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)-b1, but manifested reduced response to TGF-b1. 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.

Prostaglandin E2 possesses different potencies in inducing Vascular Endothelial Growth Factor and Interleukin-8 production in COPD human lung fibroblasts

“…Pulmonary fibroblasts confer structural support to the lung connective tissue and play a role in stimulating and amplifying inflammatory signals through the expression of COX-2 and of microsomal prostaglandin E2 synthase in response to cigarette smoke [1]. Cigarette smoke, the major risk factor of COPD, also promotes the induction of COX-2 and PGE 2 receptor expression in neutrophils and alveolar macrophages (AM), therefore contributing to the proinflammatory effects of PGE 2 in the airways of COPD subjects [24,26]; indeed a significant overlap with minor, but statistically significant, differences was observed between HS and COPD subjects in terms of COX-2 and PGE 2 , but clearcut increases, in agreement with previously published data [27], were observed in COPD subjects only for EP2 and EP4 expressions, both as mRNA and protein, suggesting that the increase in PGE 2 -dependent IL-8 formation may be the result of concomitant higher PGE2 concentration and enhanced receptor expression when compared to C., Fibroblasts are the major mesenchymal cells present within the interstitium of the lung and have been shown to be a major source of VEGF [4]. VEGF in the lung is required to maintain endothelial cell survival of pulmonary capillaries and therefore a normal alveolar wall [28], but VEGF is also an extremely potent pro-angiogenic factor, 13 and relatively small changes in its concentrations may promote pathological blood vessel expansion.…”

“…Previously published evidence showed the increased expression of EP2 and EP4 receptors in COPD [27], as well as the ability of cigarette smoke to induce VEGF release from fibroblasts [31] or the positive correlation between PGE 2 and VEGF [4], but with the present work we provide evidence that different levels of PGE 2 production, as a result of COX-2 expression, can differentiate between the homeostatic pro-angiogenic or the proinflammatory role of this prostanoid, underlining its critical role in normal physiology as well as in COPD pathophysiology.…”

Cigarette Smoke Induces Akt Protein Degradation by the Ubiquitin-Proteasome System

“…Similarly, CSE causes suppression of proliferation (36), apoptosis (37), senescence (3), and inhibition of collagen gel contraction (38) in lung fibroblasts in vitro, and it reduces proliferation (39), chemotaxis, and collagen gel contraction (40) in lung fibroblasts from patients with COPD. Considering the structural support by lung fibroblasts, Akt may play an important role in maintenance of lung integrity by lung fibroblasts, because PI3K/Akt signaling is involved in the production of extracellular matrix proteins.…”

Pulmonary vascular changes in asthma and COPD

“…Treatments with prostacyclin analogues have shown positive effects on gas exchange and improved lung function capacity in a small study with COPD patients [107,108]. Prostacyclin and other cAMP generating substances appear to have a central role in remodelling processes since prostacyclin reduces fibroblast activity and migration and reduced collagen type-I synthesis [106,109,110].…”