1996;14:131C38. corroborated by immunogold labeling for Cldn10. Further, immunohistochemical double-labeling for Cldn10 and -smooth muscle actin (-SMA) demonstrated that aberrant -SMA signals are frequently encountered near disorganized Cldn10-positive cells in hyperplastic bronchiolar epithelium and thickened interstitium Curculigoside of IPF lungs. Collectively, these data indicate that club cells actively participate in the initiation and progression of IPF through phenoconversion involving the acquisition of proliferative and migratory abilities. Thus, our new findings open the possibility for club cell-targeted therapy to become a strategic option for the treatment of IPF. strong class=”kwd-title” Keywords: club cells, idiopathic pulmonary fibrosis (IPF), Claudin10/Cldn10/Claudin-10, club cell secretory protein (CCSP), migration INTRODUCTION Idiopathic pulmonary fibrosis (IPF) is an age-related, chronic, and progressive lung disease of unknown etiology [1]. Notably, the key cellular and molecular events in early stage IPF are poorly understood [2]. Recent reports suggest that type II alveolar epithelial cell (AEC) dysfunction, caused by gene mutations, coupled with repetitive exposure to noxious stimuli contributes to IPF development [3,4]. As an example of such genetic predispositions related to pulmonary Curculigoside fibrosis, mutations in SFTPC, a gene encoding surfactant protein C (pro-SPC, a representative marker of type II AECs), have been associated with familial pulmonary fibrosis (FPF) kindreds. Patients with SFTPC Curculigoside mutations present with a histopathological pattern of usual interstitial pneumonia (UIP), a key pathological feature of IPF [5,6]. In the meantime, a particular minor allele of single-nucleotide polymorphism (SNP) in the putative promoter region of MUC5B, a gene largely expressed in bronchiolar epithelium has also been linked to familial interstitial pneumonia and IPF [7]. This indicates that not only type II AEC dysfunction, but also functional perturbation of the bronchiolar epithelial cells is a risk factor for pulmonary fibrosis. club cells (previously Clara cells) are non-ciliated bronchiolar epithelial cells with multiple functions including (i) xenobiotic metabolism, (ii) immuno-modulation through secretion of club cell secretory protein (CCSP), and (iii) regeneration through progenitor activity [8]. The involvement of club cells in IPF or other lung diseases featuring pulmonary fibrosis is not clear, however, it has been continually suggested since the 1980s that there is a Nos1 link between lung fibrosis and alveolar bronchiolization, a process where club cells and other bronchiolar epithelial cell types migrate and populate alveolar walls [9C13]. Intriguingly, a recent report provided novel insights into a pathological role for club cells in Curculigoside IPF, wherein the authors proposed that club cells accelerate IPF progression through promoting lung epithelial cell death [13]. Madala et al. demonstrated that club cell-specific overexpression of transforming growth factor alpha (TGF-) activate mesenchymal cell migration and accumulation in lung fibrosis [14]. In spite of such rising attention of recent years being paid to club cells, the cumulative attention that club cells have garnered so far in the field of IPF is very little when it is Curculigoside compared to type II AECs. One of the reasons attributed to this is the relative sparsity of club cells, as defined and assessed by the expression of CCSP, in IPF lungs in comparison to type II AECs. In most of the lung fibrosis studies published so far, CCSP expression was used to define and trace club cells. However, a recent study has identified an additional club cell markers [15]. Given the availability of newly established club cell markers, no studies were initiated with these markers to investigate the potential contribution of club cells to IPF pathology. The newly identified club cell markers include, but are not limited to, Flavin monooxygenase 3 (Fmo3), paraoxonase 1 (Pon1), aldehyde oxidase 3 (Aox3) and Claudin-10 (Cldn10). Among these newly identified club cell markers, Claudin-10 (referred to as Cldn10 hereinafter) is a very unique protein. In the early developing lungs of mice, Cldn10 first appears throughout the developing airway epithelium, and as club.