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The Role of High Mobility Group Box1 in Pulmonary Fibrosis

¹ Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; ² Central Institute, Shino-Test Corporation, Kanagawa, Japan; and ³ Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Kazuyoshi Kuwano, M.D., Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, 105-8641, Tokyo, Japan. E-mail: kkuwano{at}jikei.ac.jp

High mobility group box1 protein (HMGB1) was originally discovered as a nuclear binding protein, and is known to play an important role in acute lung injury. However, the role of HMGB1 in pulmonary fibrosis has not been addressed. Therefore, we measured the HMGB1 levels in serum and bronchoalveolar lavage fluids (BALF) from patients with idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, interstitial pneumonia associated with collagen vascular diseases, and hypersensitivity pneumonitis (HP) by enzyme-linked immunosorbent assay. We also assessed the HMGB1 expression in bleomycin-induced pulmonary fibrosis in mice, and examined the effect of anti-HMGB1 antibody and ethyl pyluvate, which inhibits the HMGB1 secretion from alveolar macrophages. In addition, we examined the effect of HMGB1 on fibroblast proliferation, apoptosis, and collagen synthesis in vitro. Serum HMGB1 levels were not significantly increased in interstitial lung diseases compared with control subjects. BALF HMGB1 levels were significantly increased in IPF and HP compared with control subjects. HMGB1 protein was predominantly detected in inflammatory cells and hyperplasic epithelial cells in IPF. In bleomycin-induced pulmonary fibrosis in mice, HMGB1 protein was predominantly up-regulated in bronchiolar epithelial cells at early phase and in alveolar epithelial and inflammatory cells in fibrotic lesions at later phase. Intraperitoneal injection of anti-HMGB1 antibody or ethyl pyluvate significantly attenuated lung inflammation and fibrosis in this model. HMGB1 significantly induced proliferation, but not apoptosis or collagen synthesis on cultured fibroblasts. HMGB1 may be a promising target against pulmonary fibrosis as well as acute lung injury.

Key Words: HMGB1 • pulmonary fibrosis • fibroblast

CLINICAL RELEVANCE We demonstrated that high mobility group box1 protein (HMGB1) was expressed in pulmonary fibrosis, and that anti-HMGB1 therapy significantly attenuated animal models of pulmonary fibrosis. HMGB1 may be a promising target against pulmonary fibrosis as well as acute lung injury.