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CRITICAL CARE AND TRAUMA

Hemeoxygenase-1 Upregulation Is Critical for Sirtinol-Mediated Attenuation of Lung Injury After Trauma-Hemorrhage in a Rodent Model

Fu-Chao Liu, MD^*, Yuan-Ji Day, MD, PhD^*, Chang-Hui Liao, PhD, Jiin-Tarng Liou, MD^*, Chih-Chieh Mao, MD, PhD^*, and Huang-Ping Yu, MD, PhD^*||

From the *Department of Anesthesiology, Chang Gung Memorial Hospital; College of Medicine; Graduate Institute of Clinical Medical Sciences; Institution of Natural Products; and ||Aging Healthy Center, Chang Gung University, Taoyuan, Taiwan.

Address correspondence and reprint requests to Dr. Huang-Ping Yu, Department of Anesthesiology Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kwei-Shan Tao-Yuan, Taiwan 333. Address e-mail to yuhp2001{at}adm.cgmh.org.tw.

BACKGROUND: Hemeoxygenase-1 induction in response to adverse circulatory conditions is protective. Our recent study has shown that administration of sirtinol attenuates hepatic injury in male Sprague-Dawley rats after trauma-hemorrhage; however, the mechanism by which sirtinol produces the salutary effects remains unknown. We hypothesized that sirtinol administration in male Sprague-Dawley rats after trauma-hemorrhage decreases cytokine production and protects against lung injury through a hemeoxygenase-1 related pathway.

METHODS: Male Sprague-Dawley rats (n = 8 per group) underwent trauma-hemorrhage (mean arterial blood pressure 40 mm Hg for 90 min, then resuscitation). A single dose of sirtinol (1 mg/kg of body weight) with or without a hemeoxygenase enzyme inhibitor (chromium-mesoporphyrin) or vehicle was administered IV during resuscitation. Twenty-four hours thereafter, myeloperoxidase activity (a marker of neutrophil sequestration) and tumor necrosis factor , interleukin-6, and interleukin-10 levels in the lung, protein concentrations in bronchoalveolar lavage fluid and tissue histology were measured. Lung hemeoxygenase-1 protein level was also determined.

RESULTS: In the sirtinol-treated rats subjected to trauma-hemorrhage, there were significant improvements in lung myeloperoxidase activity (4.68 ± 0.31 vs 9.36 ± 1.03 U/mg protein, P < 0.05), tumor necrosis factor levels (710.7 ± 28 vs 1288 ± 40.69 pg/mg protein, P < 0.05), interleukin-6 levels (343.6 ± 18.41 vs 592.7 ± 22.3 pg/mg protein, P < 0.05), and protein concentrations (303.8 ± 24.54 vs 569.6 ± 34.82 µg/mL, P < 0.05) and lesser damage in histology. There was no statistically significant difference in interleukin-10 levels in the lung between sirtinol-treated trauma-hemorrhaged rats and vehicle-treated trauma-hemorrhaged rats (842.5 ± 54.18 vs 756.2 ± 41.34 pg/mg protein, respectively). Lung hemeoxygenase-1 protein levels were increased in rats receiving sirtinol treatment as compared with vehicle-treated trauma-hemorrhaged rats (5.18 ± 0.25 vs 2.70 ± 0.16, P < 0.05). Administration of the hemeoxygenase inhibitor chromium-mesoporphyrin prevented the sirtinol-induced attenuation of shock-induced lung damage.

CONCLUSION: The salutary effects of sirtinol administration on attenuation of lung inflammation after trauma-hemorrhage are mediated via upregulation of hemeoxygenase-1 expression.