Challenges in Approaching Management of Pulmonary Fibrosis

Main Article Content

Manar Khaled Al- Hayfani
Hala Salah Abdel Kawy
Fatemah Omar Kamel

Abstract

Pulmonary fibrosis is a condition defined as a recurrent and progressive interstitial fibrotic disease and is considered to be terminated by interstitial lung disease disorders. Accumulating evidence indicates that epigenetic alterations, including histone acetylation, play a pivotal role in this process. Histone acetylation is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Vorinostat is a member of a larger class of compounds that inhibit histone deacetylases. Even though the pathogenesis of lung fibrosis is complicated, hypotheses have been proposed in recent years that include inflammation, epithelial degradation, differentiated fibroblast, angiogenesis, and oxidative stress. Emerging evidence from several preclinical studies has shown that Vorinostat has beneficial effects in preventing or reversing fibrogenesis. In this review, we summarize the latest findings of the roles of HDACs in the pathogenesis of pulmonary fibrosis and highlight the potential antifibrotic mechanism of Vorinostat in this diseases.

Keywords:
Pulmonary fibrosis, Vorinostat, histone deacetylase, inflammation, cytokines.

Article Details

How to Cite
Hayfani, M. K. A.-, Kawy, H. S. A., & Kamel, F. O. (2020). Challenges in Approaching Management of Pulmonary Fibrosis. Journal of Pharmaceutical Research International, 32(23), 52-70. https://doi.org/10.9734/jpri/2020/v32i2330788
Section
Review Article

References

Liu G, Zhai H, Zhang T, Li S, Li N, Chen J, Min Gu M, Qin Z, Liu X. New therapeutic strategies for IPF: Based on the “phagocytosis-secretion-immunization” network regulation mechanism of pulmonary macrophages. Biomedicine & Pharmacotherapy. Elsevier BV. 2019;118:109230. DOI: 10.1016/j.biopha.2019.109230

Walter ND, Rice PL, Redente EF, Kauvar EF, Lemond L, Aly T, Wanebo K, Chan ED. Wound healing after trauma may predispose to lung cancer metastasis: Review of potential mechanisms. American journal of respiratory cell and molecular biology. American Thoracic Society. 2011;44(5):591–596.

Hecker L. Mechanisms and consequences of oxidative stress in lung disease: Therapeutic implications for an aging populace. American Journal of Physiology-Lung Cellular and Molecular Physiology. American Physiological Society Bethesda, MD. 2017;314(4):L642–L653.

Karampitsakos T, Vraka A, Bouros D, Liossis SN, Tzouvelekis A. Biologic treatments in interstitial lung diseases. Front Med. 2019;6:41-51.

Korfei M, Skwarna S, Henneke I, MacKenzie B, Klymenko O, et al. Aberrant expression and activity of histone deacetylases in sporadic idiopathic pulmonary fibrosis. Thorax. BMJ Publishing Group Ltd. 2015;70(11):1022–1032.

Pasini A, Delmonte A, Tesei A, Calistri D, Giordano E. Targeting chromatin-mediated transcriptional control of gene expression in non-small cell lung cancer therapy: Preclinical rationale and clinical results. Drugs. Springer. 2015;75(15):1757–1771.

Rasmussen TA, Tolstrup M, Brinkmann CR, Olesen R, Erikstrup C, Solomon A, Winckelmann A, Palmer S, Dinarello C, Buzon M, Lichterfeld M, Lewin SR, Østergaard L, Søgaard OS. Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: A phase 1/2, single group, clinical trial. The lancet HIV. Elsevier. 2014;1(1):e13–e21.

Wynn TA, Ramalingam TR. Mechanisms of fibrosis: Therapeutic translation for fibrotic disease. Nature medicine. Nature Publishing Group. 2012;18(7):1028.

Herrera J, Henke CA, Bitterman PB. Extracellular matrix as a driver of progressive fibrosis. The Journal of clinical investigation. Am Soc Clin Investig. 2018;128(1):45–53.

Van Linthout S, Miteva K, Tschöpe C. Crosstalk between fibroblasts and inflammatory cells. Cardiovascular research. Oxford University Press. 2014;102(2):258–269.

Kendall RT, Feghali-Bostwick CA. Fibroblasts in fibrosis: Novel roles and mediators. Frontiers in pharmacology. Frontiers. 2014;5:123.

Klingberg F, Hinz B, White ES. The myofibroblast matrix: implications for tissue repair and fibrosis. The Journal of pathology. Wiley Online Library. 2013;229(2):298–309.

Darby IA, Laverdet B, Bonté F, Desmoulière A. Fibroblasts and myofibroblasts in wound healing. Clinical, cosmetic and investigational dermatology. Dove Press. 2014;7:301.

Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget. Impact Journals, LLC. 2018;9(6):7204.

Wenzke KE, BS, Cantemir-Stone C, Zhang J, Marsh CB, Huang K. Identifying common genes and networks in multi-organ fibrosis. AMIA Summits on Translational Science Proceedings. American Medical Informatics Association. 2012;106.

Wynn TA. Cellular and molecular mechanisms of fibrosis. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland. Wiley Online Library. 2008;214(2):199–210.

Dhooria S, Agarwal R, Sehgal IS, Prasad KT, Garg M, Bal A, Aggarwal AN, Behera D. Spectrum of interstitial lung diseases at a tertiary center in a developing country: A study of 803 subjects. PloS one. Public Library of Science. 2018;13(2): e0191938.

Turner MD, Nedjai B, Tara Hurst T, Pennington DJ. Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease’, Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. Elsevier. 2014;1843(11):2563–2582.

Liu Z, Wang Y, Wang Y, Ning Q, Zhang Y, Chunzhi Gong C, Wenxiang Zhao W, Jing G, Wang Q. Dexmedetomidine attenuates inflammatory reaction in the lung tissues of septic mice by activating cholinergic anti-inflammatory pathway. International immunopharmacology. Elsevier. 2016;35: 210–216.

Ye LL, Wei XS, Zhang M, Niu YR, Zhou Q. The significance of tumor necrosis factor receptor type II in CD8+ regulatory T cells and CD8+ effector T cells. Frontiers in immunology. Frontiers. 2018;9:583.

Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. Elsevier. 2010;140(6):805–820.

Yamamoto M, Takeda K. Current views of toll-like receptor signaling pathways. Gastroenterology research and practice. Hindawi; 2010.

Borthwick LA, Wynn TA, Fisher AJ. Cytokine mediated tissue fibrosis. Biochimica et biophysica acta (BBA)-molecular basis of disease. Elsevier. 2013;1832(7):1049–1060.

Yue X, Shan B, Lasky JA. TGF-β: Titan of Lung Fibrogenesis. Current enzyme inhibition. 2010;6(2):10.2174/ 10067. Available:https://doi.org/10.2174/10067

Choy E, Rose-John S. Interleukin-6 as a multifunctional regulator: inflammation, immune response, and fibrosis. Journal of Scleroderma and Related Disorders. SAGE Publications Sage UK: London, England. 2017;2(2_suppl):S1–S5.

Rothaug M, Becker-Pauly C, Rose-John S. The role of interleukin-6 signaling in nervous tissue. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. Elsevier. 2016;1863(6):1218–1227.

Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro-and anti-inflammatory properties of the cytokine interleukin-6’, Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. Elsevier. 2011;1813(5):878–888.

Sripa B, Thinkhamrop B, Mairiang E, Laha T, Kaewkes S, Sithithaworn P, Periago MV, Bhudhisawasdi V, Yonglitthipagon P, Mulvenna J, Brindley PJ, Loukas A, Bethony JM. Elevated plasma IL-6 associates with increased risk of advanced fibrosis and cholangiocarcinoma in individuals infected by Opisthorchis viverrini. PLoS neglected tropical diseases. Public Library of Science. 2012;6(5):e1654.

Khan K, Xu S, Nihtyanova S, Derrett-Smith E, Abraham D, Denton CP, Ong VH. Clinical and pathological significance of interleukin 6 over expression in systemic sclerosis. Annals of the rheumatic diseases. BMJ Publishing Group Ltd. 2012;71(7):1235–1242.

O’Reilly S, Ciechomska M, Cant R, Laar JM. Interleukin-6 (IL-6) trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-β (TGF-β) signaling promoting SMAD3 activation and fibrosis via Gremlin protein’, Journal of Biological Chemistry. ASBMB. 2014;289(14):9952–9960.

Fielding CA, Gareth W, Jones GW, McLoughlin RM, McLeod L, Hammond VJ, Uceda J, Williams AS, Lambie M, Foster TL, Liao C, Rice CM, Greenhill CJ, Colmont CS, Hams E, Coles B, Morgan AK, Newton Z, Craig KJ, Williams JD, Williams GT, Davies SJ, Humphreys IR, O'Donnell VB, Taylor PR, Jenkins BJ, Topley N, Jones SA. Interleukin-6 signaling drives fibrosis in unresolved inflammation. Immunity. Elsevier. 2014;40(1):40–50.

Ray S, Ju X, Sun H, Finnerty CC, Herndon DN, Brasier AR. The IL-6 trans-signaling-STAT3 pathway mediates ECM and cellular proliferation in fibroblasts from hypertrophic scar. Journal of Investigative Dermatology. Elsevier. 2013;133(5):1212–1220.

Desai O, Winkler J, Minasyan M, Herzog EL. The role of immune and inflammatory cells in idiopathic pulmonary fibrosis. Frontiers in Medicine. Frontiers. 2018;5:43.

Eckschlager T, Plch J, Stiborova M, Hrabeta J. Histone deacetylase inhibitors as anticancer drugs. International Journal of Molecular Sciences. MDPI. 2017;18(7):1414.

Bringardner BD, Baran CP, Eubank TD, Marsh CB. The role of inflammation in the pathogenesis of idiopathic pulmonary fibrosis. Antioxidants & redox signaling. Mary Ann Liebert, Inc. 2 Madison Avenue Larchmont, NY 10538 USA. 2008;10(2):287–302.

Tsuda M, Zhang W, Yang GX, Tsuneyama K, Ando Y, Kawata K, Park O, Leung PS, Coppel RL, Ansari AA, Ridgway WM, Gao B, Lian ZX, Flavell R, He XS, Gershwin ME. Deletion of interleukin (IL)‐12p35 induces liver fibrosis in dominant‐negative TGFβ receptor type II mice. Hepatology. Wiley Online Library. 2013;57(2):806– 816.

Hamza T, Barnett JB, Li B. Interleukin 12 a key immunoregulatory cytokine in infection applications. International journal of molecular sciences. Molecular Diversity Preservation International. 2010;11(3): 789–806.

Hewlett JC, Kropski JA, Blackwell TS. Idiopathic pulmonary fibrosis: Epithelial-mesenchymal interactions and emerging therapeutic targets’, Matrix Biology. Elsevier. 2018;71:112–127.

Datta A, Scotton CJ, Chambers RC. Novel therapeutic approaches for pulmonary fibrosis. British Journal of Pharmacology. Wiley Online Library. 2011;163(1):141–172.

Sgalla G, Iovene B, Calvello M, Ori M, Varone F, Richeldi L. Idiopathic pulmonary fibrosis: Pathogenesis and management. Respiratory research. Springer. 2018;19(1):32.

Kottmann RM, Hogan CM, Phipps RP, Sime PJ. Determinants of initiation and progression of idiopathic pulmonary fibrosis’, Respirology. Wiley Online Library. 2009;14(7):917–933.

Taskar V, Coultas D. Exposures and idiopathic lung disease. Seminars in respiratory and critical care medicine. © Thieme Medical Publishers. 2008;670–679.

Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. The Lancet. Elsevier. 2017;389(10082):1941–1952.

Betensley A, Sharif R, Karamichos D. A systematic review of the role of dysfunctional wound healing in the pathogenesis and treatment of idiopathic pulmonary fibrosis. Journal of clinical medicine. Multidisciplinary Digital Publishing Institute. 2017;6(1):2.

Zoz DF, Lawson WE, Blackwell TS. Idiopathic pulmonary fibrosis: A disorder of epithelial cell dysfunction. The American journal of the medical sciences. Elsevier. 2011;341(6):435–438.

Sisson TH, Mendez M, Choi K, Subbotina N, Courey A, et al. Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis. American Journal of Respiratory and Critical care Medicine. 2010;181(3):254-263.

Grimminger F, Günther A, Vancheri C. The role of tyrosine kinases in the pathogenesis of idiopathic pulmonary fibrosis’, European Respiratory Journal. Eur Respiratory Soc. 2015;45(5):1426–1433.

Phan SH. The myofibroblast in pulmonary fibrosis. Chest. Elsevier. 2002;122(6):286S-289S.

Hinz B. Mechanical aspects of lung fibrosis: A spotlight on the myofibroblast. Proceedings of the American Thoracic Society. American Thoracic Society. 2012;9(3):137–147.

Malli F, Koutsokera A, Paraskeva E, Zakynthinos E, Papagianni M, Makris D, Tsilioni I, Molyvdas PA, Gourgoulianis KI, Daniil Z. Endothelial progenitor cells in the pathogenesis of idiopathic pulmonary fibrosis: An evolving concept. PLoS One. Public Library of Science. 2013;8(1):e53658.

Selman M, Pardo A. Role of epithelial cells in idiopathic pulmonary fibrosis: From innocent targets to serial killers’, Proceedings of the American Thoracic Society. American Thoracic Society. 2006;3(4):364–372.

Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. Elsevier. 2016;44(3):450–462.

Blackwell TS, Tager AM, Borok Z, Moore BB, Schwartz DA, Kevin J, Anstrom KJ, et al. Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report. American Journal of Respiratory and Critical care Medicine. American Thoracic Society. 2014;189(2):214–222.

Zhang L, Wang Y, Wu G, Xiong W, Gu W, Wang CY. Macrophages: Friend or foe in idiopathic pulmonary fibrosis? Respiratory research. BioMed Central. 2018;19(1): 170.

Arango Duque G, Descoteaux A. Macrophage cytokines: Involvement in immunity and infectious diseases. Frontiers in immunology. Frontiers. 2014;5:491.

Mayadas TN, Cullere X, Lowell CA. The multifaceted functions of neutrophils. Annual Review of Pathology: Mechanisms of Disease. Annual Reviews. 2014;9:181–218.

Chrysanthopoulou A, Mitroulis I, Apostolidou E, Arelaki S, Mikroulis D, Konstantinidis T, Sivridis E, Koffa M, Giatromanolaki A, Boumpas DT, Ritis K, Kambas K. Neutrophil extracellular traps promote differentiation and function of fibroblasts. The Journal of pathology. Wiley Online Library. 2014;233(3):294–307.

Obayashi Y, Yamadori I, Fujita J, Yoshinouchi T, Ueda N, Takahara J. The role of neutrophils in the pathogenesis of idiopathic pulmonary fibrosis. Chest. 1997;112:1338–1343.

Perona JJ, Craik CS. Evolutionary divergence of substrate specificity within the chymotrypsin-like serine protease fold. Journal of Biological Chemistry. ASBMB. 1997;272(48):29987–29990.

Gregory AD, Kliment CR, Metz HE, Kim K, Kargl J, Agostini BA, Crum LT, Oczypok EA, Oury TA, Houghton AM. Neutrophil elastase promotes myofibroblast differentiation in lung fibrosis. Journal of leukocyte biology. Wiley Online Library. 2015;98(2):143–152.

Chua F, Dunsmore SE, Clingen PH, Mutsaers SE, Shapiro SD, Segal AW, Roes J, Laurent GJ. Mice lacking neutrophil elastase are resistant to bleomycin-induced pulmonary fibrosis. The American journal of pathology. Elsevier. 2007;170(1):65–74.

Takemasa A, Ishii Y, Fukuda T. A neutrophil elastase inhibitor prevents bleomycin-induced pulmonary fibrosis in mice. European Respiratory Journal. Eur Respiratory Soc. 2012;40(6):1475–1482.

Kruger P, Saffarzadeh M, Weber ANR, Rieber N, Radsak M, Bernuth HV, Benarafa C, Roos D, Skokowa J, Hartl D. Neutrophils: Between host defence, immune modulation, and tissue injury. PLoS Pathogens. Public Library of Science. 2015;11(3):e1004651.

Onishi RM, Gaffen SL. Interleukin‐17 and its target genes: Mechanisms of interleukin‐17 function in disease. Immunology. Wiley Online Library. 2010;129(3):311–321.

Wilson MS, Madala SK, Ramalingam TR, Gochuico BR, Rosas IO, Cheever AW, Wynn TA. Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent. Journal of Experimental Medicine. Rockefeller University Press. 2010;207(3):535–552.

Liang SC, Tan X, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, Fouser LA. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. Journal of Experimental Medicine. Rockefeller University Press. 2006;203(10):2271–2279.

Whittington HA, Armstrong L, Uppington KM, Millar AB. Interleukin-22: A potential immunomodulatory molecule in the lung. American journal of respiratory cell and molecular biology. American Thoracic Society. 2004;31(2):220–226.

Agostini C, Gurrieri C. Chemokine/cytokine cocktail in idiopathic pulmonary fibrosis. Proceedings of the American Thoracic Society. 2006;3(4):357–363.

Cottin V, Bruno Crestani B, Dominique Valeyre D, Wallaert B, Cadranel J, Dalphin J, Delaval P, Biet D, Kessler R, Gaubert M, Aguilaniu B, Bouquillon B, Carré P, Danel C, Faivre J, Ferretti G, Just N, Kouzan S, Lebargy F, Adam S, Philippe B, Prévot G, Stach B, Béjui F, Cordier J. French national reference centre and network of competence centres for rare lung diseases. Diagnosis and management of idiopathic pulmonary fibrosis: French practical guidelines’, European Respiratory Review. Eur Respiratory Soc. 2014;23(132):193–214.

Papiris SA, Kagouridis K, Kolilekas L, Papaioannou AI, Roussou A, Triantafillidou C, Baou K, Malagari K, Argentos S, Kotanidou A, Karakatsani A, Manali ED. Survival in Idiopathic pulmonary fibrosis acute exacerbations: The non-steroid approach’, BMC pulmonary medicine. BioMed Central. 2015;15(1):162.

Raghu G, Collard HR, Egan JJ, Martinez FJ, et al. An official ATS/ERS/JRS/ALAT statement: Idiopathic pulmonary fibrosis: Evidence-based guidelines for diagnosis and management’, American Journal of Respiratory and Critical Care Medicine. American Thoracic Society. 2011;183(6):788–824.

Maher TM, Wuyts W. Management of fibrosing interstitial lung diseases. Advances in Therapy. Springer. 2019;1–14.

Raghu G, Amatto VC, Behr J, Stowasser S. Comorbidities in idiopathic pulmonary fibrosis patients: A systematic literature review. European Respiratory Journal. Eur Respiratory Soc. 2015;46(4):1113–1130.

Kim ES, Keating GM. Pirfenidone: A review of its use in idiopathic pulmonary fibrosis. Drugs. Springer. 2015;75(2):219–230.

Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, Brown KK, Flaherty KR, Noble PW, Raghu G, Brun M, Gupta A, Juhel N, Klüglich M, Bois RM. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis’, New England Journal of Medicine. Mass Medical Soc. 2011;365(12):1079–1087.

Van Manen MJ, Birring SS, Vancheri C, Vindigni V, Renzoni E, Russell AM, Wijsenbeek MS. Effect of pirfenidone on cough in patients with idiopathic pulmonary fibrosis. European Respiratory Journal. 2017;50(4).

Lyu X, Hu M, Peng J, Zhang X, Sanders YY. HDAC inhibitors as antifibrotic drugs in cardiac and pulmonary fibrosis. Therapeutic advances in chronic disease. SAGE Publications Sage UK: London, England. 2019;10: 2040622319862697.

Kavanaugh SA, White LA, Kolesar JM. Vorinostat: A novel therapy for the treatment of cutaneous T-cell lymphoma’, American journal of health-system pharmacy. Oxford University Press. 2010;67(10):793–797.

Marks PA, Dokmanovic M. Histone deacetylase inhibitors: Discovery and development as anticancer agents. Expert opinion on investigational drugs. Taylor & Francis. 2005;14(12):1497–1511.

Secrist JP, Zhou X, Richon VM. HDAC inhibitors for the treatment of cancer. Current opinion in investigational drugs (London, England: 2000. 2003;4(12):1422–1427.

Kelly WK, O'Connor OA, Krug LM, Chiao JH, et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO). 2005;23(17):3923–3931.

Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R. FDA approval summary: Vorinostat for treatment of advanced primary cutaneous T-Cell lymphoma. The Oncologist. 2007;12(10): 1247–1252.

Bubna AK. Vorinostat-An overview. Indian Journal of Dermatology. Medknow Publications & Media Pvt Ltd. 2015;60(4): 419.

Wang Z, Chen C, Finger SN, Kwajah S, Jung M, Schwarz H, Swanson N, Lareu FF, Raghunath M. Suberoylanilide hydroxamic acid: A potential epigenetic therapeutic agent for lung fibrosis? European Respiratory Journal. European Respiratory Society (ERS). 2009;34(1):145–155.

DOI: 10.1183/09031936.00084808.

Sanders YY, Hagood JS, Liu H, Zhang W, Ambalavanan N, Thannickal VJ. Histone deacetylase inhibition promotes fibroblast apoptosis and ameliorates pulmonary fibrosis in mice. European Respiratory Journal. 2014;43(5):1448–1458.

DOI: 10.1183/09031936.00095113.

Conforti F, Davies ER, Calderwood CJ, Thatcher TH, et al. The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis’, Oncotarget. Impact Journals, LLC. 2017;8:30.

Korfei M, Stelmaszek D, MacKenzie B, Skwarna S, Chillappagari S, et al. Comparison of the antifibrotic effects of the pan-histone deacetylase-inhibitor panobinostat versus the IPF-drug pirfenidone in fibroblasts from patients with idiopathic pulmonary fibrosis. PLOS ONE. Public Library of Science (PLoS). 2018;13(11):e0207915.

Pasini A, Brand OJ, Jenkins G, Knox AJ, Pang L. Suberanilohydroxamic acid prevents TGF-β1-induced COX-2 repression in human lung fibroblasts post-transcriptionally by TIA-1 downregulation. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. Elsevier BV, V. 2018;1861(5):463–472. DOI: 10.1016/j.bbagrm.2018.03.007.

Ronald LA, Campbell JR, Rose C, Balshaw R, Romanowski K, Roth DZ, et al. Estimated impact of world health organization latent tuberculosis screening guidelines in a low TB incidence region: Retrospective cohort study. Clinical Infectious Diseases. Oxford University Press (OUP); 2019. DOI: 10.1093/cid/ciz188

Wang X, Zhang J, Liang J, Zhang Y, Teng X, et al. Protection against Mycobacterium tuberculosis infection offered by a new multistage subunit vaccine correlates with increased number of IFN-γ+IL-2+ CD4+and IFN-γ+CD8+T cells. PLoS ONE. 2015;10(3):1–18. DOI: 10.1371/journal.pone.0122560.

Barreto ML, Pereira SM, Ferreira AA. Vacina BCG: Eficácia e indicações da vacinação e da revacinação. FapUNIFESP (SciELO). 2006;82:3.

Shkurupiy VA, Kim LB, Nikonova IK, Potapova OV, Cherdantseva LA, Sharkova TV. Hydroxyproline content and fibrogenesis in mouse liver and lungs during the early stages of BCG granulomatosis. Bulletin of Experimental Biology and Medicine. 2013;154(3):299–302. DOI: 10.1007/s10517-013-1935-5.

Garcia-Pelayo MC, Bachy VS, Kaveh DA, Hogarth PJ. BALB/c mice display more enhanced BCG vaccine induced Th1 and Th17 response than C57BL/6 mice but have equivalent protection. Elsevier BV. 2015;95(1):48–53.