title: Thalidomide Improves the Intestinal Mucosal Injury and Suppresses Mesenteric Angiogenesis and Vasodilatation by Down-Regulating Inflammasomes-Related Cascades in Cirrhotic Rats.
abstract: OBJECTIVE
  By blocking TNFα-related effects, thalidomide not only inhibits hepatic fibrogenesis but improves peripheral vasodilatation and portal hypertension in cirrhotic rats. Nonetheless, the investigation of thalidomide's effects on splanchnic and collateral microcirculation has been limited. Our study explored the roles of intestinal and mesenteric TNFα along with inflammasome-related pathway in relation to cirrhosis and the splanchnic/collateral microcirculation.
  
  
  METHODS
  Using in vivo and in vitro approaches, mechanisms of the effects of thalidomide on intestinal and mesenteric inflammatory, vasodilatory and angiogenic cascades-related abnormalities were explored in cirrhotic rats that had received 1-month thalidomide (C-T) treatment.
  
  
  RESULTS
  In cirrhotic rats, high tumor necrosis factor (TNF)α, vascular endothelial growth factor (VEGF) and nitric oxide (NO)x levels were associated with the NOD-like receptors protein 3 (NLRP3), IL-1β and caspase-1 inflammasome over-expression in splenorenal shunt and mesenteric tissues. The thalidomide-related inhibition of mesenteric and splenorenal shunt inflammasome expression was accompanied by a significantly decreased intestinal mucosal injury and inflammasome immunohistochemical staining expression. Suppression of various angiogenic cascades, namely VEGF-NOS-NO, was paralleled by a decrease in mesenteric angiogenesis as detected by CD31 immunofluorescence staining and by reduced portosystemic shunting (PSS) in C-T rats. The down-regulation of the mesenteric and collateral vasodilatory VEGF-NOS-NO cascades resulted in a correction of vasoconstrictive hypo-responsiveness and in an attenuation of vasodilatory hyper-responsiveness when analyzed by in situ perfusion of the superior mesenteric arterial (SMA) and portosystemic collaterals. There was also a decrease in SMA blood flow and an increase in SMA resistance in the C-T rats. Additionally, acute incubation with thalidomide abolished TNFα-augmented VEGF-mediated migration of and tube formation of human umbilical vein endothelial cells, which was accompanied by corresponding changes in inflammatory and angiogenic substances release.
  
  
  CONCLUSIONS
  The suppression of inflammasome over-expression by chronic thalidomide treatment ameliorates inflammatory, angiogenic and vasodilatory cascades-related pathogenic changes in the splanchnic and collateral microcirculation of cirrhotic rats. Thalidomide seems to be a promising agent that might bring about beneficial changes to the disarrangements of peripheral, hepatic, splanchnic and collateral systems in cirrhosis.
authors.affiliation: Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Tzu-Hao
authors.initials: TH
authors.lastname: Li
authors.affiliation: Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chia-Chang
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Yang
authors.affiliation: Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Kuei-Chuan
authors.initials: KC
authors.lastname: Lee
authors.affiliation: Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Shie-Liang
authors.initials: SL
authors.lastname: Hsieh
authors.affiliation: Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yun-Cheng
authors.initials: YC
authors.lastname: Hsieh
authors.affiliation: Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Lin
authors.initials: L
authors.lastname: Alan
authors.affiliation: Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Lin
authors.affiliation: Cheng Hsin General Hospital, Taipei, Taiwan.
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
authors.affiliation: Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Chang-Youh
authors.initials: CY
authors.lastname: Tsai
mesh_terms: D002478:Cells, Cultured; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006975:Hypertension, Portal / Q000188:drug therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D058847:Inflammasomes / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D013792:Thalidomide / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D007166:Immunosuppressive Agents; D058847:Inflammasomes; D013792:Thalidomide
references.citation: Hepatology. 2009 Apr;49(4):1245-56
references.pmid: 19137587
references.citation: Biochem Biophys Res Commun. 2009 Mar 13;380(3):666-72
references.pmid: 19285019
references.citation: Liver Int. 2009 May;29(5):678-85
references.pmid: 19413671
references.citation: J Chin Med Assoc. 2009 May;72(5):234-42
references.pmid: 19467946
references.citation: J Immunol. 2009 Jul 15;183(2):792-6
references.pmid: 19542372
references.citation: J Hepatol. 2009 Sep;51(3):475-82
references.pmid: 19560225
references.citation: J Immunol. 2009 Oct 1;183(7):4705-14
references.pmid: 19752225
references.citation: J Clin Invest. 2009 Oct;119(10):2954-64
references.pmid: 19759514
references.citation: J Immunol. 2009 Nov 1;183(9):5593-9
references.pmid: 19843943
references.citation: J Biol Chem. 2010 Oct 15;285(42):32087-95
references.pmid: 20702413
references.citation: Mol Cell Biol. 2011 Feb;31(4):756-65
references.pmid: 21135124
references.citation: Nature. 2012 Jan 19;481(7381):278-86
references.pmid: 22258606
references.citation: J Vis Exp. 2012;(63):e3954
references.pmid: 22643964
references.citation: Gastroenterology. 2012 Nov;143(5):1330-40.e1
references.pmid: 22841787
references.citation: Hepatology. 2013 Feb;57(2):577-89
references.pmid: 22987396
references.citation: PLoS One. 2013;8(8):e71477
references.pmid: 23940760
references.citation: Cell Rep. 2013 Sep 12;4(5):945-58
references.pmid: 24012762
references.citation: PLoS One. 2015;10(3):e0119106
references.pmid: 25793779
references.citation: J Clin Invest. 1999 Nov;104(9):1223-33
references.pmid: 10545521
references.citation: Gastroenterology. 1999 Dec;117(6):1271-7
references.pmid: 10579967
references.citation: Gastroenterology. 2002 Jul;123(1):291-300
references.pmid: 12105857
references.citation: Biochem Pharmacol. 2002 Jul 1;64(1):1-8
references.pmid: 12106600
references.citation: Br J Cancer. 2002 Nov 4;87(10):1166-72
references.pmid: 12402158
references.citation: Cytokine Growth Factor Rev. 2003 Jun-Aug;14(3-4):181-4
references.pmid: 12787557
references.citation: Arch Surg. 1970 Oct;101(4):478-83
references.pmid: 5457245
references.citation: J Immunol. 1986 Mar 1;136(5):1680-7
references.pmid: 3485132
references.citation: Science. 1990 Mar 9;247(4947):1219-22
references.pmid: 1690453
references.citation: Hepatology. 1990 Apr;11(4):628-34
references.pmid: 2184115
references.citation: Gastroenterology. 1992 Jul;103(1):264-74
references.pmid: 1612333
references.citation: J Biol Chem. 1993 Jan 25;268(3):1842-6
references.pmid: 7678411
references.citation: J Appl Physiol (1985). 1993 Dec;75(6):2392-9
references.pmid: 8125855
references.citation: J Clin Invest. 1994 May;93(5):2236-43
references.pmid: 7514193
references.citation: Gastroenterology. 1995 Mar;108(3):761-7
references.pmid: 7875478
references.citation: Hepatology. 1996 Jun;23(6):1616-21
references.pmid: 8675185
references.citation: Am J Pathol. 2005 Jun;166(6):1861-70
references.pmid: 15920170
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 May;290(5):G980-7
references.pmid: 16603731
references.citation: Life Sci. 2006 Apr 25;78(22):2558-63
references.pmid: 16310808
references.citation: BMC Cell Biol. 2006;7:17
references.pmid: 16584574
references.citation: Liver Int. 2006 Sep;26(7):889-98
references.pmid: 16911473
references.citation: Pathol Res Pract. 2006;202(11):777-88
references.pmid: 17030452
references.citation: Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G109-19
references.pmid: 17975131
references.citation: Curr Opin Immunol. 2009 Feb;21(1):10-6
references.pmid: 19223160