Fibroblast activation protein: a serine protease expressed at the remodeling interface in idiopathic pulmonary fibrosis

Fibroblast activation protein (FAPα) is a member of the cell surface dipeptidyl peptidase (DPP) family of serine proteases. In its dimer form, FAPα exhibits gelatinase, collagenase, and DPP activity in vitro. Reactive fibroblasts in healing wounds and stromal fibroblasts associated with epithelial tumors express FAPα. Idiopathic pulmonary fibrosis (IPF) is a disease of the lung characterized by progressive fibrosis with no clear etiology or molecular marker for disease activity. Recently, it has been shown that fibroblast FAPα expression is induced in liver cirrhosis, with an expression pattern distinct from alpha-smooth muscle actin (α-SMA). In this study, we determine whether FAPα expression is selectively induced in areas of ongoing tissue remodeling characterized by fibroblast foci in IPF. Human lung tissue was obtained from patients with IPF, centrilobular emphysema, and normal lung. Immunohistochemical studies were performed using anti-FAPα antibody and antibodies against α-SMA and CD26 (DPPIV), another member of the DPP family. We found that FAPα was not expressed in normal human lung tissue or tissue with evidence of centriacinar emphysema, but was induced in all patients with IPF and with a pattern distinct from that of CD26 found primarily on hyperplastic alveolar epithelium. Specifically, FAPα was detected in fibroblast foci and in fibrotic interstitium and not in the interstitium of adjacent architecturally normal lung. Alveolar/airway epithelium and vascular smooth muscle did not express FAPα. This is the first report of FAPα expression in IPF and our results suggest that FAPα is selectively induced in fibrotic foci, but not in normal or emphysematous lung. Future studies will address whether FAPα may be used as a marker for disease activity in IPF.