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1 ISSN: (Print)/ (Online) Tuberc Respir Dis 2011;71: CopyrightC2011. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. 간질성폐질환 Review 성균관대학교의과대학내과학교실삼성서울병원호흡기내과 정만표 Interstitial Lung Disease Man Pyo Chung, M.D. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Recently published articles on interstitial lung disease (ILD) have focused on the accurate diagnosis of idiopathic pulmonary fibrosis (IPF), serum biomarkers, acute exacerbation of IPF, the prognostic factors of ILD and the trial of new treatment. In particular, reports on the serum biomarkers such as CC-chemokine ligand 18, surfactant protein, circulating fibrocytes, and acute exacerbation of IPF are sufficient to be mentioned here. Pirfenidone therapy is the most important trial for the treatment of IPF. Other newer treatment trials such as interferon-gamma, sildenafil and imatinib have been reported to be unsuccessful. On the other hand, the sirolimus trial for lymphangioleiomyomatosis is promising. Combined pulmonary fibrosis and emphysema and IgG4-related disease are established to be the new disease entities of ILD. Key Words: Lung Disease, Interstitial; Idiopathic Pulmonary Fibrosis; Pirfenidone 서 간질성폐질환 (interstitial lung disease, ILD) 은아직도진단및치료에관하여논란이많은분야이고난치성폐질환이많지만, 지난수년간발표된 ILD 관련논문들은이런논란에대한해답을조금씩주기시작한다는점에서매우주목할만하다. 이에최근발표된중요 review article 을참고문헌에소개하고 1-25, 최근 1 2년내에발표된 ILD 관련 original article 만을 6개의주제로나누어기술하고자한다. Address for correspondence: Man Pyo Chung, M.D. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Irwon-dong, Kangnamgu, Seoul , Korea Phone: , Fax: mp.chung@samsung.com Received: Apr. 19, 2011 Accepted: Apr. 21, 2011 론 특발성폐섬유화증 (idiopathic pulmonary fibrosis, IPF) 진단 IPF의확진은폐조직검사에서통상성간질성폐렴 (usual interstitial pneumonia, UIP) 을증명하고원인미상이라는것이확인되어야가능하지만, 고해상도흉부전산화단층촬영 (high resolution chest computer tomography, HRCT) 의발전과더불어진단민감도가증가하여폐조직검사없이 IPF를진단하는것이점점흔해지고있다. 그러나전체확진 IPF환자의 1/2 2/3 에서만전형적인 HRCT 소견을보이고있어 26 폐조직검사이외의 IPF 진단방법에대한논란은많은상태이다. 1. Fell et al. Clinical predictors of a diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2010;181: 폐조직검사로확진된 97명의 IPF환자와 38명의 non- IPF 특발성간질성폐렴 (idiopathic interstitial pneumonia, IIP) 환자를후향적으로분석하여 IPF 진단을예측할수있는임상지표를찾아낸결과, 고령의나이 (odd ratio 163

2 MP Chung: Review on interstitial lung disease [OR], 1.10; 95% confidence interval [CI], ), 흉부 HRCT의간질평가점수 (OR, 17.20; 95% CI, ) 가 IPF 진단예측지표이고흉부 HRCT 의 GGO 증가가 IPF가아니라는 (OR, 0.61; 95% CI, ) 것을시사한다고하였다. 기존의보고에비해연령이 IIP 진단에영향을준다는것, 즉고령의환자일수록 IPF 일가능성이높다는것을보여주었다. 그러나전체대상환자중에 IPF환자가너무많다는단점이있어전향적인연구를통해확인이필요하다. 2. Ohshimo et al. Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009;179: 기관지폐포세척술 (bronchoalveolar lavage, BAL) 소견이포함되어있지않은 2002년 IPF 임상적진단기준을만족하는 74명의 ILD환자에서 BAL 의유용성을평가한결과, BAL lymphocytosis >30% 를보이는 6명 (8%) 은최종적으로비특이성간질성폐렴 (Nonspecific interstitial pneumonia, NSIP) (3명) 과과민성폐렴 (3명) 으로진단되어아직도 IPF 진단에있어 BAL이유용하다는것을주장하였다. 그러나, 모든환자에서폐조직검사가이루어지지않은점과 BAL lymphocytosis 가없는나머지 68명의환자에서도충분한문진과임상경과관찰이이루어졌는지여부가불분명한점이제한점이라할수있다. 3. Sverzellati et al. Biopsy-proved idiopathic pulmonary fibrosis: spectrum of nondiagnostic thinsection CT diagnoses. Radiology 2009;254: 폐조직검사로확진된 55명 IPF 환자의흉부 HRCT 를후향적으로 3명의영상의학과의사가임상정보없이독립적으로진단한결과, 34명 (62%) 의환자에서는다른진단이내려졌는데 NSIP (53%), 과민성폐렴 (12%), 유육종증 (9%), organizing pneumonia (3%), 여러가지진단가능성 (23%) 으로나타났다. 따라서 IPF환자의흉부 HRCT 소견이굉장히다양하다는것을보여주는연구라고하겠다. 4. Song et al. Pathologic and radiologic differences between idiopathic and collagen vascular diseaserelated usual interstitial pneumonia. Chest 2009; 136: 결체조직질환 (collagen vascular disease, CVD) 과연관된 UIP환자의예후는 IPF에비해좋다고알려져있는데, IPF환자에비해 CVD-UIP 환자를시사하는임상적, 방사선학적및병리학적차이를후향적으로분석한연구이다. CVD-UIP 환자가 IPF환자에비해나이가젊고여성이많았으며흉부 HRCT 에서폐기종점수가낮았고 honeycombing 이없는비전형적 CT 소견을더많이보였다. 폐조직검사소견에서는 CVD-UIP 환자에서 germinal center가많은것이 IPF와가장잘구별할수있는점 (OR, 2.948; p=0.001) 이었다. 특히, CVD 연관여부가불확실한 UIP환자의폐조직검사에서 germinal center 가보이면 CVD 연관가능성이많다는점에주목할만하다. 5. van Moorsel et al. Surfactant protein C mutations are the basis of a significant portion of adult familial idiopathic pulmonary fibrosis in a Dutch cohort. Am J Respir Crit Care Med 2010;182: 네덜란드의 familial IPF환자 20명과비가족성 IPF환자 20명에서 surfactant protein (SP)-C 유전자변이를조사한결과, SP-C 유전자변이가 familial IPF에서는 25%, 비가족성 IPF에서는 0% 발견되었다. SP-C 유전자변이가성인 familial IPF 발생의한원인이라는것을발견한점에서의의가있다. IPF 혈청생체표지자 (Biomarker) IPF의생체표지자로는 FVC, DLco 와같은폐기능검사, 도보거리와최저산소포화도수치와같은 6분도보검사, 흉부 HRCT 가알려져있으나, 다양한임상상과경과를보이는 IPF환자에서좀더간단한방법으로진단및예후를예측하기위해서혈청생체표지자를개발하려는노력은계속되어왔다 32,

3 Tuberculosis and Respiratory Diseases Vol. 71. No. 3, Sep Prasse et al. Serum CC-chemokine ligand 18 concentration predicts outcome in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009; 179: 폐포대식세포에서만들어져서폐섬유화세포의콜라겐생성을증가시키는 CC-chemokine ligand 18 (CCL18) 을 72명의 IPF환자혈청에서진단당시와추적시측정하여예후반응정도를평가하였다. 기저혈청 CCL18 이높을수록 6개월후 FVC 감소 (r=0.59, p<0.0001) 및 TLC 감소 (r=0.54, p<0.0001) 와밀접한상관관계를가졌고, 혈청농도 150 ng/ml 이상이폐기능감소를가장잘예측하는 cut-off value이면서사망률증가와관련이있어 (hazard ratio [HR]=7.98; 95% CI, ; p=0.0005), 혈청 CCL18 이 IPF환자의진행및사망을예측하는생체표지자로이용될수있음을보여주었다. 그러나, 이연구는대상환자들에서통일된치료지침을사용하지않아서전향적연구를통해확인이필요하고, 혈청 CCL18 을측정한 enzyme-linked immunosorbent assay (ELISA) 방법이표준화되어있지않아다른 lab에서이측정치를그대로사용할수없는단점이있다. 2. Kinder et al. Serum surfactant protein-a is a strong predictor of early mortality in idiopathic pulmonary fibrosis. Chest 2009;135: 제2형폐포상피세포에서손상초기에분비되어혈청에서상승하는 SP-A를 82명의 IPF환자에서측정하여진단당시혈청 SP-A 농도가 1년내사망률과폐이식까지의기간과밀접한관련이있음 (HR=3.27; 95% CI, ; p=0.003) 을보여줘서, 질환활동성이높은 IPF환자를찾아내는데도움을줄수있다는점을시사하였다. 3. Moeller et al. Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009;179: 섬유화된폐에서발견되는 myofibroblasts 는골수에서나오는 fibrocytes 에서도유래되는것으로알려져있는데, 전체백혈구중차지하는혈청 fibrocyte 의 % 를 51명의안정상태 IPF환자와 7명의급성악화 IPF환자에서측정하여 7명의정상인과 10명의급성호흡곤란증후군환자를대조군으로비교한연구이다. 혈청 fibrocyte % 는정상인에비해안정상태 IPF환자에서 2.72배증가해있었고 (p <0.05), 급성악화 IPF환자에서는 14.51배증가해있었다 (p<0.001). 또한혈청 fibrocyte가 5% 이상인 IPF환자의평균생존기간은 7.5개월로, 5% 이하인 IPF환자의 27 개월에비해유의하게낮았다 (p<0.0001). 이로써혈청 fibrocyte % 는 IPF환자의질환활동성을잘반영하고초기사망률을예측하는지표로유용함을시사하였다. 이연구의결과를토대로혈청 fibrocyte % 는 IPF Network 에서진행하는 prednisone, azathioprine and N-acetylcysteine: a three arm study that evaluates responses in IPF (PANTHER) 임상시험에서기저, 중간추적및연구종료단계에측정하도록설계되었다 Collard et al. Plasma biomarker profiles in acute exacerbation of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2010;299:L 명의급성악화 IPF환자, 20명의안정상태 IPF환자와 20명의급성폐손상환자의혈청에서 KL-6, von Willebrand factor, SP-D, receptor for advanced glycation endproduct (RAGE) 와같은세포활동성 / 손상지표, IL-6와같은전신염증지표와 protein C, thrombomodulin과같은 coagulation/fibrinolysis 지표를측정한결과, 급성악화 IPF환자에서이런혈청지표가모두유의하게상승하여제 2형폐포상피세포가 IPF 급성악화에서중추적역할을한다는것을시사하였다. ILD 급성악화 1. Song et al. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J 2011;37: 중앙값 22.9개월을추적한 461명의 IPF환자를후향적으로조사한결과 163명 (35.4%) 이급격한악화로병원에입원하였는데, 그원인으로급성악화가 55.2% 로가장흔했다. 급성악화의 1년째발생률은 14.2%, 3년째발생률은 20.7% 였으며, 발생위험인자는흡연력이전혀없는경우와낮은 FVC 였다. 병원사망률은 50.0% 였고 1년생존율과 5년생존율은각각 56.2%, 18.4% 였다. 2. Konishi et al. Gene expression profiles of acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009;180: IPF 급성악화시의유전자발현을이해하기위해 8 명 165

4 MP Chung: Review on interstitial lung disease 의 IPF 급성환자, 23명의안정상태 IPF환자, 15명의대조군폐에서 RNA를추출하여조사하였다. CCNA2 와 α- defensins 는가장많이발현이증가된유전자들중하나이다. CCNA2 단백질발현은증식하는폐포상피세포에서발견되었지만 mesenchymal cell에서는발견되지않아서 IPF 급성악화는폐포상피세포손상과연관이있음을시사하였다. α-defensin 발현은상피세포에서나타나면서혈청수치도안정상태의 IPF환자보다의미있게높아 (p <0.05) 급성악화의생체표지자로이용할수있음을시사하였다. Suda et al. Acute exacerbation of interstitial pneumonia associated with collagen vascular diseases. Respir Med 2009;103: Huie et al. A detailed evaluation of acute respiratory decline in patients with fibrotic lung disease: aetiology and outcomes. Respirology 2010;15: Kondoh et al. Prognostic factors in rapidly progressive interstitial pneumonia. Respirology 2010; 15: IPF가급성악화를보이는것처럼 non-ipf ILD에서도급성악화의임상경과를보일수있다는것을보고한논문들이다. ILD 예후 1. Park et al. Clinical course and lung function change of idiopathic nonspecific interstitial pneumonia. Eur Respir J 2009;33: 중앙값 53개월추적한폐조직검사확진 83명 idiopathic NSIP 환자를후향적으로분석한결과, 5년생존율은 74% 였으나 36% 의환자에서재발을보였고 8명 (8%) 에서 CVD가발생하였다. 2. Akira et al. Long-term follow-up high-resolution CT findings in non-specific interstitial pneumonia. Thorax 2011;66: 폐조직검사로확진된 50명 NSIP 환자에서중앙값 72개월후추적한흉부 HRCT 소견변화를후향적으로분석한결과, ground-glass opacity와 consolidation은감소하였으나 coarseness of fibrosis와 traction bronchiectasis는증가했으며 78% 의환자에서전반적인폐병변정도가감 소하거나안정상태를유지하였다. 흉부 HRCT 진단이 NSIP에합당했던환자들이 UIP에합당하거나다른진단을시사했던환자들에비해생존기간이길었으며 ( 각각 p <0.001, p=0.022), 다변량분석에서는 coarseness of fibrosis만이유일한예후예측지표였다 (HR=1.480; 95% CI, ). 3. Lee et al. Cryptogenic organizing pneumonia: serial high-resolution CT findings in 22 patients. AJR Am J Roentgenol 2010;195: 폐조직검사로확진되었고추적흉부 HRCT 를시행한 22명의 cryptogenic organizing pneumonia 환자에서중앙값 8개월후추적한흉부 HRCT 소견변화를후향적으로분석한결과, 27% 에서는완전관해를보였고 68% 에서는병변의감소를보였으며 1명에서만병변이변화없이관찰되었다. 병변이남아있는경우의흉부 HRCT 소견은 63% 에서 fibrotic NSIP 소견과유사하였다. 4. Ozawa et al. Cumulative incidence of and predictive factors for lung cancer in IPF. Respirology 2009;14: 진단당시폐암이없었던 103명의일본 IPF환자를추적한결과, 총 21명 (20.4%) 에서폐암이발병하였고누적발생률은 1년째 3.3%, 5년째 15.4%, 10년째 54.7% 로증가하였다. 다변량분석에서는진단당시의연령이폐암발병의유일한예측인자였다 (HR=1.085; p=0.024). 5. Olson et al. Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med 2011;183: 년에서 2004년까지 rheumatoid arthritis (RA) 연관사망을조사한결과, 임상적으로의미있는 RA-ILD 는약 10% 에서관찰되었고전체 RA 사망률은해가갈수록감소했으나 RA-ILD 로인한사망률은특히여성에서 28.3% 증가했다. 따라서 RA환자에서 ILD 발병은생존기간단축과연관된다고주장하였다. 6. Mukae et al. Clinical differences between interstitial lung disease associated with clinically amyopathic dermatomyositis and classic dermatomyositis. Chest 2009;136: 명의 amyopathic dermatomyositis (adm)-ild 환자 166

5 Tuberculosis and Respiratory Diseases Vol. 71. No. 3, Sep 와 16명의 classic DM (DM)-ILD 환자의임상경과를후향적으로분석한결과, adm-ild환자에서 2개월내급성 ILD로발현한환자가더많았고 (64% vs. 19%; p<0.05) PaO 2 /FiO 2 ratio가유의하게낮았으며 (258 mm Hg vs. 385 mm Hg; p=0.0018), 사망률도 45% 로 DM-ILD 환자의 6% 에비해유의하게높았다 (p<0.02). 이보고는 amyopathic type 의 DM연관 ILD환자가전형적인 type 의 DM연관 ILD환자에비해예후가매우나쁘다는점을잘보여준연구다. 치료 1. Taniguchi et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010;35: 총 275명의 IPF환자를대상으로일본에서시행된 a multicentre, double-blind, placebo-controlled randomized phase III clinical trial로서, pirfenidone 고용량군 (1,800 mg/day), pirfenidone 저용량군 (1,200 mg/day), 대조군을 2:1:2의비율로나누어최종적으로 267명에서 52주째에효과를분석할수있었다. Primary end point (PEP) 는 FVC 변화였고 secondary end point (SEP) 는 progression-free survival (PFS) 이었다. Pirfenidone 고용량군의 FVC 감소 ( 0.16 L) 가대조군 ( 0.09 L) 에비해유의하게낮았고 (p=0.0416), PFS도대조군에비해유의하게길었다 (p=0.0280). 부작용은광과민성이 50% 이상발생하여제일흔했으나대부분가벼운정도였다. 이연구보고의결과로 pirfenidone 은일본 FDA 심의를통과하여판매가허용되었으나 2010 년봄미국 FDA 심의는기각되었다. 2. The Idiopathic Pulmonary Fibrosis Clinical Research Network. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 2010;363: DLco 가예측치의 35% 이하인진행된 IPF 180명을대상으로미국에서시행된 a double-blind, placebo-controlled randomized clinical trial로서, sildenafil과대조약을 1:1 무작위로 12주간복용한후 (period 1) 추가 12주동안은모든환자가 sildenafil 을복용하게했다 (period 2). PEP는 6분도보검사에서도보거리 20% 증가인데 period 1 종료시에측정하였다. Sildenafil 복용환자의 10% 에서만도보거리 20% 증가가가능해서대조군의 7% 에비해차이가없었고 SEP인동맥혈가스분석치, DLco, 호흡곤 란정도, QOL 등의 SEP에서는유의한차이를보였다. 심각한부작용은관찰되지않았다. 결국이연구에서 sildenafil 은 IPF환자에서운동능력향상효과를입증하는데는실패했지만일부 SEP를달성하여향후임상연구필요성의여지가남아있다. 3. King et al. Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomized, placebocontrolled trial. Lancet 2009;374: 미국, 유럽, 캐나다의 81개 center 에서모집된 826명의 IPF환자를대상으로 interferon gamma-1b 와대조약을 2:1 비율로투여하면서 PEP를생존기간으로정하여전향적연구를시행하였지만, 추적중앙값 64주째인 2차중간평가에서 interferon gamma-1b군의사망률 15% 가대조군의 13% 와차이가없어임상연구가중단되었다. 이로써 interferon gamma-1b 는 IPF에서효과가전혀없음이입증되었고향후치료제로사용하지말라고권고되었다. 4. Daniels et al. Imatinib treatment for idiopathic pulmonary fibrosis: randomized placebo-controlled trial results. Am J Respir Crit Care Med 2010; 181: Imatinib (Gleevec) 가섬유화에관여하는 PDGF 등의억제제인점에착안하여 119명의미국 / 멕시코 IPF환자를대상으로시행한 an investigator-initiated, multicenter, multinational, double-blind, placebo-controlled randomized phase II clinical trial로서, 96주째에 imatinib 투여군은 PEP인 time to progression 과 time to death 에서대조군과비교해차이가없었고 SEP에서도의미있는차이가없었다. 결국 imatinib 은 IPF환자에서생존율이나폐기능에있어개선효과를가져오지못했다고결론지었다. 5. Klingsberg et al. Current clinical trials for the treatment of idiopathic pulmonary fibrosis. Respirology 2010;154: 년현재진행되고있는 IPF 대상임상시험들에대해기술한보고이다. 167

6 MP Chung: Review on interstitial lung disease 6. Thabut et al. Survival after bilateral versus singlelung transplantation for idiopathic pulmonary fibrosis. Ann Intern Med 2009;151: 미국에서폐이식을받은 IPF환자를 single-lung transplantation (SLT) 군과 bilateral-lung transplantation (BLT) 군으로나누어생존기간등을분석하였다. 중앙생존기간은 BLT군에서 5.2년 ( 년) 으로서 SLT군의 3.8년 ( 년) 에비해유의하게높았으나 (p<0.001) 기저특징차이를보정한생존기간에는차이가없었다. 이식첫해에는 HR가 BLT군에서높았으나그이후에는 HR가낮았고, 반대로 SLT군은이식첫해에 HR이낮았으나그이후에는 HR이낮았다. 이로써 IPF에서 SLT와 DLT는서로장단점이있지만생존기간에는차이가없음을보고하였다. 7. Bissler et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008;358: Lymphangioleiomyomatosis (LAM) 이나 tuberous sclerosis complex 환자에서발견되는 angiomyolipoma (AML) 은 mtor pathway 가활성화되어나타나는것으로기전이밝혀져서, mtor 신호전달억제제인 sirolimus 를 25명의환자에게 12개월동안투여하고 24개월을추적하였다. 12개월약물투여를완료한 20명에서 12개월째 AML volume은기저치의 53.2% 로감소했지만 (p<0.001) 24개월째에는다시기저치의 85.2% 로증가했다 (p=0.005). 5명에서는 24개월째 AML volume 이기저치에비해 30% 이상감소를유지하고있었다. 기저치에비해 12개월째평균 1초간노력성호기량 (forced expiratory volume in 1 second, FEV 1 ) 은 118±330 ml 증가했고 (p=0.06), 노력성폐활량 (forced vital capacity, FVC) 은 390±570 ml 증가했다 (p<0.001). 24개월째평균 FEV 1 과 FVC는각각기저치에비해각각 61±411 ml, 346±712 ml 증가해있었다. 이결과에고무되어현재 Multicenter International LAM Efficacy of Sirolimus (MILES) trial이미국, 유럽, 일본의 LAM 환자를대상으로진행중이고 2세대약물인 everlimus에대한임상시험도진행되고있어그결과가자못기다려지는상태이다. 최근수년에보고된새로운질환 Category 1. Combined pulmonary fibrosis and emphysema (CPFE) CPFE 는 IPF에비해흡연과관련이있고호흡곤란이심하면서 DLco가유난히많이감소하며운동시저산소혈증이많고폐상부에는폐기종이주로보이고폐하부에는폐섬유화또는 ILD가동반된것이특징이다 57. 이환자들은심한폐동맥고혈압을보이는경우가많고사망률이비교적높아예후가좋지않다고알려져있다 58, IgG4-related ILD IgG4-related disease 는최근기술되기시작한전신적경화염증질환으로서, 특징적으로자가면역췌장염과연관이있고 sclerosing cholangitis, sclerosing cholecystitis, sclerosing sialadenitis, retroperitoneal fibrosis 및 interstitial nephritis 이동반될수있다. 폐도침범되는장기중하나이며 IgG4-related ILD는다른장기와같이또는단독으로질환이나타날수있다 60,61. 남자에서더흔하고병리학적으로 IgG4 양성 plasma cell과 lymphocyte의간질침윤이특징적이며, 혈청 IgG4 상승이동반된다. 방사선학적으로는 4가지형태로분류된다 62. Corticosteroids 치료에비교적잘반응하지만중단후에재발하는환자가보고되어유지용량이필요할경우도있다. 국내 ILD 연구회주도발간논문 국내 ILD연구회는그동안국내 ILD 질환을공동으로연구하면서국내증례를모아왔고 63, 드문 ILD 질환인폐랑게르한스세포조직구증 64, 폐포단백증 65, LAM 66 에대해보고하여향후국내 ILD 연구의중심축으로자리를잡고있다. 참고문헌 1. Crosby LM, Waters CM. Epithelial repair mechanisms in the lung. Am J Physiol Lung Cell Mol Physiol 2010; 298:L Lee JS, Collard HR, Raghu G, Sweet MP, Hays SR, Campos GM, et al. Does chronic microaspiration cause idiopathic pulmonary fibrosis? Am J Med 2010;123: Rottoli P, Bargagli E, Landi C, Magi B. Proteomic analy- 168

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