Heme oxygenase-1, a potential biomarker of chronic silicosis, attenuates silica-induced lung injury.
BACKGROUND
Heme oxygenase-1 (HO-1), a rate-limiting enzyme in heme catabolism, has antioxidative, antiapoptotic, and antiinflammatory activities. We examined whether HO-1 might be involved in silicosis.


OBJECTIVE
To investigate whether HO-1 can reduce silicosis in mice and humans.


METHODS
Silicosis was studied using a murine model, and in 46 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.


RESULTS
Serum HO-1 levels were significantly elevated in patients with silicosis compared with age-matched control subjects 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 pathologic changes, thereby attenuating disease progression.
Sato
Takashi
T
Department of Internal Medicine and Clinical Immunology, Yokohama City University, and Rosai Hospital for Silicosis, Tochigi, Japan. ishigats@med.yokohama-cu.ac.jp.
Takeno
Mitsuhiro
M
Honma
Koichi
K
Yamauchi
Hideyuki
H
Saito
Yoshiaki
Y
Sasaki
Takao
T
Morikubo
Hiroshi
H
Nagashima
Yoji
Y
Takagi
Shigeto
S
Yamanaka
Kouichi
K
Kaneko
Takeshi
T
Ishigatsubo
Yoshiaki
Y
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002908:Chronic Disease; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000097:blood; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D051547:Heme Oxygenase-1 / Q000097:blood*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D018384:Oxidative Stress; D011379:Prognosis; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology* / Q000209:etiology; D012720:Severity of Illness Index; D012829:Silicosis / Q000150:complications / Q000201:enzymology*
D015415:Biomarkers; D000080242:8-Hydroxy-2'-Deoxyguanosine; D051547:Heme Oxygenase-1; D003849:Deoxyguanosine