Abstract
RationaleLack of an experimental model of portopulmonary hypertension (POPH) has been a major obstacle in understanding of pathophysiological mechanisms underlying the disease.ObjectiveWe investigated the effects of CCl4-mediated cirrhosis on the pulmonary vasculature, as an initial step towards an improved understanding of POPH.Methods And ResultsMale 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.ConclusionCollectively, 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.
Highlights
Portopulmonary hypertension (POPH) is defined as pulmonary hypertension (PH) associated with portal hypertension, whether or not portal hypertension is secondary to underlying liver disease [1]
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
Summary
Portopulmonary hypertension (POPH) is defined as pulmonary hypertension (PH) associated with portal hypertension, whether or not portal hypertension is secondary to underlying liver disease [1]. POPH can be a devastating complication in patients with advanced cirrhosis [2]. The added mortality patients experience due to POPH is clinically relevant [3]. Deficiencies in endothelial prostacyclin synthase [6], excess circulating endothelin-1 [7], and PA platelet aggregates [8] have been documented in POPH patients, the molecular mechanisms driving the pathogenesis of the disease remain unclear. One of the primary reasons that the pathophysiological mechanisms directing POPH is still unknown is that animal, and in particular, mouse models of disease have not been developed
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