Abstract
In this study, we demonstrated the importance of telomerase protein expression and determined the relationships among telomerase, endothelin-1 (ET-1) and myofibroblasts during early and late remodeling of parenchymal and vascular areas in usual interstitial pneumonia (UIP) using 27 surgical lung biopsies from patients with idiopathic pulmonary fibrosis (IPF). Telomerase+, myofibroblasts α-SMA+, smooth muscle cells caldesmon+, endothelium ET-1+ cellularity, and fibrosis severity were evaluated in 30 fields covering normal lung parenchyma, minimal fibrosis (fibroblastic foci), severe (mural) fibrosis, and vascular areas of UIP by the point-counting technique and a semiquantitative score. The impact of these markers was determined in pulmonary functional tests and follow-up until death from IPF. Telomerase and ET-1 expression was significantly increased in normal and vascular areas compared to areas of fibroblast foci. Telomerase and ET-1 expression was inversely correlated with minimal fibrosis in areas of fibroblast foci and directly associated with severe fibrosis in vascular areas. Telomerase activity in minimal fibrosis areas was directly associated with diffusing capacity of the lung for oxygen/alveolar volume and ET-1 expression and indirectly associated with diffusing capacity of the lungs for carbon monoxide and severe fibrosis in vascular areas. Cox proportional hazards regression revealed a low risk of death for females with minimal fibrosis displaying high telomerase and ET-1 expression in normal areas. Vascular dysfunction by telomerase/ET-1 expression was found earlier than vascular remodeling by myofibroblast activation in UIP with impact on IPF evolution, suggesting that strategies aimed at preventing the effect of these mediators may have a greater impact on patient outcome.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a devastating chronic fibrosing interstitial pneumonia of unknown etiology that typically increases in prevalence with advanced age, characterized by excessive collagen deposition and irreversible remodeling of the lung parenchyma [1,2]
An injured lung fibroblast population may contain telomerase expressing cells with an extended life span, which could contribute to the observed increased numbers of lung fibroblasts [12]. In view of these considerations suggesting an interaction among telomerase, endothelium and myofibroblast activation, the aim of the present study was to evaluate 1) whether telomerase, ET-1 and myofibroblast α-SMA are expressed in vascular and parenchymal areas of usual interstitial pneumonia (UIP); 2) to verify if the measures of mediator expression correlate with some measure of fibrosis, and 3) to determine the impact of the resultant parenchymal/vascular remodeling on patient survival
Open lung biopsies Pulmonary specimens were obtained by surgical lung biopsy from 27 patients with IPF/UIP (14 males and 13 females; mean age 64 ± 1.4 years), according to criteria outlined in the American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of idiopathic interstitial pneumonias [1]
Summary
Idiopathic pulmonary fibrosis (IPF) is a devastating chronic fibrosing interstitial pneumonia of unknown etiology that typically increases in prevalence with advanced age, characterized by excessive collagen deposition and irreversible remodeling of the lung parenchyma [1,2]. The etiology of IPF/UIP is not understood, many investigators hypothesize that dysregulated communication between injured epithelial cells and activated mesenchymal cells represents an important factor in its pathogenesis [3]. We found a direct relationship between progressive vascular occlusion by collagen/elastic fiber deposition and tissue remodeling in surgical lung biopsies from patients with IPF [4,5]. These findings probably are the consequence of persistent myofibroblast activation by mesenchymal cells, resulting in a heterogeneous fibroblast phenotype, intermediate between fibroblasts and smooth muscle cells [6]. Depending on the precise stimulatory milieu, fibroblasts either transform to myofibroblasts or proliferate, resulting in vascular oc-
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