Thalidomide decreases intrahepatic resistance in cirrhotic rats

Yang, Ying‐Ying; Huang, Yo-Ping; Lin, Han‐Chieh; Lee, Fa-Yauh; Lee, Kuei–Chuan; Chau, Ga-Yang; Loong, Che‐Chuan; Lai, Cheng‐chung; Lee, Shou‐Dong

doi:10.1016/j.bbrc.2009.01.160

Cited by 14 publications

(21 citation statements)

References 26 publications

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“…Cirrhosis was induced in adult male Sprague-Dawley rats (250–350 g) by bile-duct-ligation (BDL)2728. This study was approved by the Animal Experiment Committee of Yang-Ming University and conducted according to the “Guides for the care and use of laboratory animals” prepared by the National Academy of Science, USA.…”

Section: Methodsmentioning

confidence: 99%

“…The capacity of various agents on formation of capillary like tube structure and migration of HPAECs, between passages 2 and 4, were examined with Matrigel ® angiogenesis (Kurabo, Tokyo, Japan) and transwell chemotaxis filter migration assays27 in six independent experiments. For assessment of angiogenesis, matrigel was used to coat the wells of 24-well plates (0.25 ml per well) and was left to polymerize at 37 °C for 1 hour.…”

Section: Methodsmentioning

confidence: 99%

“…Thalidomide attracts us as a potential treatment for HPS and muscle wasting due to previous well-reported beneficial effects including amelioration of hepatic fibrosis, portal hypertension, hyperdynamic circulation and mesenteric angiogenesis in experimental cirrhotic models262728. Meanwhile, thalidomide is a TNFα inhibitor that down-regulating the NFκB-iNOS pathway29, which simultaneously contributes to HPS and muscle wasting in cirrhosis.…”

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confidence: 99%

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Down-regulation of common NFκB-iNOS pathway by chronic Thalidomide treatment improves Hepatopulmonary Syndrome and Muscle Wasting in rats with Biliary Cirrhosis

Lee

et al. 2016

Sci Rep

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Thalidomide can modulate the TNFα-NFκB and iNOS pathway, which involve in the pathogenesis of hepatopulmonary syndrome (HPS) and muscle wasting in cirrhosis. In bile duct ligated-cirrhotic rats, the increased circulating CD16+ (inflammatory) monocytes and its intracellular TNFα, NFκB, monocyte chemotactic protein (MCP-1) and iNOS levels were associated with increased circulating MCP-1/soluable intercellular cell adehesion molecule-1 (sICAM-1), pulmonary TNFα/NOx, up-regulated M1 polarization, exacerbated angiogenesis and hypoxemia (increased AaPO2) in bronchoalveolar lavage (BAL) fluid and pulmonary homogenates. Meanwhile, a significant correlation was noted between circulating CD16+ monocyte/M1 (%) macrophages in BAL; M1 (%) macrophages in BAL/pulmonary iNOS mRNA expression; pulmonary iNOS mRNA expression/relative pulmonary MVD; pulmonary NOx level/AaPO2; circulating CD16+ monocyte/M1 (%) macrophages in muscle homogenates; 3-nitrotyrosine (representative of peroxynitrite) concentration/M1 (%) macrophages in muscle homogenates. The in vitro data demonstrated an iNOS-dependent inhibition of thalidomide on the TNFα-stimulated angiogenesis and myogenesis in human pulmonary artery endothelial cells (HPAECs) and C2C12 myoblasts. Significantly, the co-culture of CD16+ monocyte from different rats with HPAECs, or co-culture of supernatant of above mixed cultures with HPAECs or C2C12 myoblasts stimulated angiogenesis, migration and myogenesis. Our findings demonstrate that TNFα inhibitor thalidomide markedly diminishes the severity of experimental HPS and muscle wasting by down-regulation of common peripheral and local NFκB-iNOS pathway.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Down-regulation of common NFκB-iNOS pathway by chronic Thalidomide treatment improves Hepatopulmonary Syndrome and Muscle Wasting in rats with Biliary Cirrhosis

Lee

et al. 2016

Sci Rep

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“…59,68e70 Further studies have shown that endotoxin-induced TNFa production is the key factor to induce liver injury and promote hepatic fibrogenesis. 68,70 Additionally, thromboxane A 2 has already proved to be a potent vasoconstrictor that is involved in the mechanism of increased IHR in cirrhosis. 6,54 Anandamide is an endocannabinoid that demonstrates increasing IHR through the release of thromboxanes A 2 in cirrhotic livers.…”

Section: (4) Endocannabinoidsmentioning

confidence: 99%

“…6 Our study also revealed that chronic inhibition of endogenous TNFa by thalidomide will attenuate the anandamide-mediated vasoconstriction in cirrhotic livers. 68,69 7. Interaction between endotoxemia and endocannabinoids in cirrhosis-HED Endotoxemia-related activated endocannabinoid systems induce HED and subsequently increases IHR in Figure 2.…”

Section: (4) Endocannabinoidsmentioning

confidence: 99%

Alteration of intrahepatic microcirculation in cirrhotic livers

Yang

Lin

2015

Journal of the Chinese Medical Association

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From a hemodynamic point of view, hepatic vascular resistance and portal inflow determine the level of portal pressure. Factors that determine hepatic vascular resistance include both structural and dynamic components. Among the structural components are histological characteristics such as steatosis, fibrosis, regeneration nodules, and neo-angiogenesis. Dynamic structures include cells with contractile properties such as hepatocytes, hepatic stellate cells, sinusoidal endothelial cells, and Kupffer cells. The contributions of the interactions between four cells in cirrhotic livers resulted in hepatic endothelial dysfunction, hepatic microcirculatory dysfunction, hepatic venous dysregulation, hepatic fibrogenesis, and subsequently increased intrahepatic resistance and portal hypertension in cirrhosis. The pathogenic mechanisms that trigger the associated abnormalities in hepatic microcirculations include persistent endotoxemia, increased hepatic oxidative stress, activated endocannabinoids substances, pathogenic sinusoidal remodeling, and hypoperfusion in cirrhotic livers. Cumulative data suggested that various therapeutic strategies targeting hepatic microcirculation provided effective improvement of the systemic abnormalities of cirrhosis. Accordingly, the mechanistic and therapeutic approaches focusing on the disarrangement of hepatic microcirculation will be introduced in this article.

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Rho-kinase-dependent pathway mediates the hepatoprotective effects of sorafenib against ischemia/reperfusion liver injury in rats with nonalcoholic steatohepatitis

et al. 2012

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During liver transplantation, nonalcoholic steatohepatitis (NASH) aggravates ischemia/reperfusion (IR) injury by activating various kinases and subsequently releasing cytokines and chemokines. Nonetheless, the effect of the multikinase inhibitor sorafenib on IR liver injury in rats with NASH has never been explored. Our study was designed to determine this effect and associated mechanisms in NASH rats. Sorafenib was acutely administered to NASH rats with IR liver injury that were or were not chronically pretreated with the Rho-kinase-specific inhibitor fasudil. Then, the following were evaluated: mean arterial pressure; hepatic blood flow and microcirculatory dysfunction; hepatic inflammation (serum alanine aminotransferase); necrosis; apoptosis; leukocyte infiltration; CD45 staining; caspase levels and DNA fragmentation; various serum and hepatic cytokines; and proteins and genes of the Raf/mitogen-activated protein-extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase, and apoptosis pathways. In NASH rats with IR liver injury, hepatic inflammation, necrosis, apoptosis, leukocyte infiltration, and microcirculatory dysfunction were significantly attenuated by the acute administration of sorafenib through the inhibition of the hepatic release of macrophage inflammatory protein 2, keratinocyte chemoattractant, granulocyte-monocyte colony-stimulating factor, and hepatic caspase-3 and caspase-9 as well as DNA fragmentation. Furthermore, there was decreased expression of p-Raf1 (where p indicates the phosphorylated form), p-MEK1/2, p-ERK1/2, p-Rho-kinase, B cell lymphoma 2-associated death promoter, and B cell lymphoma 2-associated X protein at the protein and messenger RNA levels. Notably, the aforementioned beneficial effects of sorafenib were significantly abolished by chronic pretreatment with the Rho-kinase-specific inhibitor fasudil. This study demonstrated that the multikinase inhibitor sorafenib protects NASH rats from IR injury by interfering with the inflammation, necrotic, and apoptotic responses causing leukocyte-dependent hepatic microcirculatory dysfunction.

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Thalidomide decreases intrahepatic resistance in cirrhotic rats

Cited by 14 publications

References 26 publications

Down-regulation of common NFκB-iNOS pathway by chronic Thalidomide treatment improves Hepatopulmonary Syndrome and Muscle Wasting in rats with Biliary Cirrhosis

Down-regulation of common NFκB-iNOS pathway by chronic Thalidomide treatment improves Hepatopulmonary Syndrome and Muscle Wasting in rats with Biliary Cirrhosis

Alteration of intrahepatic microcirculation in cirrhotic livers

Rho-kinase-dependent pathway mediates the hepatoprotective effects of sorafenib against ischemia/reperfusion liver injury in rats with nonalcoholic steatohepatitis

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