Targeting Cell Death and Sterile Inflammation Loop for the Treatment of Nonalcoholic Steatohepatitis

Seminars in Liver Disease

Volumn 36, Issue 1, 2016, Pages 27-36

  Wree, Alexander ^a,b   Mehal, Wajahat Z ^c   Feldstein, Ariel E ^a  

^a RADY CHILDREN'S HOSPITAL   (United States)

^b UNIVERSITY HOSPITAL RWTH AACHEN   (Germany)

^c YALE UNIVERSITY   (United States)

Author keywords

cell death; danger associated molecular patterns; inflammation; liver disease; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; pattern recognition receptors; therapy

Indexed keywords

CASPASE 3; CASPASE INHIBITOR; CYTOSOL RECEPTOR; DEATH RECEPTOR 4; DEATH RECEPTOR 5; EFFECTOR CASPASE; FAS LIGAND; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE P38; REACTIVE OXYGEN METABOLITE; STRESS ACTIVATED PROTEIN KINASE; TUMOR NECROSIS FACTOR RECEPTOR 1; ANTIINFLAMMATORY AGENT; AUTACOID;

ARTICLE; CELL DEATH; CELL ORGANELLE; ENZYME ACTIVATION; GENE IDENTIFICATION; HEPATOBILIARY PARAMETERS; HUMAN; INNATE IMMUNITY; INTRACELLULAR SIGNALING; LIVER FIBROSIS; LIVER INJURY; NONALCOHOLIC FATTY LIVER; NONHUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION; RANDOMIZED CONTROLLED TRIAL (TOPIC); SIGNAL TRANSDUCTION; SURFACE PROPERTY; TARGET CELL; TISSUE INJURY; TUNEL ASSAY; ADVERSE EFFECTS; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; LIVER; LIVER CIRRHOSIS; METABOLISM; MOLECULARLY TARGETED THERAPY; NON-ALCOHOLIC FATTY LIVER DISEASE; PATHOLOGY; TREATMENT OUTCOME;

ANIMALS; ANTI-INFLAMMATORY AGENTS; CELL DEATH; HUMANS; INFLAMMATION MEDIATORS; LIVER; LIVER CIRRHOSIS; MOLECULAR TARGETED THERAPY; NON-ALCOHOLIC FATTY LIVER DISEASE; SIGNAL TRANSDUCTION; TREATMENT OUTCOME;

EID: 84958178106     PISSN: 02728087     EISSN: 10988971     Source Type: Journal    
DOI: 10.1055/s-0035-1571272     Document Type: Article

References (106)

1. Levene A. P., Goldin R. D. The epidemiology, pathogenesis and histopathology of fatty liver disease. Histopathology: 2012; 61 2 141 152
2. Vernon G., Baranova A., Younossi Z. M. Systematic review: The epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther: 2011; 34 3 274 285
3. Brunt E. M., Neuschwander-Tetri B. A., Oliver D., Wehmeier K. R., Bacon B. R. Nonalcoholic steatohepatitis: Histologic features and clinical correlations with 30 blinded biopsy specimens. Hum Pathol: 2004; 35 9 1070 1082
4. Adams L. A., Lymp J. F., St Sauver J., et al. The natural history of nonalcoholic fatty liver disease: A population-based cohort study. Gastroenterology: 2005; 129 1 113 121
5. Matteoni C. A., Younossi Z. M., Gramlich T., Boparai N., Liu Y. C., McCullough A. J. Nonalcoholic fatty liver disease: A spectrum of clinical and pathological severity. Gastroenterology: 1999; 116 6 1413 1419
6. Angulo P., Kleiner D. E., Dam-Larsen S., et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology: 2015; 149 2 389 97.e10
7. Wong R. J., Aguilar M., Cheung R., et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology: 2015; 148 3 547 555
8. Tilg H., Moschen A. R. Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis. Hepatology: 2010; 52 5 1836 1846
9. Bechmann L. P., Hannivoort R. A., Gerken G., Hotamisligil G. S., Trauner M., Canbay A. The interaction of hepatic lipid and glucose metabolism in liver diseases. J Hepatol: 2012; 56 4 952 964
10. Wree A., Kahraman A., Gerken G., Canbay A. Obesity affects the liver - the link between adipocytes and hepatocytes. Digestion: 2011; 83 1-2 124 133
11. Feldstein A. E. Novel insights into the pathophysiology of nonalcoholic fatty liver disease. Semin Liver Dis: 2010; 30 4 391 401
12. Wree A., Broderick L., Canbay A., Hoffman H. M., Feldstein A. E. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol: 2013; 10 11 627 636
13. Feldstein A. E., Canbay A., Angulo P., et al. Hepatocyte apoptosis and Fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology: 2003; 125 2 437 443
14. Hirsova P., Gores G. J. Death receptor-mediated cell death and proinflammatory signaling in nonalcoholic steatohepatitis. Cell Mol Gastroenterol Hepatol: 2015; 1 1 17 27
15. Luedde T., Kaplowitz N., Schwabe R. F. Cell death and cell death responses in liver disease: Mechanisms and clinical relevance. Gastroenterology: 2014; 147 4 765 783.e4
16. Canbay A., Friedman S., Gores G. J. Apoptosis: The nexus of liver injury and fibrosis. Hepatology: 2004; 39 2 273 278
17. Canbay A., Taimr P., Torok N., Higuchi H., Friedman S., Gores G. J. Apoptotic body engulfment by a human stellate cell line is profibrogenic. Lab Invest: 2003; 83 5 655 663
18. Kroemer G., Galluzzi L., Vandenabeele P., et al. Nomenclature Committee on Cell Death 2009. Classification of cell death: Recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ: 2009; 16 1 3 11
19. Komatsu M. Liver autophagy: Physiology and pathology. J Biochem: 2012; 152 1 5 15
20. Wree A., Eguchi A., McGeough M. D., et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology: 2014; 59 3 898 910
21. Riedl S. J., Shi Y. Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol: 2004; 5 11 897 907
22. Malhi H., Guicciardi M. E., Gores G. J. Hepatocyte death: A clear and present danger. Physiol Rev: 2010; 90 3 1165 1194
23. Rasola A., Bernardi P. The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis. Apoptosis: 2007; 12 5 815 833
24. Hotchkiss R. S., Strasser A., McDunn J. E., Swanson P. E. Cell death. N Engl J Med: 2009; 361 16 1570 1583
25. Gores G. J., Herman B., Lemasters J. J. Plasma membrane bleb formation and rupture: A common feature of hepatocellular injury. Hepatology: 1990; 11 4 690 698
26. Holler N., Zaru R., Micheau O., et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol: 2000; 1 6 489 495
27. Galluzzi L., Kepp O., Kroemer G. RIP kinases initiate programmed necrosis. J Mol Cell Biol: 2009; 1 1 8 10
28. Eguchi A., Wree A., Feldstein A. E. Biomarkers of liver cell death. J Hepatol: 2014; 60 5 1063 1074
29. Fink S. L., Cookson B. T. Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell Microbiol: 2006; 8 11 1812 1825
30. Canbay A., Feldstein A., Baskin-Bey E., Bronk S. F., Gores G. J. The caspase inhibitor IDN-6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse. J Pharmacol Exp Ther: 2004; 308 3 1191 1196
31. Holsinger L. J., Coakley D. F., Dener J. M., et al. Efficacy of a reversible cathepsin B inhibitor in a rodent model of liver fibrosis and human pharmacokinetic profile. Hepatology: 2010; 52 1128A
32. Wu X., Zhang L., Gurley E., et al. Prevention of free fatty acid-induced hepatic lipotoxicity by 18beta-glycyrrhetinic acid through lysosomal and mitochondrial pathways. Hepatology: 2008; 47 6 1905 1915
33. Adams L. A., Zein C. O., Angulo P., Lindor K. D. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol: 2004; 99 12 2365 2368
34. Satapathy S. K., Sakhuja P., Malhotra V., Sharma B. C., Sarin S. K. Beneficial effects of pentoxifylline on hepatic steatosis, fibrosis and necroinflammation in patients with non-alcoholic steatohepatitis. J Gastroenterol Hepatol: 2007; 22 5 634 638
35. Gogate P., Ambardekar P., Kulkarni S., Deshpande R., Joshi S., Deshpande M. Comparison of endothelial cell loss after cataract surgery: Phacoemulsification versus manual small-incision cataract surgery: Six-week results of a randomized control trial. J Cataract Refract Surg: 2010; 36 2 247 253
36. Boetticher N. C., Peine C. J., Kwo P., et al. A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis. Gastroenterology: 2008; 135 6 1953 1960
37. Zou C., Ma J., Wang X., et al. Lack of Fas antagonism by Met in human fatty liver disease. Nat Med: 2007; 13 9 1078 1085
38. Valentino K. L., Gutierrez M., Sanchez R., Winship M. J., Shapiro D. A. First clinical trial of a novel caspase inhibitor: Anti-apoptotic caspase inhibitor, IDN-6556, improves liver enzymes. Int J Clin Pharmacol Ther: 2003; 41 10 441 449
39. Dixon L. J., Berk M., Thapaliya S., Papouchado B. G., Feldstein A. E. Caspase-1-mediated regulation of fibrogenesis in diet-induced steatohepatitis. Lab Invest: 2012; 92 5 713 723
40. Witek R. P., Stone W. C., Karaca F. G., et al. Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis. Hepatology: 2009; 50 5 1421 1430
41. Anstee Q. M., Concas D., Kudo H., et al. Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis. J Hepatol: 2010; 53 3 542 550
42. Pockros P. J., Schiff E. R., Shiffman M. L., et al. Oral IDN-6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C. Hepatology: 2007; 46 2 324 329
43. Shiffman M. L., Pockros P., McHutchison J. G., Schiff E. R., Morris M., Burgess G. Clinical trial: The efficacy and safety of oral PF-03491390, a pancaspase inhibitor - a randomized placebo-controlled study in patients with chronic hepatitis C. Aliment Pharmacol Ther: 2010; 31 9 969 978
44. Barreyro F. J., Holod S., Finocchietto P. V., et al. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int: 2015; 35 3 953 966
45. Ratziu V., Sheikh M. Y., Sanyal A. J., et al. A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis. Hepatology: 2012; 55 2 419 428
46. Elbekai R. H., Paranjpe M. G., Contreras P. C., Spada A. Carcinogenicity assessment of the pan-caspase inhibitor, Emricasan, in Tg.rasH2 mice. Regul Toxicol Pharmacol: 2015; 72 2 169 178
47. Kyriakis J. M., Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev: 2001; 81 2 807 869
48. Wang Y., Singh R., Lefkowitch J. H., Rigoli R. M., Czaja M. J. Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway. J Biol Chem: 2006; 281 22 15258 15267
49. Kohl T., Gehrke N., Schad A., et al. Diabetic liver injury from streptozotocin is regulated through the caspase-8 homolog cFLIP involving activation of JNK2 and intrahepatic immunocompetent cells. Cell Death Dis: 2013; 4 e712
50. Gan L. T., Van Rooyen D. M., Koina M. E., McCuskey R. S., Teoh N. C., Farrell G. C. Hepatocyte free cholesterol lipotoxicity results from JNK1-mediated mitochondrial injury and is HMGB1 and TLR4-dependent. J Hepatol: 2014; 61 6 1376 1384
51. Kim K. Y., Kim B. C., Xu Z., Kim S. J. Mixed lineage kinase 3 (MLK3)-activated p38 MAP kinase mediates transforming growth factor-beta-induced apoptosis in hepatoma cells. J Biol Chem: 2004; 279 28 29478 29484
52. Sharma M., Urano F., Jaeschke A. Cdc42 and Rac1 are major contributors to the saturated fatty acid-stimulated JNK pathway in hepatocytes. J Hepatol: 2012; 56 1 192 198
53. Ibrahim S. H., Gores G. J., Hirsova P., et al. Mixed lineage kinase 3 deficient mice are protected against the high fat high carbohydrate diet-induced steatohepatitis. Liver Int: 2014; 34 3 427 437
54. Jiang J. X., Török N. J. MLK3 as a regulator of disease progression in non-alcoholic steatohepatitis. Liver Int: 2014; 34 8 1131 1132
55. Ichijo H., Nishida E., Irie K., et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science: 1997; 275 5296 90 94
56. Matsuzawa A., Ichijo H. Redox control of cell fate by MAP kinase: Physiological roles of ASK1-MAP kinase pathway in stress signaling. Biochim Biophys Acta: 2008; 1780 11 1325 1336
57. Yamamoto E., Dong Y. F., Kataoka K., et al. Olmesartan prevents cardiovascular injury and hepatic steatosis in obesity and diabetes, accompanied by apoptosis signal regulating kinase-1 inhibition. Hypertension: 2008; 52 3 573 580
58. Nakagawa H., Maeda S., Hikiba Y., et al. Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by inhibiting c-Jun N-terminal kinase activation. Gastroenterology: 2008; 135 4 1311 1321
59. Lim P. L., Liu J., Go M. L., Boelsterli U. A. The mitochondrial superoxide/thioredoxin-2/Ask1 signaling pathway is critically involved in troglitazone-induced cell injury to human hepatocytes. Toxicol Sci: 2008; 101 2 341 349
60. Lin J. H., Zhang J. J., Lin S. L., Chertow G. M. Design of a phase 2 clinical trial of an ASK1 inhibitor, GS-4997, in patients with diabetic kidney disease. Nephron: 2015; 129 1 29 33
61. Gilead S. A phase 2, dose-ranging, randomized, double-blind, placebo-controlled study of GS-4997 in subjects with pulmonary arterial hypertension. ClinicalTrials.gov I.D. #NCT02234141. Bethesda, MD: National Institutes of Health
62. Gilead S. A phase 2 double-blind, placebo-controlled, dose-ranging study evaluating the efficacy, safety, and tolerability of GS-4997 in subjects with diabetic kidney disease. ClinicalTrials.gov I.D. #NCT02177786. Bethesda, MD: National Institutes of Health
63. Gilead S. A phase 2, randomized, open label study evaluating the safety, tolerability, and efficacy of GS-4997 alone or in combination with simtuzumab (sim) in subjects with nonalcoholic steatohepatitis (NASH) and fibrosis stages F2-F3. ClinicalTrials.gov I.D. #NCT02466516. Bethesda, MD: National Institutes of Health
64. Zhang D., Lin Han J. Receptor-interacting protein (RIP) kinase family. Cell Mol Immunol: 2010; 7 4 243 249
65. Zhang Y. F., He W., Zhang C., et al. Role of receptor interacting protein (RIP)1 on apoptosis-inducing factor-mediated necroptosis during acetaminophen-evoked acute liver failure in mice. Toxicol Lett: 2014; 225 3 445 453
66. Takemoto K., Hatano E., Iwaisako K., et al. Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-induced acute liver failure. FEBS Open Bio: 2014; 4 777 787
67. Li J. X., Feng J. M., Wang Y., et al. The B-Raf(V600E) inhibitor dabrafenib selectively inhibits RIP3 and alleviates acetaminophen-induced liver injury. Cell Death Dis: 2014; 5 e1278
68. Gautheron J., Vucur M., Reisinger F., et al. A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis. EMBO Mol Med: 2014; 6 8 1062 1074
69. Mandal P., Berger S. B., Pillay S., et al. RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol Cell: 2014; 56 4 481 495
70. Deutsch M., Graffeo C. S., Rokosh R., et al. Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury. Cell Death Dis: 2015; 6 e1759
71. Garcia-Martinez I., Mehal W. Z. DNA: Adding injury to insult. Hepatology: 2015; 61 1 35 36
72. Garcia-Martinez I., Shaker M. E., Mehal W. Z. Therapeutic opportunities in damage-associated molecular pattern-driven metabolic diseases. Antioxid Redox Signal: 2015
73. Mehal W. Z. Cells on fire. Sci Am: 2015; 312 6 44 49
74. Scaffidi P., Misteli T., Bianchi M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature: 2002; 418 6894 191 195
75. Huttunen H. J., Fages C., Rauvala H. Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem: 1999; 274 28 19919 19924
76. Yang H., Hreggvidsdottir H. S., Palmblad K., et al. A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release. Proc Natl Acad Sci U S A: 2010; 107 26 11942 11947
77. Chen G. Y., Tang J., Zheng P., Liu Y. CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science: 2009; 323 5922 1722 1725
78. Venereau E., Casalgrandi M., Schiraldi M., et al. Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J Exp Med: 2012; 209 9 1519 1528
79. Tsung A., Sahai R., Tanaka H., et al. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med: 2005; 201 7 1135 1143
80. McGill M. R., Staggs V. S., Sharpe M. R., Lee W. M., Jaeschke H.; Acute Liver Failure Study Group. Serum mitochondrial biomarkers and damage-associated molecular patterns are higher in acetaminophen overdose patients with poor outcome. Hepatology: 2014; 60 4 1336 1345
81. Marques P. E., Oliveira A. G., Pereira R. V., et al. Hepatic DNA deposition drives drug-induced liver injury and inflammation in mice. Hepatology: 2015; 61 1 348 360
82. Bala S., Petrasek J., Mundkur S., et al. Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases. Hepatology: 2012; 56 5 1946 1957
83. Kay E., Scotland R. S., Whiteford J. R. Toll-like receptors: Role in inflammation and therapeutic potential. Biofactors: 2014; 40 3 284 294
84. Di Virgilio F. P2X receptors and inflammation. Curr Med Chem: 2015; 22 7 866 877
85. Miura K., Kodama Y., Inokuchi S., et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology: 2010; 139 1 323 34.e7
86. Soares J. B., Pimentel-Nunes P., Roncon-Albuquerque R., Leite-Moreira A. The role of lipopolysaccharide/toll-like receptor 4 signaling in chronic liver diseases. Hepatol Int: 2010; 4 4 659 672
87. Mcdonald K. A., Huang H., Tohme S., et al. Toll-like receptor 4 (TLR4) antagonist eritoran tetrasodium attenuates liver ischemia and reperfusion injury through inhibition of high-mobility group box protein B1 (HMGB1) signaling. Mol Med: 2014; 20 639 648
88. Barrat F. J., Meeker T., Chan J. H., Guiducci C., Coffman R. L. Treatment of lupus-prone mice with a dual inhibitor of TLR7 and TLR9 leads to reduction of autoantibody production and amelioration of disease symptoms. Eur J Immunol: 2007; 37 12 3582 3586
89. Garcia-Martinez I., Ouyang X., Santoro N., et al. Elevated plasma DNA in patients with NASH and reduced liver injury in mice with absence of TLR9 on Kupffer cells. Hepatology: 2014; 60 517A
90. Rice J. W., Veal J. M., Fadden R. P., et al. Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis. Arthritis Rheum: 2008; 58 12 3765 3775
91. Tago K., Tsukahara F., Naruse M., Yoshioka T., Takano K. Hsp90 inhibitors attenuate effect of dexamethasone on activated NF-kappaB and AP-1. Life Sci: 2004; 74 16 1981 1992
92. Wang X., Wang S., Liu Y., et al. Comparative effects of SNX-7081 and SNX-2112 on cell cycle, apoptosis and Hsp90 client proteins in human cancer cells. Oncol Rep: 2015; 33 1 230 238
93. López-Castejón G., Pelegrín P. Current status of inflammasome blockers as anti-inflammatory drugs. Expert Opin Investig Drugs: 2012; 21 7 995 1007
94. Hoque R., Vodovotz Y., Mehal W. Therapeutic strategies in inflammasome mediated diseases of the liver. J Hepatol: 2013; 58 5 1047 1052
95. Szabo G., Csak T. Inflammasomes in liver diseases. J Hepatol: 2012; 57 3 642 654
96. Gross O., Thomas C. J., Guarda G., Tschopp J. The inflammasome: An integrated view. Immunol Rev: 2011; 243 1 136 151
97. Lamkanfi M., Dixit V. M. Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol: 2012; 28 137 161
98. Henao-Mejia J., Elinav E., Jin C., et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature: 2012; 482 7384 179 185
99. Wree A., McGeough M. D., Peña C. A., et al. NLRP3 inflammasome activation is required for fibrosis development in NAFLD. J Mol Med (Berl): 2014; 92 10 1069 1082
100. Han Y. P., Zhou L., Wang J., et al. Essential role of matrix metalloproteinases in interleukin-1-induced myofibroblastic activation of hepatic stellate cell in collagen. J Biol Chem: 2004; 279 6 4820 4828
101. Moltó A., Olivé A. Anti-IL-1 molecules: New comers and new indications. Joint Bone Spine: 2010; 77 2 102 107
102. Petrasek J., Bala S., Csak T., et al. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest: 2012; 122 10 3476 3489
103. Mack M. A phase 2, double-blind randomized controlled trial of anakinra, pentoxifylline, and zinc compared to methylprednisolone in severe acute alcoholic hepatitis. ClinicalTrials.gov. I.D. #NCT01809132. Bethesda, MD: National Institutes of Health
104. Coll R. C., Robertson A., Butler M., Cooper M., O'Neill L. A. The cytokine release inhibitory drug CRID3 targets ASC oligomerisation in the NLRP3 and AIM2 inflammasomes. PLoS ONE: 2011; 6 12 e29539
105. Coll R. C., Robertson A. A., Chae J. J., et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med: 2015; 21 3 248 255
106. Mridha A. WA, Robertson A., Teoh N. C., et al. Blocking the NLRP3 inflammasome prevents inflammatory recruitment and fibrotic progression in experimental NASH. Paper presented at: The AASLD Liver Meeting; November 13-17, 2015; San Francisco, CA