Pathological changes in pulmonary circulation in carbon tetrachloride (CCl4)-induced cirrhotic mice.
BACKGROUND
Lack of an experimental model of portopulmonary hypertension (POPH) has been a major obstacle in understanding of pathophysiological mechanisms underlying the disease.


OBJECTIVE
We investigated the effects of CCl4-mediated cirrhosis on the pulmonary vasculature, as an initial step towards an improved understanding of POPH.


RESULTS
Male C57BL/6 mice received intraperitoneal injection of either sterile olive oil or CCl4 3 times/week for 12 weeks. Cirrhosis and portal hypertension were confirmed by evidence of bridging fibrosis and nodule formation in CCl4-treated liver determined by trichrome/picrosirius red staining and an increase in spleen weight/body weight ratio, respectively. Staining for the oxidative stress marker, 4-hydroxynonenal (4-HNE), was strong in the liver but was absent in the lung, suggesting that CCl4 did not directly induce oxidative injury in the lung. Pulmonary acceleration time (PAT) and the ratio of PAT/pulmonary ejection time (PET) measured by echocardiography were significantly decreased in cirrhotic mice. Increase in right ventricle (RV) weight/body weight as well as in the weight ratio of RV/(left ventricle + septum) further demonstrated the presence of pathological changes in the pulmonary circulation in these mice. Histological examination revealed that lungs of cirrhotic mice have excessive accumulation of perivascular collagen and thickening of the media of the pulmonary artery.


CONCLUSIONS
Collectively, our data demonstrate that chronic CCl4 treatment induces pathological changes in pulmonary circulation in cirrhotic mice. We propose that this murine cirrhotic model provides an exceptional tool for future studies of the molecular mechanisms mediating pulmonary vascular diseases associated with cirrhosis and for evaluation of novel therapeutic interventions.
Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Mita
M
Das
Department of Pharmaceutical Sciences, Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Marjan
M
Boerma
Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Jessica R
JR
Goree
Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Elise G
EG
Lavoie
Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
Michel
M
Fausther
Research Service, Central Arkansas Veterans Health Service, Little Rock, Arkansas, United States of America.
Igor B
IB
Gubrij
Research Service, Central Arkansas Veterans Health Service, Little Rock, Arkansas, United States of America.
Amanda K
AK
Pangle
Division of Pulmonary and Critical Care University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America; Research Service, Central Arkansas Veterans Health Service, Little Rock, Arkansas, United States of America.
Larry G
LG
Johnson
Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America; Research Service, Central Arkansas Veterans Health Service, Little Rock, Arkansas, United States of America.
Jonathan A
JA
Dranoff
D000818:Animals; D002251:Carbon Tetrachloride; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D006880:Hydroxy Acids / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D008168:Lung / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress
C406867:4-hydroxynonenoic acid; D005231:Fatty Acids, Unsaturated; D006880:Hydroxy Acids; D003094:Collagen; D002251:Carbon Tetrachloride