGE2, HGF, KGF, VEGF and fibronectin release were examined with or without inflammatory cytokines, IL-1β and tumor necrosis factor (TNF)-α. MiR-503 expression was decreased in COPD lung fibroblasts. The expression of miR-503 was positively correlated with %FVC, %FEV1, and %DLco as well as IL-6, -8, PGE2, HGF, KGF, and VEGF in the absence or presence of IL-1ß/TNF-α. In addition, IL-8 and VEGF release from COPD lung fibroblasts were increased compared to those from control. Exogenous miR-503 inhibited VEGF release from primary adult and fetal lung fibroblasts but not IL-8 release. As expected, COPD fibroblasts proliferated more slowly than control fibroblasts. MiR-503 did not affect proliferation of either control or COPD lung fibroblasts. MiR-503 inhibition of VEGF protein production and mRNA was mediated by direct binding to the 3' untranslated region of VEGF mRNA. Endogenous miR-503 was differently regulated by exogenous stimulants associated with COPD pathogenesis, including IL-1ß/TNF-α, TGF-ß1 and PGE2. Endogenous miR-503 inhibition augmented VEGF release by IL-1ß/TNF-α and TGF-ß1 but not by PGE2, demonstrating selectivity of miR-503 regulation of VEGF. In conclusions, reduced miR-503 augments VEGF release from lung fibroblasts from patients with COPD. Since VEGF contributes to disturbed vasculature in COPD, altered miR-503 production might play a role in modulating fibroblast-mediated vascular homeostasis in COPD.

Dataset Information

Lung fibroblast repair functions in patients with chronic obstructive pulmonary disease are altered by multiple mechanisms.

Rationale

Objectives

Methods

Measurements and main results

Conclusions

Publications

Lung fibroblast repair functions in patients with chronic obstructive pulmonary disease are altered by multiple mechanisms.

Similar Datasets

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