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Am. J. Respir. Cell Mol. Biol., Volume 24, Number 4, April, 2001 398-404

Microsatellite Instability in Transforming Growth Factor-beta 1 Type II Receptor Gene in Alveolar Lining Epithelial Cells of Idiopathic Pulmonary Fibrosis

Masahide Mori, Hiroshi Kida, Hiroshi Morishita, Sho Goya, Hiroto Matsuoka, Toru Arai, Tadashi Osaki, Isao Tachibana, Satoru Yamamoto, Mitsunori Sakatani, Masami Ito, Takeshi Ogura, and Seiji Hayashi

Department of Molecular Medicine, Osaka University Graduate School of Medicine, Suita; Department of Internal Medicine, National Kinki-chuo Hospital for Chest Diseases, Sakai; and Department of Internal Medicine, National Toneyama Hospital, Toyonaka, Osaka, Japan

It has been reported that transforming growth factor (TGF)-beta , which plays an integral role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), suppresses proliferation of alveolar epithelial cells in vitro. Although hyperplastic lesions of alveolar lining epithelial cells (ALECs) are characteristic pathologic features of IPF, the mechanism of their involvement in the pathogenesis has not yet been extensively studied. On the assumption that the hyperplastic ALECs have escaped from the growth-inhibitory effects of TGF-beta , we searched for mutations in the microsatellite of the TGF-beta receptor type II (Tbeta RII) gene. To detect a deletion in the polyadenine tract in exon 3 of the Tbeta RII gene, cells were isolated by microdissection from lung sections of IPF patients, and DNA was extracted from these cells and amplified by high-fidelity polymerase chain reaction. A total of 121 sites of hyperplastic ALECs from 11 IPF patients were analyzed, and a one-base-pair deletion was detected in nine sites from five patients. The mutation was also detected in smooth muscle-like cells of the thickened pulmonary artery. In some tissue areas where the deletion was detected, low Tbeta RII expression was confirmed by immunohistochemical staining. These data suggest that microsatellite instability in the Tbeta RII gene occurred in some lesions of hyperplastic ALECs in IPF, although at a low incidence, and that this genetic disorder might play a partial role in the pathologic changes of IPF.

Abbreviations: alveolar lining epithelial cell, ALEC; base pair(s), bp; hematoxylin and eosin, H&E; idiopathic pulmonary fibrosis, IPF; pulmonary artery, PA; phosphate-buffered saline, PBS; polymerase chain reaction, PCR; standard deviation, SD; TGF-beta receptor type II, Tbeta RII; transforming growth factor, TGF.




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