Published ahead of print on July 20, 2006, doi:10.1164/rccm.200508-1237OC Am. J. Respir. Crit. Care Med., Volume 174, Number 8, October 2006, 906-914 A more recent version of this article appeared on October 15, 2006
Submitted on August 10, 2005 Heme Oxygenase-1, a Potential Biomarker of Chronic Silicosis, Attenuates Silica-induced Lung InjuryTakashi Sato1,1 Department of Internal Medicine and Clinical Immunology, Yokohama City University, Yokohama, Japan, 2 Department of Pathology, Dokkyo University School of Medicine, Tochigi, Japan, 3 Department of Internal Medicine, Rosai Hospital for Silicosis, Tochigi, Japan, 4 Department of Radiology, Rosai Hospital for Silicosis, Tochigi, Japan, 5 Department of Pathology, Yokohama City University, Yokohama, Japan, 6 AMHTS Clinic, Seamen's Insurance, Yokohama, Japan * To whom correspondence should be addressed. E-mail: ishigats{at}med.yokohama-cu.ac.jp.
Rationale: Heme oxygenase-1 (HO-1), a rate-limiting enzyme in heme catabolism, has anti-oxidative, anti-apoptotic, and anti-inflammatory activities. We examined whether HO-1 might be involved in silicosis. Objectives: To investigate whether HO-1 can reduce silicosis in mice and humans. Methods and measurements: Silicosis was studied using a murine model, and in forty-six male patients. Serum HO-1 and 8-hydroxydeoxyguanosine (a marker of oxidative stress) were measured by enzyme-linked immunosorbent assay. Levels of HO-1 were measured by immunohistochemistry and immunoblotting. Main results: Serum HO-1 levels were significantly elevated in silicosis patients compared to age-matched controls or patients with chronic obstructive pulmonary disease. Serum HO-1 levels also correlated inversely with serum 8-hydroxydeoxyguanosine levels and positively with vital capacity and forced expiratory volume in one second in patients with silicosis. HO-1 was present in the lungs of humans and mice with silicosis, especially at sites of silica particle deposition. In mice, silica exposure was associated with acute leukocyte infiltration, leading to development of silicotic lung lesions. The inflammation was suppressed by treatment with hemin, an inducer of HO-1, and enhanced by zinc protoporphyrin, an inhibitor of HO-1. Conclusions: Pulmonary HO-1 expression is increased in silicosis. HO-1 suppresses reactive oxygen species activity, and subsequent pathological changes, thereby attenuating disease progression. Key words: Occupational diseases, Oxidative Stress, Antioxidants
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