대한내과학회지 : 제 78 권제 1 호 2010 특집 (Special Review) - 폐고혈압 폐동맥고혈압의병인및병태생리 성균관대학교의과대학삼성서울병원심장내과 장성아 Pathogenesis and pathophysiology of pulmonary arterial hypertension Sung-A Chang, M.D. Division of Cardiology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Pulmonary arterial hypertension (PAH) is a rare disease with progressive pathology in pulmonary arteries. Although we lack full understanding of PAH pathophysiology, a variety of vascular components are known to be involved in the pathogenesis of PAH. Endothelial dysfunction is one of the most important components, resulting in vasoconstriction and thrombus formation in pulmonary arteries. Muscularization of pulmonary artery with neointima formation contributes to the occlusion of pulmonary arteries. Hyperplasia of smooth muscle cells as well as vasoconstriction are associated with abnormal Ca 2+ and K + transport within smooth muscle cells. Plasma level of 5-HT (serotonin) and expression of its transporters are elevated in PAH, which also mediates vasoconstriction and hyperplasia of smooth muscle cells. On top of the changes found in vessel itself, alterations in extracellular matrix and a cell-to-cell interaction also play an important role in PAH pathogenesis. Inflammatory process with associated cytokines is believed to generate vascular remodeling and as such inhibitor of these processes can be a potential treatment target for PAH. Thanks to all of this pathological interplay briefly described above, plexiform lesion develops at the late stage of PAH and clinically a high pulmonary vascular resistance ensues, consequently resulting in right ventricular failure. Given prognostic relevance of pulmonary vascular resistance, the understanding of pathogenesis and pathophysiology of PAH is essential in guiding a window to developing novel treatment targets and finally improving prognosis as well as increasing a quality of life in PAH patients. (Korean J Med 78:14-19, 2010) Key Words: Pulmonary arterial hypertension; Pathogenesis; Pathophysiology 서론폐동맥고혈압 (pulmonary arterial hypertension, PAH) 은폐의혈관중에서도특히폐동맥의병적인변화로인하여폐동맥이좁아지고이로인하여우심실압력이상승하며우심실부전을초래하여환자를사망에이르게하는질환이다. 폐동맥고혈압은최근 10년전까지도특별한약이없다고여겨져왔으나, 과거수십년간이어진폐동맥고혈압의병인과 병태생리에대한연구결과들이누적되면서이를바탕으로병의진행을완화시키는치료약제가개발되었으며, 이에따라환자들의삶의질과생존기간이과거에비하여괄목할만하게개선되었다 1,2). 따라서폐동맥고혈압의병인및병태생리를이해하는것은폐동맥고혈압의임상경과와치료경과를이해고, 나아가새로운치료약제개발을위한이론적인바탕이된다고하겠다. 본글에서는폐동맥고혈압의병인및병태생리에대하여살펴보고자한다. - 14 -
- Sung-A Chang. Pathogenesis and pathophysiology of pulmonary arterial hypertension - A B C D Figure 1. Development of pathology in pulmonary arterial hypertension. (A) Early stage of pulmonary arterial hypertension with muscularization of peripheral artery. (B) Development of medial hypertrophy. (C) Interruption of interal elastic lamina, neointimal formation and occlusion of pulmonary artery. (D) Plexiform lesion formation. 폐동맥고혈압의병리소견폐동맥고혈압의병적인변화는주로모세혈관전단계의원위세동맥 (distal precapillary small arteries) 에서나타난다. 폐동맥고혈압환자의폐동맥에는내피세포층 (endothelium), 평활근층 (smooth muscle layer), 그리고그주위를둘러싸고있는외막층 (adventitial layer) 에걸친병적인변화가나타난다 3). 폐동맥고혈압의초기에는원위폐포관 (distal alveolar duct) 은 pericytes가평활근으로분화하면서근육화 (muscularization) 되기시작한다 ( 그림 1A) 4). 원위폐동맥이점점평활근의비후를동반한 muscular artery 로변하게되며 ( 그림 1B), 이어신생내막형성 (neointimal formation) 에따른내막층의병적비후 (intimal hyperplasia) 가일어나세동맥내부는폐쇄되게된다 ( 그림 1C). 평활근세포의수는증식및유입 (migration) 을통하여더욱더증가하며, 일부내피세포에서는세포사멸 (apoptosis) 이나타나고내피세포의기능은훼손된다. 평활근층은계속해서두꺼워지며 (smooth muscle hyperplasia) 외막도함께두꺼워지면서 (adventitial thickening) 질병의후기에는내막, 평활근층, 외막의경계가모호해지는 plexiform lesion을형성하게된다 5). 이단계에다다르면혈관기능장애와느린혈류로인하여폐동맥내에혈전 (thrombus in-situ) 이형성되게된다 ( 그림 1D). 폐동맥고혈압의병인폐동맥고혈압환자의병인은명확히밝혀져있지는않다. 폐동맥고혈압의병인은기저질환에따라서다를것으로보이지만, 폐동맥고혈압환자들에서공통적으로발생되는이상소견들은상당부분비슷한면을가지고있다. 또한, 폐동맥고혈압을호발하는기저질환을가지고있거나, BMPRII 유전자이상과같은특별한유전적이상을가지고있다고 하더라도모든환자에서폐동맥고혈압이발현되는것은아니기때문에현재로서는유전적소인을가진환자에서외부의여러가지자극이가해지면폐동맥의병적변화가시작된다고생각되고있다 (multiple hit theory). 폐동맥고혈압환자에서나타나는분자생물학적변화를살펴보면, 내피세포, 평활근세포, 세포외간질 (extracellular matrix), 외막에걸쳐이상소견이나타나는데 ( 그림 2) 이를간단히살펴보겠다. 1. 내피세포내피세포는혈관의기능을유지하는중요한세포이다. 내피세포는혈전이생기지않도록방지하고, 혈관을적절하게확장및이완시키며이를담당하는평활근세포의성장, 증식및이동 (migration) 을조절한다 6,7). 또한각종염증반응에관련된조절능력을가지고있다 8). 폐동맥고혈압환자에서는내피세포기능을유지하는데중요한 Rho guanosine triphosphatase pathyway에이상이발생하며 9,10) 이는세포의 permeability를증가시키고 barrier로써의역할에장애를유발하는것으로보고되었다. 또한내피세포의중요한기능인혈전형성억제기능에장애를가져오고이와함께혈소판을활성화시켜혈전을발생시키게된다. 폐동맥고혈압환자에서는 nitric oxide (NO) 와 prostacyclin (PGI 2) 와같은혈관확장물질의생산감소가흔히발견되며 11,12), phosphodiesterase-5 (PDE-5) 의활성이증가되어 NO작용의 2 차전달물질인 cyclic guanosine monophosphate (cgmp) 가쉽게분해된다 13,14). 따라서 PDE-5의작용을억제시킨다면 cgmp 의세포내농도가증가하면서폐동맥평활근의이완을유발할것으로기대할수있다. Sildenafil, tadalafil 등의 PDE-5 억제제는이러한이론적배경하에개발되었다 15). 또한체내에부족한 PGI 2 의양을외부에서보충해준다면폐동맥이확장될것으로기대할수있겠으며, 이러한연구는 epoprostenol, ilo- - 15 -
- 대한내과학회지 : 제 78 권제 1 호통권제 593 호 2010 - Figure 2. Schematic diagram depicting potential mechanisms involved in the development of pulmonary arterial hypertension. Ang, angiopoeitin; AVD, apoptotic volume decrease; BMP, bone morphogenetic protein; BMPR, bone morphogenetic protein receptor; CaM, calmodulin; CREB, campresponse element binding protein; DAG, diacylglycerol; Em, membrane potential; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ET, endothelin; GAP, GTPase activating protein; GPCR, G protein-coupled receptor; HHV, human herpes virus; HT, hydroxytryptamine (serotonin); HTT, hydroxytryptamine (serotonin) transporter; IP3, inositol 1,4,5-trisphosphate; Kv, voltage-gated K + ; MAPK, mitogen-activated protein kinase; MLC, myosin light chain; MLCK, myosin light chain kinase; NA(D)PH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; PASMC, pulmonary artery smooth muscle cell; PDGF, plateletderived growth factor; PGI2, prostacyclin; PKC, protein kinase C; PLC, phospholipase C; ROC, receptor-operated Ca2 + channels; ROS, reactive oxygen species; RTK, receptor tyrosine kinase; SR, sarcoplasmic reticulum; SRF, serum response factor; TCF, T cell factor; TIE, endothelial-specific tyrosine kinase; VDCC, voltage-dependent calcium channel. Reprinted from Cellular and molecular basis of pulmonary arterial hypertension. (From ref. 8, with permission from Elsevier.) prost와같은 PGI 2 유도체 (prostacyclin analogue) 를개발하고임상에서사용할수있게해주었다 1,16). 또한폐동맥고혈압환자의내피세포는엔도셀린 (endothelin) 과같은강력한혈관증식및혈관수축유발물질을비정상적으로많이생산하는것으로알려졌으며 17), 따라서엔도셀린이수용체에붙는것을억제할수있는수용체길항제 (bosentan, amrisentan) 가폐동맥고혈압약제로개발되었다 18,19). 2. 평활근세포폐동맥고혈압환자의폐동맥평활근세포는비정상적으로증식되어있다. 평활근세포의증식에관여하는물질로는세로토닌 (serotonin, 5-HT) 이잘알려져있다. 폐동맥고혈압의평활근세포에는 5-HT transporter가증가되어있으며이는세포밖의 5-HT를세포내로유입시키는데기여한다. 이에더하여폐동맥고혈압의동물모델에서는 5-HT의수용체가증가되는것이보고되었으며 20) 폐동맥고혈압환자의혈청내 5-HT 농도도증가되어있는것으로보고되었다 21). 5-HT 는혈관의증식뿐만아니라평활근수축에도관여하여폐동맥고혈압의병인에관여한다 22). 외부에서지속적인 5-HT를공급하는경우폐동맥고혈압이유발될수있으며 fenfluramine 과관련된폐동맥고혈압의발생이그예가되겠다 23,24). 폐동맥고혈압환자의폐동맥평활근은그수가증가되어있을뿐만아니라과도하게혈관을수축시킨다. 평활근세포의수축과이완을조절하는가장중요한요소는세포내칼슘농도인데폐동맥고혈압에서는이러한칼슘의이동에관여하는 Calcium (Ca 2+ ) channel과 voltage dependent potassium (K + ) channel의발현과기능에이상이있으며 25,26), 이로인하여세포내칼슘농도가상승되고과도한평활근수축을유발하게된다. 3. 세포외기질 (extracellular matrix) 혈관을이루는요소중세포외기질은세포사이를채워주 - 16 -
- 장성아. 폐동맥고혈압의병인및병태생리 - 는물질적인역할뿐만아니라다양한수용체와상호작용하며, 세포의기능을조절해주는역할을준다. 폐동맥고혈압에서는이러한세포외기질의이상소견도보여지는데대표적으로 Tenascin-C 는평활근층에서흔히발현되며, 평활근세포의증식을촉진하고 apoptosis를억제하여생존을늘리는것으로알려져있는세포외기질로 27), 폐동맥고혈압에서비정상적으로증가되는것으로보고되었다 28). 4. 염증세포와싸이토카인폐동맥고혈압환자와동물모델에서염증반응이발생한다는것이보고되었으며, 이러한염증반응이폐혈관의재형성 (remodeling) 에관여한다고생각되고있다 29). 폐동맥고혈압의혈관병변에서는 macrophage, B cell, T cell, dendritic cell이흔히관찰되며, 각종 chemokine과 cytokine이과발현된다. 혈관증식과염증반응에관여하는 vascular endothelia growth factor (VEGF) 와 platelet-derived growth factor (PDGF) 는폐동맥고혈압에서증가되는것으로알려져있으며이러한환자에서흔히염증반응을조절하는전사인자 (nuclear factor of activated T cells) 가관찰되어, 폐동맥고혈압의염증반응에기여하고평활근세포와내피세포의증식에관여할것으로생각되고있다 30). 이러한배경하에 PDGF receptor 에길항제로작용하는 tyrosine kinase inhibitors인 imatinib에대한연구가진행되었으며, 최근폐동맥고혈압의새로운치료제로서의가능성이보고되고있다 31,32). 5. TGF-β (transforming growth factor beta) superfamily 와 BMPR-II (bone morphogenic protein receptor II) TGF-β superfamily 는혈관및심장의발생및발달에있어필수적인역할을하는싸이토카인 (cytokine) 들로 TGF-β를비롯하여 activin, BMP-2 등을포함하고있다. 이들의수용체는두개의단위로이루어져있으며이중 type II receptor는 serine/threonine kinase 를가지고있어이를통하여세포내로신호를전달하게된다 33). 이들수용체의변이는 hereditary hemorrhagic telangiectasia를비롯한각종혈관질환을유발하게된다. 이중 BMPR-II gene 은 type II receptor 의하나로서 BMP2 signaling 뿐만아니라 angiopoietin, tanacin과도연관되어있으며, 앞서기술한세포내이상들과도직간접적으로연결되어있다 34,35). 더욱이 BMPR-II gene 은가족성폐동맥고혈압환자에서가장흔히발견되는유전적이상이다. 유전자이상에대해서는따로다루기때문에본글에서는생략하려 하나, 이러한 mutation에따른 BMPRII 의기능저하는앞서언급한분자생물학적이상들과서로상호작용하여영향을미치는것으로생각된다 ( 그림 2). 이에대해서는좀더연구가필요할것이다. Asymptomatic Cardiac output RA pressure 폐동맥고혈압의병태생리 폐동맥고혈압환자의사망을유발하는가장흔한원인은우심실부전이다 36). 또한환자의예후에있어가장중요한것중하나가우심실의기능과심박출량이다 37). 이를이해하기위해서는폐동맥고혈압의병태생리를살펴볼필요가있겠다. 폐동맥고혈압환자의폐동맥이비후되고수축되면서폐동맥의혈관저항은점점상승하게되고이에따라폐동맥압력도증가하게된다. 그러나어느정도이상으로혈관저항이증가하고폐동맥압력이증가하기전까지우심실의수축기능은크게영향받지않고심박출량은거의정상으로유지된다. 따라서이단계의환자는종종증상을보이지않는다 ( 그림 3). 질병이진행하여우심실의기능이악화되면이에따라심박출량이서서히감소하게되며, 우심실의압력상승이우심방까지전달되면서우심방의압력도서서히증가하기시작한다. 우심방의압력증가는곧전신에서돌아오는중심정맥압의상승을의미하며, 질병이진행하면서하지부종과복수, 심한전신피로감등의임상적인우심실부전의증상들이나타나기시작한다. 한가지주목해야할것은폐동맥압력인데, 폐동맥압력은 Symptomatic /compensated Symptomatic/ Decompensated Symptom Threshold Overt RV failure Right Heart Failure Figure 3. Hemodynamic change of pulmonary arterial hypertension. RA, right atrium; PVR, pulmonary vascular resistance; PA, pulmonary arterial, RV, right ventricular. - 17 -
- The Korean Journal of Medicine: Vol. 78, No. 1, 2010 - 심박출량이어느정도유지되는동안에는폐동맥혈관저항이증가함에따라함께증가한다. 그러나압력은저항뿐만아니라혈류에의해서도결정되므로, 심박출량을유지하지못할정도로우심실기능이떨어지는 decompensated heart failure 단계에다다르면, 폐동맥압력도함께떨어지게된다. 따라서진행된폐동맥고혈압환자에서폐동맥의압력은치료효과의판정기준이되지못하며, 예후와의연관성도희박하다 37). 이에비하여심박출량, 폐혈관저항, 우심실의기능저하는환자의상태를평가하는데매우중요한요소가된다 38). 결 폐동맥고혈압은폐동맥자체의병적인변화로인하여폐동맥압력과이에따른우심실부전을가져오는질환이다. 폐동맥고혈압의발생기전은명확하지않으나환자가가지고있는유전적소인, 기저질환에더하여환경적자극에의한세포내외의신호전달체계의변화가복합적으로영향을미치는것으로보인다. 폐동맥고혈압의병인을이해하는것은기존폐동맥고혈압특이약제 (pulmonary arterial hypertension specific drug) 를이해하고, 새로운약제의개발하는데이론적바탕을제공한다. 폐동맥고혈압에대한이해가높아질수록폐동맥고혈압이불치의병에서치료할수있는만성질환으로변모하기를기대해본다. 론 중심단어 : 폐동맥고혈압 ; 병인 ; 병태생리 REFERENCES 1) Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 351:1425-1436, 2004 2) Hoeper MM, Markevych I, Spiekerkoetter E, Welte T, Niedermeyer J. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J 26:858-863, 2005 3) Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 118:2372-2379, 2008 4) Meyrick B, Reid L. Ultrastructural findings in lung biopsy material from children with congenital heart defects. Am J Pathol 101:527-542, 1980 5) Greenway S, van Suylen RJ, Du Marchie Sarvaas G, Kwan E, Ambartsumian N, Lukanidin E, Rabinovitch M. S100A4/Mts1 produces murine pulmonary artery changes resembling plexogenic arteriopathy and is increased in human plexogenic arteriopathy. Am J Pathol 164:253-262, 2004 6) Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373-376, 1980 7) Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524-526, 1987 8) Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR, McMurtry IF, Stenmark KR, Thistlethwaite PA, Weissmann N, Yuan JX, Weir EK. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 54:S20-31, 2009 9) Csortos C, Kolosova I, Verin AD. Regulation of vascular endothelial cell barrier function and cytoskeleton structure by protein phosphatases of the PPP family. Am J Physiol Lung Cell Mol Physiol 293:L843-854, 2007 10) Wojciak-Stothard B, Tsang LY, Paleolog E, Hall SM, Haworth SG. Rac1 and RhoA as regulators of endothelial phenotype and barrier function in hypoxia-induced neonatal pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 290:L1173-1182, 2006 11) Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 333:214-221, 1995 12) Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, Loyd JE. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 327:70-75, 1992 13) Corbin JD, Francis SH. Cyclic GMP phosphodiesterase-5: target of sildenafil. J Biol Chem 274:13729-13732, 1999 14) Rondelet B, Kerbaul F, Van Beneden R, Motte S, Fesler P, Hubloue I, Remmelink M, Brimioulle S, Salmon I, Ketelslegers JM, Naeije R. Signaling molecules in overcirculation-induced pulmonary hypertension in piglets: effects of sildenafil therapy. Circulation 110:2220-2225, 2004 15) Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353:2148-2157, 2005 16) Hoeper MM, Schwarze M, Ehlerding S, Adler-Schuermeyer A, Spiekerkoetter E, Niedermeyer J, Hamm M, Fabel H. Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med 342:1866-1870, 2000 17) Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 328:1732-1739, 1993 18) Benigni A, Remuzzi G. Endothelin antagonists. Lancet 353: 133-138, 1999 19) Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch DB, Roux S, Rainisio M, Bodin F, Rubin LJ. Effects of the dual endothelin-receptor antagonist bosentan in pa- - 18 -
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