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

Abstract

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.

Pulmonary vascular changes in asthma and COPD

“…Prostacyclin is generated via the cyclooxygenase (COX) pathway and is an important regulator of vascular tone and thrombocyte function [105]. The prostacyclin receptor, IP, is expressed in high amounts by endothelial cells but also by fibroblasts in the human lung [106]. 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].…”

“…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].…”

“…In vitro studies with pulmonary fibroblasts from patients with IPF showed an altered balance in the synthesis of prostacyclin and thromboxane, with reduced levels of prostacyclin [112], while lung fibroblasts from patients with severe COPD (GOLD IV) synthesised an increased amount of prostacyclin [106]. Nevertheless, the distal lung fibroblasts from severe COPD patients appear to have altered fibroblast function and defect repair mechanisms in the ECM structure of the collagen network assembly in response to prostacyclin, which may thereby affect emphysema progression [106].…”

“…Nevertheless, the distal lung fibroblasts from severe COPD patients appear to have altered fibroblast function and defect repair mechanisms in the ECM structure of the collagen network assembly in response to prostacyclin, which may thereby affect emphysema progression [106]. Taking the data together, depending on state of disease progression, prostacyclin may therefore have different outcomes.…”

MMP-9 genetic polymorphism may confer susceptibility to COPD

“…Imbalances in ECM synthesis and degradation have severe consequences for tissue integrity and function. These imbalances can provoke sustained inflammatory responses; therefore, MMP and TIMP pathways are valuable therapeutic targets for COPD (Larsson-Callerfelt et al, 2013).…”