Anatomic Pathology / Apoptosis in Chronic Hypersensitivity Pneumonitis The Pathogenesis of Chronic Hypersensitivity Pneumonitis in Common With Idiopathic Pulmonary Fibrosis Expression of Apoptotic Markers

Previous studies showed that apoptotic epithelial cells were involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP); however, little is known about apoptosis in chronic hypersensitivity pneumonitis (HP). This study was performed to examine whether apoptosis has a role in chronic HP. We performed immunohistochemical studies for p53, p21, Fas, Fas ligand, and terminal deoxynucleotidyl transferase– mediated deoxyuridine triphosphate–biotin nick-end labeling methods on surgical lung specimens. The expression of Fas and Fas ligand was up-regulated in UIP-like lesions compared with nonspecific interstitial pneumonia (NSIP)-like lesions. The expression of p53 and p21 on epithelial cells increased significantly in UIP-like lesions compared with fibrotic NSIP-like lesions and in fibrotic NSIP-like lesions compared with normal lung tissues. These results confirm that apoptotic epithelial cells are present in chronic HP as seen in IPF. Augmented epithelial apoptosis may contribute much more to UIP-like lesions than to NSIP-like lesions in chronic HP. Epithelial cell injury and apoptosis of alveolar epithelial cells (AECs) are generally accepted findings in idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP). Previous studies have shown that apoptotic epithelial cells were present in surgical lung specimens of IPF/UIP by the terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate–biotin nick-end labeling (TUNEL) method and by ultrastructural studies describing fragmented DNA.1-7 An increased apoptosis of type II AECs has been demonstrated in areas that appear histologically normal without established fibrosis8 and in the epithelial cells overlying fibroblastic foci (FF) in patients with IPF.9 Epithelial apoptosis may contribute to the processes of pulmonary fibrosis through several mechanisms.10 Epithelial cells have several protective mechanisms from pulmonary fibrosis. These cells produce inhibitory factors such as prostaglandin E2 for fibroblast proliferation and degradation factors for the interstitial deposition of extracellular matrix (metalloproteinase). They also prevent profibrotic cytokines from reaching underlying tissue.9,10 Fas antigen (Fas), a cell surface protein that mediates apoptosis, is expressed in various cells and tissues.11 Fas ligand (FasL), a cell surface molecule belonging to the tumor necrosis factor family, binds to its receptor Fas, leading to apoptosis of Fas-bearing cells.12 Wild-type p53 normally suppresses cell growth while the cell initiates repair of DNA damage and also promotes apoptosis of the cells that have irreparably damaged DNA with sequential continuous proliferation. p21 is induced in cells positive for wild-type p53 after cellular stress and is a crucial downstream effector in the p53-specific pathway of growth control in mammalian cells. Kuwano et al13 observed p21 messenger RNA expression and positive signals for TUNEL in alveolar epithelial cells