Basic Research
Copyright ©2007 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 21, 2007; 13(47): 6385-6395
Published online Dec 21, 2007. doi: 10.3748/wjg.v13.i47.6385
Intestinal endotoxemia plays a central role in development of hepatopulmonary syndrome in a cirrhotic rat model induced by multiple pathogenic factors
Hui-Ying Zhang, De-Wu Han, Ai-Rong Su, Li-Tong Zhang, Zhong-Fu Zhao, Jing-Quan Ji, Bao-Hong Li, Cheng Ji
Hui-Ying Zhang, Zhong-Fu Zhao, Jing-Quan Ji, Bao-Hong Li, Department of Pathophysiology, Changzhi Medical College, Changzhi 046000, Shanxi Province, China
De-Wu Han, Institute of Hepatology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
Ai-Rong Su, Department of Physiology, Bengbu Medical College, Bengbu 233030, Anhui Province, China
Li-Tong Zhang, Department of Gynaecology, Shanxi Modern Women Hospital, Taiyuan 030012, Shanxi Province, China
Cheng Ji, Department of Medicine, University of Southern California, Los Angeles, CA 90033, United States
Author contributions: All authors contributed equally to the work.
Supported by the Awards to University Academic Leaders Granted by the Government of Shanxi Province of China to Hui-Ying Zhang and partially by the US National Institute of Health, NIAAA, Grant R01 AA014428 to Cheng Ji
Correspondence to: Hui-Ying Zhang, MD, Professor, Depa-rtment of Pathophysiology, Changzhi Medical College, 161 Jie Fang Dong Jie, Changzhi 046000, Shanxi Province, China. zhhy2001@hotmail.com
Telephone: +86-355-3031235 Fax: +86-355-3034065
Received: July 4, 2007
Revised: September 27, 2007
Accepted: November 22, 2007
Published online: December 21, 2007
Abstract

AIM: To characterize the correlation between severity of hepatopulmonary syndrome (HPS) and degree of hepatic dysfunction, and to explore how intestinal endotoxemia (IETM) affects the development of HPS in cirrhotic rats.

METHODS: Male Wister rats were fed with a diet containing maize flour, lard, cholesterol, and alcohol and injected subcutaneously with CCl4 oil solution every two days for 8 wk to induce typical cirrhosis and development of HPS. The animals were also given a nitric oxide (NO) production inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME) intraperitoneally, and an iNOS inhibitor, aminoguanidine hydrochloride (AG) via gavage daily from the end of the 4th wk to the end of the 6th or 8th wk, or a HO-1 inhibitor, zinc protoporphyrin (ZnPP) intraperitoneally 12 h prior to killing. Blood, liver and lung tissues were sampled.

RESULTS: Histological deterioration of the lung paralleled to that of the liver in the cirrhotic rats. The number of pulmonary capillaries was progressively increased from 6.1 ± 1.1 (count/filed) at the 4th wk to 14.5 ± 2.4 (count/filed) at the 8th wk in the cirrhotic rats. Increased pulmonary capillaries were associated with increased blood levels of lipopolysaccharide (LPS) (0.31 ± 0.08 EU/mL vs control 0.09 ± 0.03 EU/mL), alanine transferase (ALT, 219.1 ± 17.4 U/L vs control 5.9 ± 2.2 U/L) and portal vein pressure. Compared with normal control animals, the number of total cells in bronchoalveolar lavage fluid (BALF) of the cirrhotic rats at the 8th wk was not changed, but the number of macrophages and the ratio of macrophages to total cells were increased by nearly 2-fold, protein expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) started to increase significantly at the 4th wk, and reached its peak at the 8th wk in the lung of cirrhotic rats. The increase of iNOS expression appeared to be quicker than that of eNOS. NO2-/NO3- was also increased, which was correlated to the increase of iNOS (r = 0.7699, P < 0.0001) and eNOS (r = 0.5829, P < 0.002). mRNA expression of eNOS and iNOS was highly consistent with their protein expression.

CONCLUSION: Progression and severity of HPS as indicated by both increased pulmonary capillaries and histological changes are closely associated with LPS levels and progression of hepatic dysfunction as indicated by increased levels of ALT and portal vein pressure. Intestinal endotoxemia plays a central role in the development of HPS in the cirrhotic rat model by inducing NO and/or CO.

Keywords: Endotoxin; Alcohol; Nitric oxide synthase; Hemeoxygenase-1; Capillary; Macrophage; Cirrhosis; Hepatopulmonary syndrome