Pathological Changes in Pulmonary Circulation in Carbon Tetrachloride (ccl4)-Induced Cirrhotic Mice

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.

Determination of extracellular matrix collagen fibril architectures and pathological remodeling by polarization dependent second harmonic microscopy

“…It is tempting to suggest that the driving force of this collagen remodeling is the blood pressure. Interestingly, a relationship between porto-pulmonary hypertension and lung fibrosis has recently been established in a mouse model of CCl 4 -mediated cirrhosis 36 suggesting that the heterogeneity of peri-portal tracts and central veins collagen remodeling that we found in CCl 4 -treated liver could reflect heterogeneity in the amount of portal tracts and central vein hypertension. According to action-reaction mechanical law, myofiboblasts should contract in response to an increase in blood pressure resulting in perivascular collagen fibrils compression and reduction in dispersion of their angular orientations.…”

Modelling of systemic lesion of organism for development of multitarget cellular and cytokine therapy

“…This idea is so alluring that there is a constant research in this direction, although the publications of successful results are quite rare. Rather successful example may be found in the publication of Das et al (2014) [11], which describes the lesion of both liver and lungs. However, in this study the liver lesions in mice were induced not by pure CCl 4 , but by a unique complex -with preliminary application of phenobarbital for a week and then during the whole experiment (for 12 weeks).…”

“…The vascular and oncology predispositions are most common for humans, determining two main reasons of mortality. The vascular lesions after the injection of CCl 4 were previously described in literature [11]. As for the oncology predispositions, they were excluded in the previous studies due to the use of the mice without oncology predisposition.…”

Antioxidant, anti-inflammatory and hepatoprotective activities on carbon tetrachloride - induced hepatic damage in mice of trang to <i> (ixora duffii) </i> leaf extract

“…Hơn nữa, sự gia tăng khối lượng cơ thể chuột cũng do sự gia tăng khối lượng gan do sự xâm nhập của các acid béo và glycerol vào tế bào gan qua màng tế bào bị tổn thương gây ra sự trương phồng tế bào và hoại tử tế bào gan dẫn đến sự thay đổi hình thái gan (hình 2C) và thể hiện trên tiêu bản mô bệnh học của gan (hình 3B). Những thay đổi này đã được nhiều tác giả báo cáo do tác hại của CCl 4 (Huang et al, 2012;Das et al, 2014;Simeonova et al, 2014).…”