Download PDF
Semin Respir Crit Care Med 2016; 37(03): 477-484
DOI: 10.1055/s-0036-1580688
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Recent Advances and Future Needs in Interstitial Lung Diseases

Mark G. Jones
1   National Institute for Health Research Southampton Respiratory Biomedical Research Unit and Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom
,
Luca Richeldi
1   National Institute for Health Research Southampton Respiratory Biomedical Research Unit and Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom
› Author Affiliations
Further Information

Publication History

Publication Date:
27 May 2016 (online)

    Permissions and Reprints

Abstract

Interstitial lung diseases (ILDs) are a diverse range of conditions affecting the lung interstitium. The prototypic ILD, idiopathic pulmonary fibrosis (IPF), is a chronic progressive fibrotic lung disease with a median survival of only 3 years from the time of diagnosis. Recently significant progress has been made in both our understanding of the pathogenesis and of the therapeutic targeting of IPF. This culminated in the worldwide approval of the first antifibrotic therapies nintedanib and pirfenidone. While an important first step, patients continue to progress and better therapies are urgently required. The aim of this article is to highlight some of the recent advances that have been made in our understanding of genetics, disease classification, clinical trial design, and novel antifibrotic therapy in IPF. It discusses future priorities if we are to continue to increase the length and quality of life of patients with IPF, and considers possible approaches to translate the progress made in IPF to other progressive fibrotic lung diseases where our understanding remains limited.

Keywords

interstitial lung disease - idiopathic pulmonary fibrosis - genetics - antifibrotic therapy - pirfenidone - nintedanib
 

  • References

  • 1 Interstitial lung diseases. In: Gibson J, Loddenkember R, Sibille Y, Lundbäck B. , eds. The European Lung White Book: Respiratory Health and Disease in Europe. Sheffield, UK: European Respiratory Society Journals; 2013: 256-259
    Google Scholar
  • 2 Raghu G, Collard HR, Egan JJ , et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183 (6) 788-824
    CrossrefPubMedGoogle Scholar
  • 3 Ley B, Collard HR, King Jr TE. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 183 (4) 431-440
    CrossrefPubMedGoogle Scholar
  • 4 Kuhn III C, Boldt J, King Jr TE, Crouch E, Vartio T, McDonald JA. An immunohistochemical study of architectural remodeling and connective tissue synthesis in pulmonary fibrosis. Am Rev Respir Dis 1989; 140 (6) 1693-1703
    CrossrefPubMedGoogle Scholar
  • 5 King Jr TE, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet 2011; 378 (9807) 1949-1961
    CrossrefPubMedGoogle Scholar
  • 6 Karimi-Shah BA, Chowdhury BA. Forced vital capacity in idiopathic pulmonary fibrosis—FDA review of pirfenidone and nintedanib. N Engl J Med 2015; 372 (13) 1189-1191
    CrossrefPubMedGoogle Scholar
  • 7 Kropski JA, Blackwell TS, Loyd JE. The genetic basis of idiopathic pulmonary fibrosis. Eur Respir J 2015; 45 (6) 1717-1727
    CrossrefPubMedGoogle Scholar
  • 8 Rosas IO. Genetics and Idiopathic Interstitial Pneumonias. Semin Respir Crit Care Med , In press
    PubMedGoogle Scholar
  • 9 Fingerlin TE, Murphy E, Zhang W , et al. Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat Genet 2013; 45 (6) 613-620
    CrossrefPubMedGoogle Scholar
  • 10 Noth I, Zhang Y, Ma S-F , et al. Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study. Lancet Respir Med 2013; 1 (4) 309-317
    CrossrefPubMedGoogle Scholar
  • 11 Seibold MA, Wise AL, Speer MC , et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med 2011; 364 (16) 1503-1512
    CrossrefPubMedGoogle Scholar
  • 12 Hunninghake GM, Hatabu H, Okajima Y , et al. MUC5B promoter polymorphism and interstitial lung abnormalities. N Engl J Med 2013; 368 (23) 2192-2200
    CrossrefPubMedGoogle Scholar
  • 13 Peljto AL, Selman M, Kim DS , et al. The MUC5B promoter polymorphism is associated with idiopathic pulmonary fibrosis in a Mexican cohort but is rare among Asian ancestries. Chest 2015; 147 (2) 460-464
    CrossrefPubMedGoogle Scholar
  • 14 Stock CJ, Sato H, Fonseca C , et al. Mucin 5B promoter polymorphism is associated with idiopathic pulmonary fibrosis but not with development of lung fibrosis in systemic sclerosis or sarcoidosis. Thorax 2013; 68 (5) 436-441
    CrossrefPubMedGoogle Scholar
  • 15 Zhang Y, Noth I, Garcia JGN, Kaminski N. A variant in the promoter of MUC5B and idiopathic pulmonary fibrosis. N Engl J Med 2011; 364 (16) 1576-1577
    CrossrefPubMedGoogle Scholar
  • 16 Roy MG, Livraghi-Butrico A, Fletcher AA , et al. Muc5b is required for airway defence. Nature 2014; 505 (7483) 412-416
    PubMedGoogle Scholar
  • 17 Molyneaux PL, Cox MJ, Willis-Owen SAG , et al. The role of bacteria in the pathogenesis and progression of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2014; 190 (8) 906-913
    CrossrefPubMedGoogle Scholar
  • 18 Peljto AL, Steele MP, Fingerlin TE , et al. The pulmonary fibrosis-associated MUC5B promoter polymorphism does not influence the development of interstitial pneumonia in systemic sclerosis. Chest 2012; 142 (6) 1584-1588
    CrossrefPubMedGoogle Scholar
  • 19 Borie R, Crestani B, Dieude P , et al. The MUC5B variant is associated with idiopathic pulmonary fibrosis but not with systemic sclerosis interstitial lung disease in the European Caucasian population. PLoS ONE 2013; 8 (8) e70621
    CrossrefPubMedGoogle Scholar
  • 20 Peljto AL, Zhang Y, Fingerlin TE , et al. Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. JAMA 2013; 309 (21) 2232-2239
    CrossrefPubMedGoogle Scholar
  • 21 Martinez FJ, de Andrade JA, Anstrom KJ, King Jr TE, Raghu G ; Idiopathic Pulmonary Fibrosis Clinical Research Network. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370 (22) 2093-2101
    CrossrefPubMedGoogle Scholar
  • 22 Raghu G, Rochwerg B, Zhang Y , et al; American Thoracic Society; European Respiratory society; Japanese Respiratory Society; Latin American Thoracic Association. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of idiopathic pulmonary fibrosis. An update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med 2015; 192 (2) e3-e19
    CrossrefPubMedGoogle Scholar
  • 23 Oldham JM, Ma S-F, Martinez FJ , et al; IPFnet Investigators. TOLLIP, MUC5B, and the response to N-acetylcysteine among individuals with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2015; 192 (12) 1475-1482
    CrossrefPubMedGoogle Scholar
  • 24 Ley B, Brown KK, Collard HR. Molecular biomarkers in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2014; 307 (9) L681-L691
    CrossrefPubMedGoogle Scholar
  • 25 van den Blink B, Wijsenbeek MS, Hoogsteden HC. Serum biomarkers in idiopathic pulmonary fibrosis. Pulm Pharmacol Ther 2010; 23 (6) 515-520
    CrossrefPubMedGoogle Scholar
  • 26 Kass DJ, Flynn M, Baker E. Idiopathic pulmonary fibrosis biomarkers: clinical utility and a way of understanding disease pathogenesis. Current Biomrker Findings 2015; 5: 21-33
    PubMedGoogle Scholar
  • 27 Saini G, Porte J, Weinreb PH , et al. αvβ6 integrin may be a potential prognostic biomarker in interstitial lung disease. Eur Respir J 2015; 46 (2) 486-494
    CrossrefPubMedGoogle Scholar
  • 28 Chien JW, Richards TJ, Gibson KF , et al. Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression. Eur Respir J 2014; 43 (5) 1430-1438
    CrossrefPubMedGoogle Scholar
  • 29 DePianto DJ, Chandriani S, Abbas AR , et al. Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis. Thorax 2015; 70 (1) 48-56
    CrossrefPubMedGoogle Scholar
  • 30 Jenkins RG, Simpson JK, Saini G , et al. Longitudinal change in collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis from the prospective, multicentre PROFILE study. Lancet Respir Med 2015; 3 (6) 462-472
    CrossrefPubMedGoogle Scholar
  • 31 Richeldi L, du Bois RM, Raghu G , et al; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370 (22) 2071-2082
    CrossrefPubMedGoogle Scholar
  • 32 Noble PW, Albera C, Bradford WZ , et al; CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377 (9779) 1760-1769
    CrossrefPubMedGoogle Scholar
  • 33 King Jr TE, Bradford WZ, Castro-Bernardini S , et al; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014; 370 (22) 2083-2092
    CrossrefPubMedGoogle Scholar
  • 34 Antoniou KM. Idiopathic pulmonary fibrosis (IPF): pathogenesis. Semin Respir Crit Care Med , In press
    PubMedGoogle Scholar
  • 35 Hilberg F, Roth GJ, Krssak M , et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 2008; 68 (12) 4774-4782
    CrossrefPubMedGoogle Scholar
  • 36 Coward WR, Saini G, Jenkins G. The pathogenesis of idiopathic pulmonary fibrosis. Ther Adv Respir Dis 2010; 4 (6) 367-388
    CrossrefPubMedGoogle Scholar
  • 37 Allen JT, Spiteri MA. Growth factors in idiopathic pulmonary fibrosis: relative roles. Respir Res 2002; 3: 13
    CrossrefPubMedGoogle Scholar
  • 38 Abdollahi A, Li M, Ping G , et al. Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis. J Exp Med 2005; 201 (6) 925-935
    CrossrefPubMedGoogle Scholar
  • 39 Chaudhary NI, Roth GJ, Hilberg F , et al. Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis. Eur Respir J 2007; 29 (5) 976-985
    CrossrefPubMedGoogle Scholar
  • 40 Nakayama S, Mukae H, Sakamoto N , et al. Pirfenidone inhibits the expression of HSP47 in TGF-β1-stimulated human lung fibroblasts. Life Sci 2008; 82 (3–4) 210-217
    CrossrefPubMedGoogle Scholar
  • 41 Lee BS, Margolin SB, Nowak RA. Pirfenidone: a novel pharmacological agent that inhibits leiomyoma cell proliferation and collagen production. J Clin Endocrinol Metab 1998; 83 (1) 219-223
    CrossrefPubMedGoogle Scholar
  • 42 Kakugawa T, Mukae H, Hayashi T , et al. Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis. Eur Respir J 2004; 24 (1) 57-65
    CrossrefPubMedGoogle Scholar
  • 43 Schaefer CJ, Ruhrmund DW, Pan L, Seiwert SD, Kossen K. Antifibrotic activities of pirfenidone in animal models. Eur Respir Rev 2011; 20 (120) 85-97
    CrossrefPubMedGoogle Scholar
  • 44 Oku H, Shimizu T, Kawabata T , et al. Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis. Eur J Pharmacol 2008; 590 (1–3) 400-408
    CrossrefPubMedGoogle Scholar
  • 45 Nakazato H, Oku H, Yamane S, Tsuruta Y, Suzuki R. A novel anti-fibrotic agent pirfenidone suppresses tumor necrosis factor-alpha at the translational level. Eur J Pharmacol 2002; 446 (1–3) 177-185
    CrossrefPubMedGoogle Scholar
  • 46 Iyer SN, Gurujeyalakshmi G, Giri SN. Effects of pirfenidone on transforming growth factor-beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther 1999; 291 (1) 367-373
    PubMedGoogle Scholar
  • 47 Iyer SN, Gurujeyalakshmi G, Giri SN. Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther 1999; 289 (1) 211-218
    PubMedGoogle Scholar
  • 48 Jones MG, Fletcher S, Richeldi L. Idiopathic pulmonary fibrosis: recent trials and current drug therapy. Respiration 2013; 86 (5) 353-363
    CrossrefPubMedGoogle Scholar
  • 49 Moore BB, Hogaboam CM. Murine models of pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2008; 294 (2) L152-L160
    PubMedGoogle Scholar
  • 50 Booth AJ, Hadley R, Cornett AM , et al. Acellular normal and fibrotic human lung matrices as a culture system for in vitro investigation. Am J Respir Crit Care Med 2012; 186 (9) 866-876
    CrossrefPubMedGoogle Scholar
  • 51 American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002; 165 (2) 277-304
    CrossrefPubMedGoogle Scholar
  • 52 Flaherty KR, King Jr TE, Raghu G , et al. Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis?. Am J Respir Crit Care Med 2004; 170 (8) 904-910
    CrossrefPubMedGoogle Scholar
  • 53 Jacob J, Hansell DM. HRCT of fibrosing lung disease. Respirology 2015; 20 (6) 859-872
    CrossrefPubMedGoogle Scholar
  • 54 Kaarteenaho R. The current position of surgical lung biopsy in the diagnosis of idiopathic pulmonary fibrosis. Respir Res 2013; 14: 43-3
    CrossrefPubMedGoogle Scholar
  • 55 Morell F, Villar A, Montero M-Á , et al. Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: a prospective case-cohort study. Lancet Respir Med 2013; 1 (9) 685-694
    CrossrefPubMedGoogle Scholar
  • 56 Raghu G, Anstrom KJ, King Jr TE, Lasky JA, Martinez FJ ; Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012; 366 (21) 1968-1977
    CrossrefPubMedGoogle Scholar
  • 57 Kim SY, Diggans J, Pankratz D , et al. Classification of usual interstitial pneumonia in patients with interstitial lung disease: assessment of a machine learning approach using high-dimensional transcriptional data. Lancet Respir Med 2015; 3 (6) 473-482
    CrossrefPubMedGoogle Scholar
  • 58 Casoni GL, Tomassetti S, Cavazza A , et al. Transbronchial lung cryobiopsy in the diagnosis of fibrotic interstitial lung diseases. PLoS ONE 2014; 9 (2) e86716
    CrossrefPubMedGoogle Scholar
  • 59 Fernandez IE, Eickelberg O. New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis. Lancet 2012; 380 (9842) 680-688
    CrossrefPubMedGoogle Scholar
  • 60 Mehal WZ, Iredale J, Friedman SL. Scraping fibrosis: expressway to the core of fibrosis. Nat Med 2011; 17 (5) 552-553
    CrossrefPubMedGoogle Scholar
  • 61 Collard HR. Where do we go from here? Clinical drug development in idiopathic pulmonary fibrosis. Eur Respir J 2015; 45 (5) 1218-1220
    CrossrefPubMedGoogle Scholar
  • 62 O'Riordan TG, Smith V, Raghu G. Development of novel agents for idiopathic pulmonary fibrosis: progress in target selection and clinical trial design. Chest 2015; 148 (4) 1083-1092
    CrossrefPubMedGoogle Scholar
  • 63 Collard HR, Bradford WZ, Cottin V , et al. A new era in idiopathic pulmonary fibrosis: considerations for future clinical trials. Eur Respir J 2015; 46 (1) 243-249
    CrossrefPubMedGoogle Scholar
  • 64 Durheim MT, Collard HR, Roberts RS , et al; IPFnet investigators. Association of hospital admission and forced vital capacity endpoints with survival in patients with idiopathic pulmonary fibrosis: analysis of a pooled cohort from three clinical trials. Lancet Respir Med 2015; 3 (5) 388-396
    CrossrefPubMedGoogle Scholar
  • 65 Russell A-M, Sprangers MA, Wibberley S, Snell N, Rose DM, Swigris JJ. The need for patient-centred clinical research in idiopathic pulmonary fibrosis. BMC Med 2015; 13: 240
    CrossrefPubMedGoogle Scholar