Original contributionFibroblast activation protein: a serine protease expressed at the remodeling interface in idiopathic pulmonary fibrosis☆
Introduction
Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology characterized by progressive fibrosis of the lung interstitium. Histopathology reveals a pattern of usual interstitial pneumonia (UIP) typified by patchy areas of interstitial fibrosis interspersed with areas of honeycomb changes and normal lung parenchyma [1]. Closer examination of fibrotic regions reveals foci of actively proliferating mesenchymal cells that approximate areas of injured alveolar epithelium. These cellular regions have been termed “fibroblast foci” and are composed mainly of fibroblasts and myofibroblasts. Fibroblast foci and areas of scarring define the temporal heterogeneity of the disease, a central feature that distinguishes IPF/UIP from other interstitial pneumonias. Although the etiology of IPF/UIP is not understood, many hypothesize that the myofibroblast represents an important effector cell in its pathogenesis.
Fibroblasts play a major role in the production and turnover of extracellular matrix (ECM) components, a process critical for wound healing and tissue remodeling [2]. In this regard, transforming growth factor β1 (TGF-β1) is one of the more potent inducers of connective tissue formation, with its fibrogenic effects being central in wound healing and tissue repair. A major role of TGF-β1 involves transition of quiescent fibroblasts to an “activated” phenotype, whereby matrix production and wound contraction are important consequences [3]. Although heterogeneity in fibroblast phenotype is evident, a subset of differentiated activated fibroblasts is characterized by the expression of alpha-smooth muscle actin (α-SMA) [4]. Although α-SMA is considered to be a phenotypic marker for myofibroblasts, recent studies have shown that its expression does not correlate with the development of irreversible scarring in models of human tissue fibrosis [5], [6]. Myofibroblasts are typically found in areas of granulation tissue and wound healing and are thought to play a major role in the pathogenesis of tissue fibrosis [7]. Fibroblast foci in IPF/UIP are considered to represent areas of recent injury where myofibroblast differentiation is the result of an unknown injurious event [8]. Central to hypotheses regarding the pathogenesis of IPF/UIP is the persistence of activated fibroblasts that continue to actively synthesize matrix.
Fibroblast activation protein (FAPα) is a cell surface atypical serine protease that has collagenase, gelatinase, and dipeptidyl peptidase (DPP) activity in vitro and shares 54% homology to CD26 (DPPIV) [9], [10]. Its lack of expression in normal tissue and induced expression in areas of tissue remodeling and tumor stroma suggest that it may play a role in the functional program of mesenchymal cells. In the current study, we sought to determine the expression pattern of FAPα in IPF/UIP as compared with normal and emphysematous lung tissue. We hypothesized that FAPα would be up-regulated in lung tissue from patients with IPF/UIP and may identify a functional subset of fibroblasts as determined by their expression of FAPα. These findings may provide for a diagnostic marker and additional hypotheses regarding possible mechanisms of progressive fibrosis in IPF/UIP.
Section snippets
Study population
This study was approved by the institutional review boards of the Wistar Institute and the Hospital of the University of Pennsylvania. The study group consisted of 8 patients (6 men and 2 women; mean age, 60.6 years) with clinical, radiographic (chest radiograph, high-resolution computed tomography), and physiological findings consistent with the diagnosis of IPF. Diagnosis of UIP on surgical lung biopsies was based on previously published pathological criteria [11]. The 8 samples of IPF and 4
No evidence of FAPα expression in normal or emphysematous lung
No expression of FAPα was detected in any of the lung tissue (bronchiolar epithelium, type I and II pneumocytes, endothelium, smooth muscle, and alveolar macrophages) of normal lung and centriacinar emphysema cases (Fig 1, Fig 2). α-SMA stained the smooth muscle cells within the vascular and bronchiolar walls in all cases, as well as muscle bundles in areas of scarring. CD26 stain was not detected in either normal or centriacinar emphysema tissue sections, except for rare positive cells within
Discussion
The present study reveals that the plasma membrane–bound serine protease FAPα is expressed in IPF, and that its expression pattern is restricted to a subset of fibroblasts in areas of ongoing tissue injury. Our study further suggests that the expression of FAPα is more restricted than the traditional myofibroblast marker α-SMA. The spatial relationship of FAPα within fibroblast foci and CD26 in adjacent hyperplastic epithelium lends further support to the hypothesis that epithelial injury and
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This study was supported by PHS grant P50-HL67663 and the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health.