Abstract
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.
Highlights
Thalidomide can modulate the TNFα-NFκB and inducible nitric oxide synthase (iNOS) pathway, which involve in the pathogenesis of hepatopulmonary syndrome (HPS) and muscle wasting in cirrhosis
In comparison with S-V rats, significantly higher plasma TNF-α, monocyte chemoattractant protein-1 (MCP-1), soluable intercellular cell adehesion molecule-1 (sICAM-1), vascular endothelial growth factor (VEGF), ALT and AST levels and hepatic hydroxyproline as well as lower mean arterial pressure (MAP) were noted in the Bile-duct ligation-vehicle (BDL-V) rats (Table 1), which were significantly reversed by current dose and duration of thalidomide treatment in Bile-duct ligation-thalidomide (BDL-thal) rats (Table 1)
Percentage (%) of circulating CD16+ monocyte in total monocytes and its intracellular levels of TNF-α, NFκB, MCP-1 and iNOS were significantly higher in BDL-V rats than those in S-V rats, and chronic thalidomide treatment inhibited the elevated circulating CD16+ monocytes in BDL-thal rats (Table 1, Fig. 1A–D)
Summary
Thalidomide can modulate the TNFα-NFκB and iNOS pathway, which involve in the pathogenesis of hepatopulmonary syndrome (HPS) and muscle wasting in cirrhosis. Recruitment of circulating monocytes to lung tissue produces substances that trigger inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO)-mediated angiogenesis and increased alveoloarterial oxygen difference (AaPO2) in experimental hepatopulmonary syndrome (HPS)[1,2]. TNFα-NFκB and iNOS-NO cascades mediate the pulmonary angiogenesis and abnormal gas exchange in experimental HPS of biliary cirrhosis[2,5,6]. The pathogenic roles of recruited muscular macrophages and activated TNFα-NFκB-iNOS cascades have not yet been explored in muscle wasting of cirrhosis. In tissue with chronic inflammation, increased inflammatory monocytes and M1 macrophages polarization result in angiogenesis and protein degradation[6,18,21,22]. NFκB-mediated MyoD decay during muscle wasting is an iNOS-dependent process[25]
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