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Modulation of hepatic stellate cell survival 서울대학교의과대학내과학교실간연구소, 서울대병원강남센터소화기내과 Hepatic fibrosis develops as a healing response but also causes many clinical problems that are associated with the

1 Modulation of hepatic stellate cell survival 서울대학교의과대학내과학교실간연구소, 서울대병원강남센터소화기내과 Hepatic fibrosis develops as a healing response but also causes many clinical problems that are associated with the progression of portal hypertension and liver failure. Recent basic and clinical evidences suggest that hepatic fibrosis is reversible and that even cirrhosis can be reversed. Removal of activated hepatic stellate cell (HSC) is regarded essential for this fibrosis reversal. Because apoptosis of activated HSCs can lead to the elimination of the main fibrogenic cells and increase the ECM degradation, induction of activated HSC apoptosis is an effective therapeutic method for targeting and removing activated HSCs. This article will highlight recent advances in the understanding of modulation strateges for HSC survival, especially focused on the methods for the apoptosis induction of HSCs. Key words: Hepatic stellate cell; Fibrosis; Apoptosis; Antifibrotic therapy 서 간섬유화는간의손상이발생하였을때손상부위를일련의세포들과교원질이둘러싸게되는치유과정의일환으로발생한다. 1-6 이러한간섬유화는대부분간손상이만성적으로지속되는상황에서발생하게되고, 이에대한반응으로섬유화도지속적으로진행하게되어, 결국에는간기능부전과간섬유화에의한 2차적인합병증들을유발하게하는임상적인문제를초래하게된다. 과거에는이러한일련의과정들이비가역적인것으로여겨졌지만, 최근여러기초및임상연구들에서만성적인간손상을초래하는원인을제거하는적절한치료를시행할경우상당히진행된간섬유화조차도가역적일수있다는 것이보고되면서, 간섬유화를치료하는방법에대한관심과중요성이커졌다 간섬유화를완전하게 치료하기위하여서는만성간손상의원인을치료하는것외에도, 간섬유화자체를발생시키고유지및진행하게하는핵심섬유모세포에대한치료와이미형성된간섬유화부분의관해를유도할수있는치료가중요한데, 최근까지의여러연구들에서간성상세포가간섬유화의발생, 유지및진행과섬유량을조절하는데가장핵심적인역할을하는것으로보고되어왔다. 이에본고에서는간섬유화에서간성상 43

2 2011 년대한간학회춘계 Single Topic Symposium 세포의생존을조절하는방법들, 특히간성상세포의자멸사를유도하는방법들에어떠한발전이있고이들이간섬유화를치료하는데어떤역할을할것으로기대되는지를고찰해보고자한다 ( 그림 1). 본 1. 간성상세포가간섬유화에서가지는중요성간섬유화의시작과진행에서간성상세포가주된역할을하는것은여러연구들을통하여알려져왔다. 1,11,12 만성적인간손상에의하여활성화된간성상세포는안정상태의지방을저장하는세포로부터저장된지방을소실하고세포골격단백인 smooth muscle α-actin (α-sma) 와조면소포체가증가하는형태를가지는근섬유모세포로활성화된후다량의세포외기질들을생성하여간섬유화를진행시킨다. 12 간성상세포를활성화시키고이를지속시키는데에는다양한수용체들및세포내신호전달체계가작동하게되는데, 이들은항섬유화치료에있어서좋은치료표적이될수있는중요성을가지며, 실제이에대한연구들이최근많이진행되어오고있다. 13 이와같은기존의역할외에도최근의연구들을통하여간성상세포가케모카인의분비및항원발현세포로작용하여간섬유화에기여하는기전들이알려지면서간섬유화의진행과치료에서간성상세포에대하여이해하는것은더욱중요하게되었다. 14 간섬유화에대한연구가진행됨에따라최근에는간성상세포외에도골수로부터유래한섬유세포나문맥섬유모세포와같은다른세포들도간손상을일으키는원인에따라서로다른정도로간섬유화에기여하는것이알려지면서섬유화의기전에대한심도있는이해는더욱중요하게되었다. 간성상세포는간섬유화에서가장중추적인역할을담당하는세포인점과간섬유화과정에기여하는분자생물학적인기전들이상당부분체계적으로연구된중추섬유화세포임을고려하면, 간성상세포의활성화와생존에영향을미치는기전과이를활용하여자멸사를유도하는치료법을개발하는것은간섬유화를치료함에있어서향후다양한섬유화유발세포들을복합적으로치료하는초석을마련하는데에도중요할수있다. 9, 세포자멸사의특성및기전세포자멸사는세포가둥글게변하고, 세포및핵의용적감소 (pyknosis), 핵의치밀화와분절화 (karyorrhexis) 및원형질막의수포형성과같은형태학적인특징을가지는세포사멸을일컫는데, 특히원형질막이세포사멸에참여하는형태로세포괴사와구별하게된다. 19,20 세포자멸사는크게 death receptor (DR) 경로나미토콘드리아경로중하나의경로가활성화된후이들로부터유래된 initiator caspase들이 effector caspase들을활성화시켜세포내에존재하는다양한단백질들을분해하고 DNase를활성화시켜진행하게된다. Death receptor경로는세포막표면에존재하는 death receptor에 tumor necrosis factor superfamily 가결합한후수용체들이결찰되면서형성된다중단백사멸유도신호복합체가 caspase 8의촉매작용을활성화시켜자멸사를유도하는외인성경로이다. 반면, 미토콘드리아경로는세포내감지체가과 44

3 도한활성산소들이나 DNA 손상또는세포내성장인자결핍이나단백질구조이상등과같은과다한세포손상이발생할경우이들에의하여미토콘드리아의투과성이증가하게되어, 미토콘드리아내부에존재하던시토크롬 c (cytochrome c) 가세포질로나오게되고, 세포질로유리된시토크롬 c는 apoptosome 형성을촉진하여궁극적으로개시 caspase인 caspase 9을활성화시킴으로써자멸사가진행되는내인성자멸사경로이다. 이들자멸사경로중어떤경로가활성화되는지는세포활성화정도와세포주기및자멸사자극의종류와크기등에의하여결정되는것으로알려져있으므로, 자멸사유도치료요법에서어떤경로가활성화되는지에대한연구가필요하여, 특히복합요법등으로치료효과를극대화하는시도를하고자할경우에는각치료법에의하여활성화되는경로에대한이해가필수적이다. 2,21,22 3. 간성상세포의생존및자멸사에관한연구들간성상세포의생존및활성화에관련된분자생물학적인기전들은각각의단계를억제하거나차단하는방법으로간섬유화를치료하는데활용할수있다. 1 이러한분자생물학적인기전들을살펴보면, 우선간섬유화의시작과진행에직접적으로관여하는 type I collagen, α-smooth muscle actin, matrix metalloproteinase, tissue inhibitors of metalloproteinases, Foxf1, JunD, c/ebpβ등의체계와, 간성상세포의안정형의유지에중요하게작용하는 Lhx2 등의체계소실로인한간성상세포의활성화, 억제단백인 IκB을메틸화시킴으로써간성상세포의생존에관여하는 NFκB를활성화시키는 CBP1, MeCP2나담즙산처럼 COX-2와 Mcl-1 등을유도하여간성상세포를활성화시키는유전자외조절체계등을들수있다. 1,9,23 한편, 활성화된간성상세포의자멸사를유도하는것은간섬유화의치료에서더이상간섬유화가진행되는것을막고섬유화를회복시키는데있어서가장확실하면서도, 간자체에내재된경로를이용하는장점이있다. 2,3,24 이러한생존체계와자멸사유도등을이용하여섬유화를극복하고자한최근의연구들로는 sulfasalszine이 IκK를억제하여 IκB를활성화시켜간성상세포의자멸사를유도하고, 면역세포인 Natural Killer 세포가 Death Receptor를통하여간성상세포의자멸사를유도하고, proteasome inhibitor가 NFκB활성화의억제를통하여간세포자멸사를일으키고, statin이 caspase 9의활성화를통한내인성자멸사경로를활성화시켜간성상세포의자멸사를일으킴으로서간섬유화를감소시키며, Hsp90 inhibitor가 sphingomyelinase와 NFκB 의존적인경로로간성상세포의자멸사를유도한다는보고등을들수있다. 2,13,25-29 또한, 간암과간경변에서같이작용할수있는 Wnt 신호전달체계가간성상세포에서존재하며이를억제할경우간성상세포의자멸사가능성을제시한연구를고려하면, 오래지속된간섬유화와간암을같이치료해야하는상황에도간성상세포의생존과관련된경로를이용할수있는가능성을고려해볼수있다. 30 결 본고에서는간섬유화의발생과유지및진행에가장중요한역할을하고있는간성상세포의활성화 45

4 2011 년대한간학회춘계 Single Topic Symposium 와생존에는실제치료에활용될가능성이있는다양한분자생물학적기전들이관여하고있고, 특히분자생물학적기반위에서간성상세포의자멸사를유도하는치료법은내재적으로존재하는기전에근거를둔가장효율적인항섬유화치료법으로이용될가능성이있다는것을살펴보았다. 만성바이러스성간염에서항바이러스치료와같이만성간손상원인을치료하거나억제할수있는방법들이많이알려졌지만, 이미발생한간섬유화까지회복시키기위하여보다효과적인항섬유화치료법의개발이필요한실정에서, 자멸사유도과정에서간세포자체의자멸사가동반됨으로인하여역설적으로간섬유화를악화시키는것을피할수있는간성상세포특이적자멸사유도전략에대한연구와, 활성화된간성상세포를안정상태로회복시킬수있다는연구보고들을고려하여극도로활성화된간성상세포는자멸사를유도하고초기활성화단계의간성상세포는안정상태로회복시키는방법과같이보다효율적일수있는자멸사유도전략에관한연구들도고려하여야하겠다. 31,32 참고문헌 1. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008;134: Yang JI, Yoon JH, Bang YJ, et al. Synergistic antifibrotic efficacy of statin and protein kinase C inhibitor in hepatic fibrosis. Am J Physiol Gastrointest Liver Physiol;298:G Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115: Bonis PA, Friedman SL, Kaplan MM. Is liver fibrosis reversible? N Engl J Med 2001;344: Benyon RC, Iredale JP. Is liver fibrosis reversible? Gut 2000;46: Xu L, Hui AY, Albanis E, et al. Human hepatic stellate cell lines, LX-1 and LX-2: new tools for analysis of hepatic fibrosis. Gut 2005;54: Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology 2006;131: Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med 2007;147: Kisseleva T, Brenner DA. Hepatic stellate cells and the reversal of fibrosis. J Gastroenterol Hepatol 2006;21 Suppl 3:S Issa R, Zhou X, Constandinou CM, et al. Spontaneous recovery from micronodular cirrhosis: evidence for incomplete resolution associated with matrix cross-linking. Gastroenterology 2004;126: Friedman SL. Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies. N Engl J Med 1993;328: Tsukada S, Parsons CJ, Rippe RA. Mechanisms of liver fibrosis. Clin Chim Acta 2006;364: Oakley F, Meso M, Iredale JP, et al. Inhibition of inhibitor of kappab kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis. Gastroenterology 2005;128: Winau F, Hegasy G, Weiskirchen R, et al. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity 2007;26: Forbes SJ, Russo FP, Rey V, et al. A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 2004;126: Kisseleva T, Uchinami H, Feirt N, et al. Bone marrow-derived fibrocytes participate in pathogenesis of liver 46

5 fibrosis. J Hepatol 2006;45: Kruglov EA, Nathanson RA, Nguyen T, Dranoff JA. Secretion of MCP-1/CCL2 by bile duct epithelia induces myofibroblastic transdifferentiation of portal fibroblasts. Am J Physiol Gastrointest Liver Physiol 2006;290:G Elsharkawy AM, Oakley F, Mann DA. The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. Apoptosis 2005;10: Galluzzi L, Maiuri MC, Vitale I, et al. Cell death modalities: classification and pathophysiological implications. Cell Death Differ 2007;14: Hotchkiss RS, Strasser A, McDunn JE, Swanson PE. Cell death. N Engl J Med 2009;361: Green DR. Apoptotic pathways: ten minutes to dead. Cell 2005;121: Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell 2004;116: Kim KM, Yoon JH, Gwak GY, et al. Bile acid-mediated induction of cyclooxygenase-2 and Mcl-1 in hepatic stellate cells. Biochem Biophys Res Commun 2006;342: Pinzani M, Rombouts K, Colagrande S. Fibrosis in chronic liver diseases: diagnosis and management. J Hepatol 2005;42 Suppl:S Habens F, Srinivasan N, Oakley F, Mann DA, Ganesan A, Packham G. Novel sulfasalazine analogues with enhanced NF-kB inhibitory and apoptosis promoting activity. Apoptosis 2005;10: Radaeva S, Sun R, Jaruga B, Nguyen VT, Tian Z, Gao B. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology 2006;130: Anan A, Baskin-Bey ES, Bronk SF, Werneburg NW, Shah VH, Gores GJ. Proteasome inhibition induces hepatic stellate cell apoptosis. Hepatology 2006;43: Aprigliano I, Dudas J, Ramadori G, Saile B. Atorvastatin induces apoptosis by a caspase-9-dependent pathway: an in vitro study on activated rat hepatic stellate cells. Liver Int 2008;28: Myung SJ, Yoon JH, Kim BH, Lee JH, Jung EU, Lee HS. Heat shock protein 90 inhibitor induces apoptosis and attenuates activation of hepatic stellate cells. J Pharmacol Exp Ther 2009;330: Myung SJ, Yoon JH, Gwak GY, et al. Wnt signaling enhances the activation and survival of human hepatic stellate cells. FEBS Lett 2007;581: Guyot C, Combe C, Balabaud C, Bioulac-Sage P, Desmouliere A. Fibrogenic cell fate during fibrotic tissue remodelling observed in rat and human cultured liver slices. J Hepatol 2007;46: Canbay A, Friedman S, Gores GJ. Apoptosis: the nexus of liver injury and fibrosis. Hepatology 2004;39:

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract