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1 대한내과학회지 : 제 84 권제 4 호 특집 (Special Review) - 특발성간질성폐렴 특발성폐섬유화증의병인및최신진단기준 순천향대학교서울병원호흡기 - 알레르기내과 어수택 Pathogenesis and New Diagnosis Guideline of Idiopathic Pulmonary Fibrosis Soo-Taek Uh Department of Respiratory and Allergy Medicine, Soonchunhyang University, Seoul Hospital, Seoul, Korea Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease in many patients. In spite of extensive research for many decades, the exact pathogenesis of IPF is unknown. At recent, the role of alveolar epithelial cells has been focused in the initiation of IPF in terms of epithelial-mesenchymal transition, dysregulated Wnt signaling, and activation of transforming growth factor-β (TGF-β). The resulting excess collagen deposition and destruction of lung architecture by myofibroblasts and fibroblastic foci leads to the development of IPF. IPF can be diagnosed by typical high resolution chest tomogram (HRCT) or by multidisciplinary discussion based on the new guideline published on (Korean J Med 2013;84: ) Keywords: Idiopathic pulmonary fibrosis; Pathogenesis; Diagnosis; Myofibroblasts 서론특발성폐섬유화증 (idiopathic pulmonary fibrosis, IPF) 은점점나빠지며치명적인간질성폐질환으로알려져있지만여전히정복되지않은질병으로남아있다. 지난수십년간병인을밝히기위하여수많은연구가이루어져왔으며이들연구를바탕으로새로운개념이많이정립되었지만, 불행히도현재까지폐섬유화의정확한원인이알려져있지않다. 그렇지만과거의 IPF는염증성폐질환이라는개념에서기도상피세포의손상이중요한병인으로대두되고있으며, 최 근에연구되는 epigenetics ( 후생학 ) 까지폐섬유화에관계한다는것으로연구가발전되었다. 2011년도에세계적으로몇개의유관학회가지금까지의연구결과를바탕으로 IPF의진단및치료방침을발표하였다 [1]. 중요한변화는 IPF에합당한임상양상과전형적인고해상도흉부단층소견이면폐조직검사없이 IPF로진단할수있다는것이다. 여기에서는최근새로이알려진 IPF의병인과최근의 IPF 진단방법에대해서기술하고자한다. Correspondence to Soo-Taek Uh, M.D., Ph.D. Department of Respiratory and Allergy Medicine, Soonchunhyang University, Seoul Hospital, 59 Daesakwan-ro, Seoul , Korea Tel: , Fax: , uhs@schmc.ac.kr Copyright c 2013 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - The Korean Journal of Medicine: Vol. 84, No. 4, 병인 본 론 며, 이는근육섬유모세포의 apotposis가억제되어섬유화를유발한다는것이다 [12]. 어떤이유든유전적혹은후생학적인질병의요인이있는사람에게원인물질에노출시폐포상피세포 (alveolar epithelial cells, AEC) 혹은섬유아세포에서 transforming growth factor-β (TGF-β) 를활성화시키고, 이로인하여폐의간질에섬유화가일어난다고알려져있지만이설명만으로는폐섬유화를설명하기는한계가있다. 아마도조절되지않는면역기전 (deregualted immune mechanism) 과계속해서일어나는염증성반응에의해서섬유화가진행될것으로판단된다 [2]. 여기에서는섬유화에관계하는폐포상피세포의역할, 세포의변환 (cellular plasticity), 후생학에관해서기술하고자한다. 폐포상피세포흡연, virus 감염, 흡인등주위환경이 AEC에상처를주면 AEC가활성화되는것이 IPF 병인의시초라고할수있다 [1,3]. AEC가활성화되면서불적절한세포내신호전달체계 (dysregulation of signal transduction), 응고반응 (coagulation pathway), epithelial-mesenchymal transition (EMT) 등의반응이나타나면서폐섬유화가일어난다 [4-6]. EMT 는아래에서다시기술한다. 신호전달체계의이상 (dysregulation of signal transduction) Wnt는 세포파괴 에중요한역할을하는데, 만약활성화되면세포내의 β-catenin을증가시키고, 이로인하여세포의 apoptosis 가억제되고활성화가일어난다 [7]. IPF 환자의 fibrobastic foci에서는 non-specific interstitial pneumonia (NSIP) 환자의조직에서는보이지않는 β-catenin이핵내에서많이발견되는데 [8], 이현상도 IPF 환자에서는 Wnt가활성화되어있다는것을시사하는소견이다. 특히최근연구에의하면 TGF-β 자체가 Wnt를활성화시키며 [9], 그리고 Wnt의활성화는 TGF-β에의한섬유화에필요하다는것이밝혀졌다 [10]. 따라서 Wnt가섬유화의중요한매개체임을알수있고, 이의활성화를억제할수있으면섬유화를조절할수있을것으로추측된다. Phosphatase and tensin homologue (PTEN) 은세포의 apoptosis 에관계하는데 [11], IPF 환자의 fibroblastic foci 내의근육섬유모세포 (myofibroblast) 에서 PTEN의발현이감소되어있으 응고반응상피세포의손상은 TGF-β의활성화와 PAI-I 합성의증가를통하여 plasmin 활성화를억제시키고, 이어섬유소용해성 (fibrinolysis) 을억제하여섬유화를촉진한다. 이는 TGF-β 활성화가일어나면상피세포의 PAI-I 합성증가가일어나는것이확인되었으며 [13], bleomycin에의한동물모델에서 plasmin 활성화를억제시키면섬유화가나타나는것으로알수있다 [14]. 상피세포가손상을받으면활성화된 factor X 합성이증가되고, 이는 TGF-β 활성화를증가시켜근육섬유모세포의분화를촉진시킨다 [15]. 따라서상피세포손상에의한응고반응이섬유화의병인에관계할수있다. 세포의변환 (cellular plasticity) 폐의치유과정에서섬유화가일어나는데, 이섬유화에중요한역할을하는세포가궁극적으로근육섬유모세포이며, 이세포는섬유모세포 (fibroblast) 와평활근 (smooth muscle) 세포의성질을모두갖고있다. 근육섬유모세포가어디에서기원하고어떤기전으로나타나는지알아본다. 상주하는섬유모세포의활성화가장잘알려져있는것은폐의간질에있는섬유모세포가 TGF-β, PDGF 등의성장인자 (growth factor) 에의해활성화된근육섬유모세포로분화되고증식된다는것이다 [16,17]. 최근의흥미를끄는가설은기질 (matrix) 자체가섬유모세포를근육섬유모세포로분화시킨다는것이며, 그기전은섬유모세포가기질에느슨하게붙어있다가상처가치유되는과정에서기질이딱딱해지면근육섬유모세포로분화된다는것이다 [18]. 이런현상은기질이딱딱해지면서 integrin의세포질도메인에의해 TGF-β가활성화되는것이며주로 αvβ3 와 αvβ5 를통해서이루어진다 [19]. 하지만이가설에대해서는지속적인연구가필요하다. Epithelial-mesenchymal transition EMT는상피세포가상피세포의특징이없어지면서중간엽세포 (mesenchymal cell) 의특징을갖는과정을말한다 [20]. 생체연구에서 TGF-β를과발현시키는동물모델의폐 [21] 와

3 - Soo-Taek Uh. Pathogenesis and new diagnosis guideline of idiopathic pulmonary fibrosis - 그리고 bleomycin으로처리한동물의폐 [22] 에서상피세포의특징인 E-cadherin과 surfactant-protein C의표현이감소되고중간엽세포의특징인 α-smooth muscle actin (α-sma) 과 S1000- A4의표현이증가되는상피세포가많아진다는것이다. 또한 IPF 환자의조직의폐상피세포에서도 α-sma 과폐포상피세포의특징인 pro-surfactant protein-b가동시에발현된다 [20] [29], mir-200 [30], 그리고섬유화를유발하는것은 mir-21 [31], mir-154 [32], mir-155 [33] 가있다. IPF 환자에서는증명된바없지만 TGF-β1 합성을억제할수있는 mir-744 [34], 663 [35] 도폐섬유화에관계할것으로추측되고있다. 이외에도폐이외의여러장기및동물실험에서섬유화에관계하는여러 mirs가알려지고있다. Endothelial-Mesenschymal transition Bleomycin으로유도된폐섬유화모델에서폐의혈관내피세포에서유래된섬유모세포가발견되는데이는 endothelialmesenchymal transition 에의해서분화되었으며, 섬유모세포의약 16% 가혈관내피세포에서분화한것으로추측된다 [23]. Fibrocyte Fibrocyte는혈중에존재하는것으로폐에서근육섬유모세포로바뀌게된다. 동물실험에서섬유모세포의약 20% 가골수에서생산된 fibrocyte에서기원한것으로밝혀졌으며 [22], fibrocyte를폐로들어오는것을막는경우섬유화가감소되는것을실험적으로증명하였다 [24]. IPF 환자의말초혈액과폐에서 fibrocyte가관찰되지만, 정상인의폐에서는 fibroyte가관찰되지않았다 [25]. 이소견으로 fibrocyte도근육섬유모세포의기원이라고할수있다. 후생학적측면 MicroRNA MicroRNAs (mirs) 는 21-22개정도의뉴클레오티드로구성되는 non-coding RNA 의일종으로전사후의유전자발현 (post-trasnscription) 을조절하는것으로알려져있으며 [26], messenger RNA의파괴, 혹은전사 (translation) 를억제시켜단백질합성을억제시킨다. IPF 환자에서처음으로연구된 mir은 let-7으로 TGF-β의신호전달체계의하나인 smad-3와결합한다. IPF 환자의조직에서정상인보다발현이적으며, 발현이적을수록 FVC도감소하는것으로보고되었다 [27]. Let-7 을억제시키는 antagomir를투여하면섬유화가진행되며, EMT의중요한조절인자인 high mobility group AT-hook 2 [28] 의발현이증가된다는것이다. 그러나현재까지 let-7을투여하면섬유화가억제되거나혹은개선되는연구는없으며어떤경로를통하여섬유화의억제를가져오는지는알수없다. 이외에도섬유화를억제시킬수있는 mirs에는 mir DNA methylation DNA methylation 은주위환경이나담배와같은물질에노출시 DNA의 cytosine이 methylation되는것으로이로인하여 DNA 복제가억제된다. 만약섬유화를억제시키는유전자의 promoter 부분에 methylation이발생하면섬유화가일어날것이다. 일부 IPF 환자에서 Thy-1 promoter 부분에 methlyation 이있는것이확인되었다 [36]. Thy-1은폐섬유아세포의근섬유아세포로의분화를억제하는단백질 [37] 로 IPF 환자의폐조직내 fibroblastic foci에서감소되어있다 [38]. IFN-γ-inducible protein 10 (IP-10) 이감소하면섬유화가증가하는것이알려져있다 [39]. IPF 환자의섬유아세포에서 IP-10 promoter 부분의 methylation이일어나는것이증명되었다 [40]. 이외에도 methylation chip을이용한연구에서정상인과 IPF 환자사이에여러유전자의 methylation 차이를확인하였다 [41,42]. 이러한일련의실험들은 DNA methylation 이 IPF의병인에중요하다는것을시사하는소견이라고하겠다. Figure 1. Diagnostic algorithm for idiopathic pulmonary fibrosis (IPF)

대한내과학회지: 제 84 권 제 4 호 통권 제 632 호 2013 discussion)를 통하여 진단한다는 것이다.

진단에서 중요한 점은 고해상도 흉부 단층 촬영(high resolution chest 전형적인 소견을 보이는 경우는 조직 검사 없이 IPF로 진단 할 수 있다.

첫째, 간질성 폐질환을 영상의학, 병리 의사가 모이는 다자 토의(multidisciplinary 일으킬 만한 알려진 원인(환경성 노출, 교원성 혈관 질환, A B

Extensive honeycombing (arrow), reticular abnormality (arrow head), basal and peripheral

4 대한내과학회지: 제 84 권 제 4 호 통권 제 632 호 2013 discussion)를 통하여 진단한다는 것이다. 그리고 HRCT에서 진단[1] IPF가 의심되는 경우 진단 방법은 그림 1을 따른다. 진단에서 중요한 점은 고해상도 흉부 단층 촬영(high resolution chest 전형적인 소견을 보이는 경우는 조직 검사 없이 IPF로 진단 할 수 있다. tomogram, HRCT)과 조직 검사가 명확하지 않을 때는 임상, IPF의 진단 기준은 다음과 같다. 첫째, 간질성 폐질환을 영상의학, 병리 의사가 모이는 다자 토의(multidisciplinary 일으킬 만한 알려진 원인(환경성 노출, 교원성 혈관 질환, A B Figure 2. High-resolution tomography demonstraing UIP pattern. Extensive honeycombing (arrow), reticular abnormality (arrow head), basal and peripheral predominant lesion are shown in axial (A) and coronal image (B). A B Figure 3. High-resolution tomography demonstraing UIP pattern. Reticular abnormality (arrow), basal and peripheral predominant lesion are shown in axial (A) and coronal image (B)

5 - 어수택. 특발성폐섬유화증의병인및최신진단기준 - 약제독성 ) 이없어야하며, 둘째, 폐조직검사를하지않은환자에서는 HRCT에서전형적인통상성간질성폐렴 (usual interstitial pneumonia, UIP) 을보여야하며셋째, 폐조직검사를한경우에는 HRCT와폐조직소견의형태를보고결정해야한다. IPF가의심되는경우에 HRCT를시행하여 UIP 모양이면조직검사없이 IPF로진단할수있다. UIP 모양은그림 2와같이폐의아래쪽그리고변연부에주로병변이있고 (subpleural basal predominance), 벌집모양 (honeycoomb), 망상의음영 (reticular densities) 이있으면서, UIP와맞지않는소견 (Table 1의세번째열 ) 이없을때를말한다. Possible UIP는 그림 3과같이전형적인 UIP 모양에서벌집모양이없는경우이며이런경우는 IPF 진단을위해서는조직검사를반드시시행해야한다 (Table 1). 폐조직검사에서도표 2와같이 UIP pattern, possible UIP, probable UIP로나눈다. 전형적인 UIP 형태는심한섬유화소견과동반된구조의변형, 섬유화에의한 patchy involvement, fibrobasltic foci 등이다. HRCT와조직검사를종합하면표 3과같다. HRCT 에서 UIP pattern을보이면조직검사에서전형적인 UIP pattern이아니어도 IPF로진단할수있다. HRCT에서 probable UIP인경우는조직검사에서 UIP pattern이거나혹은 probable UIP Table 1. High-resolution computed tomography criteria for UIP pattern UIP pattern (all four features) Possible UIP pattern (all three features) Inconsistent with UIP pattern (any of the seven features) Subpleural, basal predominance Subpleural, basal predominance Upper or mid-lung predominance Reticular abnormality Reticular abnormality Peribronchovascular predominance Honeycombing with or without traction bronchiectasis Absence of features listed as inconsistent with UIP pattern (see third column) Absence of features listed as inconsistent with UIP pattern see third column) Extensive ground glass abnormality (extent > reticular abnormality) Profuse micronodules (bilateral, predominantly upper lobes) Discrete cysts (multiple, bilateral, away from areas of honeycombing) Diffuse mosaic attenuation/air-trapping (bilateral, in three or more lobes) Consolidation in bronchopulmonary segment (s)/lobe (s) Table 2. Histopathological criteria for UIP pattern UIP pattern Probable UIP pattern (all four criteria) Evidence if marked fibrosis/architectural distortion, ± honeycombing in a predominantly subpleural/paraseptal distribution Presence of patchy involvement of lung parenchyma by fibrosis Presence of fibroblast foci Absence of features against a diagnosis of UIP suggesting an alternate diagnosis(see fourth column ) Evidence of marked fibrosis/architectural distortion, ± honeycombing Absence of either patchy involvement or fibroblastic foci, but not both Absence of features against a diagnosis of UIP suggesting an alternate diagnosis (see fourth column ) OR Honeycomb changes only Possible UIP pattern (all three criteria) Patch or diffuse involvement of lung parenchyma by fibrosis, with or without interstitial inflammation Absence of other criteria for UIP (see UIP PATTERN column) Absence of features against a diagnosis of UIP suggesting an alternate diagnosis (see fourth column ) Not UIP pattern (any of the six criteria) Hyaline membranes Organizing pneumonia Granulomas Marked interstitial inflammatory cell infiltrate away from honeycombing Predominant airway centered changes Other features suggestive of an alternate diagnosis

6 - The Korean Journal of Medicine: Vol. 84, No. 4, Table 3. Combination of high-resolution computed tomography and surgical lung biopsy for the diagnosis of IPF (requires multidisciplinary discussion) HRCT pattern Surgical lung biopsy pattern (when performed) Diagnosis of IPF? UIP UIP YES Probable UIP Possible UIP Nonclassifiable fibrosis Possible UIP Not UIP No UIP YES Probable UIP Probable UI Probable Nonclassifiable fibrosis Inconsistent with UIP Not UIP No UIP Possible Probable UIP No Possible UIP Nonclassifiable fibrosis Not UIP 인경우는 UIP로진단할수있다. 기관지폐포세척술과경기관지폐생검은진단을위하여대부분의 IPF 환자에서추전되지않는다. 결론현재까지도 IPF의발생원인은알려져있지않지만, 여러연구의발달로병인을밝히는데많은발전이있었다. 특히후생학연구의발달로 IPF의병인을 DNA부터전사후 (post-transcription) 의변화까지알수있게되었다. 하지만섬유화에가장중요한 TGF-β 활성화만으로는 IPF의병인을모두설명할수없으며, 섬유화에이르게하는여러세포와단백질이상호활성화시키면서섬유화가계속진행하는것으로보이며, 이에대한연구가진행되어야할것이다. 병인과달리진단은많은발전이있었다. 특히최근에발표된지침을통하여폐조직검사없이도진단할수있는근거를마련하였으며, IPF의진단을위하여관계하는과간의상의를통하여진단할수있게되었다. 중심단어 : 특발성폐섬유화증 ; 병인 ; 진단 ; 근육섬유모세포 REFERENCES 1. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/ JRS/ALAT statement: idiopathic pulmonary fibrosis: evidencebased guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183: Gilani SR, Vuga LJ, Lindell KO, et al. CD28 downregulation on circulating CD4 T-cells is associated with poor prognoses of patients with idiopathic pulmonary fibrosis. PLoS One 2010;5:e Tang YW, Johnson JE, Browning PJ, et al. Herpesvirus DNA is consistently detected in lungs of patients with idiopathic pulmonary fibrosis. J Clin Microbiol 2003;41: King TE Jr, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet 2011;378: Coward WR, Saini G, Jenkins G. The pathogenesis of idiopathic pulmonary fibrosis. Ther Adv Respir Dis 2010;4: Ding Q, Luckhardt T, Hecker L, et al. New insights into the pathogenesis and treatment of idiopathic pulmonary fibrosis. Drugs 2011;71: Kikuchi A, Yamamoto H, Kishida S. Multiplicity of the interactions of Wnt proteins and their receptors. Cell Signal 2007;19: Chilosi M, Poletti V, Zamò A, et al. Aberrant Wnt/betacatenin pathway activation in idiopathic pulmonary fibrosis

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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