Investigating the Level of MUC5B Expression in the Plasma of Patients with Idiopathic Pulmonary Fibrosis (IPF) Compared to Healthy Individuals
-
Sara Shahriyari
,
Seyede Zahra Fotook Kiaei
,
Abdolreza Mohamadnia
,
Masoume Farhangiyan
,
Naghmeh Bahrami
Abstract
Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease associated with high morbidity and mortality. Genetic factors, particularly the MUC5B promoter polymorphism, have been strongly implicated in disease pathogenesis. Given the shared embryological origin of the respiratory and oral epithelia, investigating systemic MUC5B expression may provide insights relevant to craniofacial and mucosal health. This study aimed to evaluate MUC5B gene expression in Iranian patients with IPF and compare the findings with healthy controls. Materials and Methods: A case–control study was conducted involving 15 IPF patients and 15 age-matched healthy individuals. Peripheral blood samples were collected, RNA was extracted, and MUC5B expression levels were quantified using quantitative real-time PCR (qRT-PCR) normalized to a housekeeping gene. Statistical analyses included ANOVA, the Least Significant Difference (LSD) test, and Spearman correlation.Results: MUC5B expression was detected in 80% of IPF patients compared to 40% of controls (P < 0.001). Relative expression analysis revealed that MUC5B mRNA levels were approximately 2.53-fold higher in the IPF group. No significant age difference was observed between groups.Conclusion: Elevated MUC5B expression is significantly associated with IPF, supporting its potential role as a genetic biomarker for disease susceptibility. The systemic nature of this dysregulation suggests it could also serve as a model for understanding mucin-related pathologies in the aerodigestive tract, including the oral cavity. Further studies with larger cohorts are warranted to confirm these findings and explore their clinical utility. Keywords: Idiopathic pulmonary fibrosis; Interstitial lung disease; Muc5b promoter polymorphism; Gene expression; Biomarker; Qrt-pcr; Iran; Genetic susceptibility; Pulmonary fibrosis pathogenesis; Mucin overexpression; Salivary mucins; Oral mucosa; Maxillofacial research; Aerodigestive tract.
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26 . Lawson WE, Grant SW, Ambrosini V, Womble KE, Dawson EP, Lane KB, Markin C, Renzoni E, Lympany P, Thomas AQ, et al. Genetic mutations in surfactant protein C are a rare cause of sporadic cases of IPF. Thorax. 2004;59:977–980. [PMC free article] [PubMed] [Google Scholar]
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28 . Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie M, Vulto I, Phillips JA, III, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356:1317–1326. [PubMed] [Google Scholar]
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30 . Cogan JD, Kropski JA, Zhao M, Mitchell DB, Rives L, Markin C, Garnett ET, Montgomery KH, Mason WR, McKean DF, et al. University of Washington Center for Mendelian Genomics. Rare variants in RTEL1 are associated with familial interstitial pneumonia. Am J Respir Crit Care Med. 2015;191:646–655. [PMC free article] [PubMed] [Google Scholar]
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32 . Seibold MA, Wise AL, Speer MC, Steele MP, Brown KK, Loyd JE, Fingerlin TE, Zhang W, Gudmundsson G, Groshong SD, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;364:1503–1512. [PMC free article] [PubMed] [Google Scholar]
33 . Zhang Y, Noth I, Garcia JG, Kaminski N. A variant in the promoter of MUC5B and idiopathic pulmonary fibrosis. N Engl J Med. 2011;364:1576–1577. [PMC free article] [PubMed] [Google Scholar]
34. Wang H, Maurano MT, Qu H, Varley KE, Gertz J, Pauli F, Lee K, Canfield T, Weaver M, Sandstrom R, et al. Widespread plasticity in CTCF occupancy linked to DNA methylation. Genome Res. 2012;22:1680–1688.
35. Evans CM, Fingerlin TE, Schwarz MI, Lynch D, Kurche J, Warg L, Yang IV, Schwartz DA. Idiopathic pulmonary fibrosis: a genetic disease that involves mucociliary dysfunction of the peripheral airways. Physiol Rev. 2016;96:1567–1591. [PMC free article] [PubMed] [Google Scholar]
36. Boucher RC. Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. Annu Rev Med. 2007;58:157–170. [PubMed] [Google Scholar]
37. Button B, Cai LH, Ehre C, Kesimer M, Hill DB, Sheehan JK, Boucher RC, Rubinstein M. A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science. 2012;337:937–941. [PMC free article] [PubMed] [Google Scholar]
38. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350:2645–2653. [PubMed] [Google Scholar]
39. Brayer KJ, Lynch VJ, Wagner GP. Evolution of a derived protein–protein interaction between HoxA11 and Foxo1a in mammals caused by changes in intramolecular regulation. Proc Natl Acad Sci USA. 2011;108:E414–E420. [PMC free article] [PubMed] [Google Scholar]
40. Roy MG, Livraghi-Butrico A, Fletcher AA, McElwee MM, Evans SE, Boerner RM, Alexander SN, Bellinghausen LK, Song AS, Petrova YM, et al. Muc5b is required for airway defence. Nature. 2014;505:412–416. [PMC free article] [PubMed] [Google Scholar]
2. Navaratnam V., Fleming K.M., West J., Smith C.J., Jenkins R.G., Fogarty A., Hubbard R.B. The rising incidence of idiopathic pulmonary fibrosis in the U.K. Thorax. 2011;66:462–467. doi: 10.1136/thx.2010.148031. [PubMed] [CrossRef] [Google Scholar]
3. Raghu G., Chen S.Y., Yeh W.S., Maroni B., Li Q., Lee Y.C., Collard H.R. Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: Incidence, prevalence, and survival, 2001–11. Lancet Respir. Med. 2014;2:566–572. doi: 10.1016/S2213-2600(14)70101-8. [PubMed] [CrossRef] [Google Scholar]
4. Hopkins R.B., Burke N., Fell C., Dion G., Kolb M. Epidemiology and survival of idiopathic pulmonary fibrosis from national data in Canada. Eur. Respir. J. 2016;48:187–195. doi: 10.1183/13993003.01504-2015. [PubMed] [CrossRef] [Google Scholar]
5. Strongman H., Kausar I., Maher T.M. Incidence, Prevalence, and Survival of Patients with Idiopathic Pulmonary Fibrosis in the UK. Adv. Ther. 2018;35:724–736. doi: 10.1007/s12325-018-0693-1. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
6. Gribbin J., Hubbard R.B., le Jeune I., Smith C.J., West J., Tata L.J. Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK. Thorax. 2006;61:980–985. doi: 10.1136/thx.2006.062836. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
7. Hutchinson J., Fogarty A., Hubbard R., McKeever T. Global incidence and mortality of idiopathic pulmonary fibrosis: A systematic review. Eur. Respir. J. 2015;46:795–806. doi: 10.1183/09031936.00185114. [PubMed] [CrossRef] [Google Scholar]
8. Diamantopoulos A., Wright E., Vlahopoulou K., Cornic L., Schoof N., Maher T.M. The Burden of Illness of Idiopathic Pulmonary Fibrosis: A Comprehensive Evidence Review. Pharmacoeconomics. 2018 doi: 10.1007/s40273-018-0631-8. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
9. Raghu G., Collard H.R., Egan J.J., Martinez F.J., Behr J., Brown K.K., Colby T.V., Cordier J.F., Flaherty K.R., Lasky J.A., et al. An official ATS/ERS/JRS/ALAT statement: Idiopathic pulmonary fibrosis: Evidence-based guidelines for diagnosis and management. Am. J. Respir. Crit. Care Med. 2011;183:788–824. doi: 10.1164/rccm.2009-040GL. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
10. Kaunisto J., Kelloniemi K., Sutinen E., Hodgson U., Piilonen A., Kaarteenaho R., Makitaro R., Purokivi M., Lappi-Blanco E., Saarelainen S., et al. Re-evaluation of diagnostic parameters is crucial for obtaining accurate data on idiopathic pulmonary fibrosis. BMC Pulm. Med. 2015;15:92. doi: 10.1186/s12890-015-0074-3. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
11. Marshall D.C., Salciccioli J.D., Shea B.S., Akuthota P. Trends in mortality from idiopathic pulmonary fibrosis in the European Union: An observational study of the WHO mortality database from 2001–2013. Eur. Respir. J. 2018;51 doi: 10.1183/13993003.01603-2017. [PubMed] [CrossRef] [Google Scholar]
12. Algranti E., Saito C.A., Silva D., Carneiro A.P.S., Bussacos M.A. Mortality from idiopathic pulmonary fibrosis: A temporal trend analysis in Brazil, 1979–2014. J. Bras. Pneumol. 2017;43:445–450. doi: 10.1590/s1806-37562017000000035. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
13. Costabel U., Albera C., Lancaster L.H., Lin C.Y., Hormel P., Hulter H.N., Noble P.W. An Open-Label Study of the Long-Term Safety of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis (RECAP) Respiration. 2017;94:408–415. doi: 10.1159/000479976. [PubMed] [CrossRef] [Google Scholar]
14. Ley B., Collard H.R., King T.E., Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2011;183:431–440. doi: 10.1164/rccm.201006-0894CI. [PubMed] [CrossRef] [Google Scholar]
15. King T.E., Jr., Tooze J.A., Schwarz M.I., Brown K.R., Cherniack R.M. Predicting survival in idiopathic pulmonary fibrosis: Scoring system and survival model. Am. J. Respir. Crit. Care Med. 2001;164:1171–1181. doi: 10.1164/ajrccm.164.7.2003140. [PubMed] [CrossRef] [Google Scholar]
16. Ley B., Ryerson C.J., Vittinghoff E., Ryu J.H., Tomassetti S., Lee J.S., Poletti V., Buccioli M., Elicker B.M., Jones K.D., et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann. Intern. Med. 2012;156:684–691. doi: 10.7326/0003-4819-156-10-201205150-00004. [PubMed] [CrossRef] [Google Scholar]
17 . Chilosi M, Doglioni C, Murer B, Poletti V. Epithelial stem cell exhaustion in the pathogenesis of idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis. 2010;27:7–18. [PubMed] [Google Scholar]
18 . Scotton CJ, Krupiczojc MA, Königshoff M, Mercer PF, Lee YC, Kaminski N, Morser J, Post JM, Maher TM, Nicholson AG, et al. Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. J Clin Invest. 2009;119:2550–2563. [PMC free article] [PubMed] [Google Scholar]
19 . Selman M, Pardo A, Kaminski N. Idiopathic pulmonary fibrosis: aberrant recapitulation of developmental programs? PLoS Med. 2008;5:e62. [PMC free article] [PubMed] [Google Scholar]
20 . Taskar VS, Coultas DB. Is idiopathic pulmonary fibrosis an environmental disease? Proc Am Thorac Soc. 2006;3:293–298. [PubMed] [Google Scholar]
21 . Ding Q, Luckhardt T, Hecker L, Zhou Y, Liu G, Antony VB, deAndrade J, Thannickal VJ. New insights into the pathogenesis and treatment of idiopathic pulmonary fibrosis. Drugs. 2011;71:981–1001. [PMC free article] [PubMed] [Google Scholar]
22 . Steele MP, Speer MC, Loyd JE, Brown KK, Herron A, Slifer SH, Burch LH, Wahidi MM, Phillips JA, III, Sporn TA, et al. Clinical and pathologic features of familial interstitial pneumonia. Am J Respir Crit Care Med. 2005;172:1146–1152. [PMC free article] [PubMed] [Google Scholar]
23 . Mathai SK, Schwartz DA, Warg LA. Genetic susceptibility and pulmonary fibrosis. Curr Opin Pulm Med. 2014;20:429–435. [PMC free article] [PubMed] [Google Scholar]
24 . Nogee LM, Dunbar AE, III, Wert SE, Askin F, Hamvas A, Whitsett JA. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med. 2001;344:573–579. [PubMed] [Google Scholar]
25 . Thomas AQ, Lane K, Phillips J, III, Prince M, Markin C, Speer M, Schwartz DA, Gaddipati R, Marney A, Johnson J, et al. Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care Med. 2002;165:1322–1328. [PubMed] [Google Scholar]
26 . Lawson WE, Grant SW, Ambrosini V, Womble KE, Dawson EP, Lane KB, Markin C, Renzoni E, Lympany P, Thomas AQ, et al. Genetic mutations in surfactant protein C are a rare cause of sporadic cases of IPF. Thorax. 2004;59:977–980. [PMC free article] [PubMed] [Google Scholar]
27 . Wang Y, Kuan PJ, Xing C, Cronkhite JT, Torres F, Rosenblatt RL, DiMaio JM, Kinch LN, Grishin NV, Garcia CK. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet. 2009;84:52–59. [PMC free article] [PubMed] [Google Scholar]
28 . Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie M, Vulto I, Phillips JA, III, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356:1317–1326. [PubMed] [Google Scholar]
29 . van Moorsel CH, van Oosterhout MF, Barlo NP, de Jong PA, van der Vis JJ, Ruven HJ, van Es HW, van den Bosch JM, Grutters JC. Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a dutch cohort. Am J Respir Crit Care Med. 2010;182:1419–1425. [PubMed] [Google Scholar]
30 . Cogan JD, Kropski JA, Zhao M, Mitchell DB, Rives L, Markin C, Garnett ET, Montgomery KH, Mason WR, McKean DF, et al. University of Washington Center for Mendelian Genomics. Rare variants in RTEL1 are associated with familial interstitial pneumonia. Am J Respir Crit Care Med. 2015;191:646–655. [PMC free article] [PubMed] [Google Scholar]
31 . Alder JK, Stanley SE, Wagner CL, Hamilton M, Hanumanthu VS, Armanios M. Exome sequencing identifies mutant TINF2 in a family with pulmonary fibrosis. Chest. 2015;147:1361–1368. [PMC free article] [PubMed] [Google Scholar]
32 . Seibold MA, Wise AL, Speer MC, Steele MP, Brown KK, Loyd JE, Fingerlin TE, Zhang W, Gudmundsson G, Groshong SD, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;364:1503–1512. [PMC free article] [PubMed] [Google Scholar]
33 . Zhang Y, Noth I, Garcia JG, Kaminski N. A variant in the promoter of MUC5B and idiopathic pulmonary fibrosis. N Engl J Med. 2011;364:1576–1577. [PMC free article] [PubMed] [Google Scholar]
34. Wang H, Maurano MT, Qu H, Varley KE, Gertz J, Pauli F, Lee K, Canfield T, Weaver M, Sandstrom R, et al. Widespread plasticity in CTCF occupancy linked to DNA methylation. Genome Res. 2012;22:1680–1688.
35. Evans CM, Fingerlin TE, Schwarz MI, Lynch D, Kurche J, Warg L, Yang IV, Schwartz DA. Idiopathic pulmonary fibrosis: a genetic disease that involves mucociliary dysfunction of the peripheral airways. Physiol Rev. 2016;96:1567–1591. [PMC free article] [PubMed] [Google Scholar]
36. Boucher RC. Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. Annu Rev Med. 2007;58:157–170. [PubMed] [Google Scholar]
37. Button B, Cai LH, Ehre C, Kesimer M, Hill DB, Sheehan JK, Boucher RC, Rubinstein M. A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science. 2012;337:937–941. [PMC free article] [PubMed] [Google Scholar]
38. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350:2645–2653. [PubMed] [Google Scholar]
39. Brayer KJ, Lynch VJ, Wagner GP. Evolution of a derived protein–protein interaction between HoxA11 and Foxo1a in mammals caused by changes in intramolecular regulation. Proc Natl Acad Sci USA. 2011;108:E414–E420. [PMC free article] [PubMed] [Google Scholar]
40. Roy MG, Livraghi-Butrico A, Fletcher AA, McElwee MM, Evans SE, Boerner RM, Alexander SN, Bellinghausen LK, Song AS, Petrova YM, et al. Muc5b is required for airway defence. Nature. 2014;505:412–416. [PMC free article] [PubMed] [Google Scholar]
| Files | ||
| Issue | Vol 12, No 3 (Summer 2025) | |
| Section | Original Article(s) | |
| Keywords | ||
| Idiopathic pulmonary fibrosis; Interstitial lung disease; Muc5b promoter polymorphism; Gene expression; Biomarker; Qrt-pcr; Iran; Genetic susceptibility; Pulmonary fibrosis pathogenesis; Mucin overexpression; Salivary mucins; Oral mucosa; Maxillofacial research; Aerodigestive tract. | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Shahriyari S, Fotook Kiaei SZ, Mohamadnia A, Farhangiyan M, Bahrami N. Investigating the Level of MUC5B Expression in the Plasma of Patients with Idiopathic Pulmonary Fibrosis (IPF) Compared to Healthy Individuals. J Craniomaxillofac Res. 2025;12(3):177-184.
