Collagen genes Expressed by Fibroblasts in Idiopathic Pulmonary Fibrosis: Association with Prognosis

Eun-Jeong Seo; Seung-Lee Park; Min-Kyung Kim; Jae-Sung Choi; Hun-Gyu Hwang; Jung-Hyun Kim; Hun-Soo Chang; Choon-sik Park; Jong-Uk Lee

doi:10.36141/svdld.2026.18053

Authors

Eun-Jeong Seo Department of Interdisciplinary Program in Biomedical Science Major, Graduate School, Soonchunhyang University, Asan, Republic of Korea https://orcid.org/0009-0000-9347-0244
Seung-Lee Park Department of Interdisciplinary Program in Biomedical Science Major, Graduate School, Soonchunhyang University, Asan, Republic of Korea https://orcid.org/0000-0002-1562-732X
Min-Kyung Kim Department of Interdisciplinary Program in Biomedical Science Major, Graduate School, Soonchunhyang University, Asan, Republic of Korea https://orcid.org/0000-0003-2996-0198
Jae-Sung Choi Division of Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea https://orcid.org/0000-0002-8673-8131
Hun-Gyu Hwang Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea https://orcid.org/0000-0001-9304-7219
Jung-Hyun Kim Division of Allergy and Clinical Immunology, Department of Internal Medicine, Soonchunhyang University Hospital, Seoul, Republic of Korea https://orcid.org/0000-0002-5498-5170
Hun-Soo Chang Department of Interdisciplinary Program in Biomedical Science Major, Graduate School, Soonchunhyang University, Asan, Republic of Korea https://orcid.org/0000-0002-4025-4182
Choon-sik Park Biobank, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea https://orcid.org/0000-0001-7955-2526
Jong-Uk Lee Department of Interdisciplinary Program in Biomedical Science Major, Graduate School, Soonchunhyang University, Asan, Republic of Korea https://orcid.org/0000-0002-0232-5381

Keywords:

idiopathic Pulmonary Fibrosis (IPF), collagen, fibroblast, extracellular matrix, rna-seq, prognostic factors

Abstract

Background and aim: Idiopathic Pulmonary Fibrosis (IPF) is a progressive interstitial lung disease characterized by aberrant extracellular matrix remodeling. While type I and III collagens are known contributors, the extensive transcriptional landscape and prognostic significance of diverse collagen genes in IPF fibroblasts remain unclear. This study aimed to comprehensively characterize gene expression of collagen genes in IPF fibroblasts and evaluate their prognostic relevance.

Methods: RNA sequencing was conducted on primary lung fibroblasts from 33 IPF patients and 10 non-fibrotic controls. Differential expression of collagen genes was analyzed using EdgeR’s exact test, with significance defined as false discovery rate-adjusted p < 0.05. Group differences were evaluated using independent t-tests or Mann–Whitney U tests, and categorical variables via chi-square tests. Prognostic significance was assessed using Cox regression and Kaplan–Meier survival analysis.

Results: Among 17 collagen genes, 14 genes — including COL1A1, COL1A2, COL3A1, COL4A4, COL4A5, COL4A6, COL5A2, COL6A6, COL8A1, COL11A1, COL14A1, COL18A1, COL24A1, and COL27A1 — were significantly upregulated in IPF fibroblasts, while COL5A3, COL13A1, and COL16A1 were downregulated. COL3A1, COL4A4, and COL24A1 were associated with reduced survival in both univariate Cox regression and Kaplan–Meier analyses. Among them, COL4A4 emerged as an independent predictor of mortality in multivariate analysis.

Conclusions: These findings highlight distinct collagen gene expression patterns in IPF fibroblasts that correlate with poor prognosis. COL4A4 and COL24A1 may serve as novel prognostic markers for disease severity. Our results underscore the potential of collagen transcript signatures as both biomarkers and therapeutic targets in IPF, supporting their integration into stratified medicine approaches.

References

1. Jessen H, Hoyer N, Prior TS, Frederiksen P, Karsdal MA, Leeming DJ. Turnover of type I and III collagen predicts progression of idiopathic pulmonary fibrosis. 2021;22(1):205.

2. Ko SJ, Choi SM, Han KD, Lee CH, Lee J. All-cause mortality of patients with idiopathic pulmonary fibrosis: a nationwide population-based cohort study in Korea. Sci Rep. 2021;11(1):15145.

3. Gimenez A, Duch P, Puig M, Gabasa M, Xaubet A, Alcaraz J. Dysregulated Collagen Homeostasis by Matrix Stiffening and TGF-beta1 in Fibroblasts from Idiopathic Pulmonary Fibrosis Patients: Role of FAK/Akt. Int J Mol Sci. 2017;18(11).

4. Hardie WD, Glasser SW, Hagood JS. Emerging concepts in the pathogenesis of lung fibrosis. Am J Pathol. 2009;175(1):3-16.

5. Staab-Weijnitz CA. Fighting the Fiber: Targeting Collagen in Lung Fibrosis. Am J Respir Cell Mol Biol. 2022;66(4):363-81.

6. Ricard-Blum S. The collagen family. Cold Spring Harb Perspect Biol. 2011;3(1):a004978.

7. Gelse K, Poschl E, Aigner T. Collagens--structure, function, and biosynthesis. Adv Drug Deliv Rev. 2003;55(12):1531-46.

8. Liu L, Stephens B, Bergman M, May A, Chiang T. Role of Collagen in Airway Mechanics. Bioengineering (Basel). 2021;8(1).

9. Hoyer N, Jessen H, Prior TS, Sand JMB, Leeming DJ, Karsdal MA, et al. High turnover of types III and VI collagen in progressive idiopathic pulmonary fibrosis. Respirology. 2021;26(6):582-9.

10. Lee JU, Cheong HS, Shim EY, Bae DJ, Chang HS, Uh ST, et al. Gene profile of fibroblasts identify relation of CCL8 with idiopathic pulmonary fibrosis. Respir Res. 2017;18(1):3.

11. Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al. Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2018;198(5):e44-e68.

12. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, 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(6):788-824.

13. Birk DE, Fitch JM, Babiarz JP, Doane KJ, Linsenmayer TF. Collagen fibrillogenesis in vitro: interaction of types I and V collagen regulates fibril diameter. J Cell Sci. 1990;95 ( Pt 4):649-57.

14. Peyser R, MacDonnell S, Gao Y, Cheng L, Kim Y, Kaplan T, et al. Defining the Activated Fibroblast Population in Lung Fibrosis Using Single-Cell Sequencing. Am J Respir Cell Mol Biol. 2019;61(1):74-85.

15. Urushiyama H, Terasaki Y, Nagasaka S, Terasaki M, Kunugi S, Nagase T, et al. Role of alpha1 and alpha2 chains of type IV collagen in early fibrotic lesions of idiopathic interstitial pneumonias and migration of lung fibroblasts. Lab Invest. 2015;95(8):872-85.

16. Chen H, Qu J, Huang X, Kurundkar A, Zhu L, Yang N, et al. Mechanosensing by the alpha6-integrin confers an invasive fibroblast phenotype and mediates lung fibrosis. Nat Commun. 2016;7:12564.

17. Li Y, Lacerda DA, Warman ML, Beier DR, Yoshioka H, Ninomiya Y, et al. A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis. Cell. 1995;80(3):423-30.

18. Grassel S, Bauer RJ. Collagen XVI in health and disease. Matrix Biol. 2013;32(2):64-73.

19. Li Q, Olsen BR. Increased angiogenic response in aortic explants of collagen XVIII/endostatin-null mice. Am J Pathol. 2004;165(2):415-24.

20. Hjorten R, Hansen U, Underwood RA, Telfer HE, Fernandes RJ, Krakow D, et al. Type XXVII collagen at the transition of cartilage to bone during skeletogenesis. Bone. 2007;41(4):535-42.

21. Loscertales M, Nicolaou F, Jeanne M, Longoni M, Gould DB, Sun Y, et al. Type IV collagen drives alveolar epithelial-endothelial association and the morphogenetic movements of septation. BMC Biol. 2016;14:59.

22. Abreu-Velez AM, Howard MS. Collagen IV in Normal Skin and in Pathological Processes. N Am J Med Sci. 2012;4(1):1-8.

23. Leeming DJ, Sand JM, Nielsen MJ, Genovese F, Martinez FJ, Hogaboam CM, et al. Serological investigation of the collagen degradation profile of patients with chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis. Biomark Insights. 2012;7:119-26.

24. Matsuo N, Tanaka S, Yoshioka H, Koch M, Gordon MK, Ramirez F. Collagen XXIV (Col24a1) gene expression is a specific marker of osteoblast differentiation and bone formation. Connect Tissue Res. 2008;49(2):68-75.

25. Oldham JM, Huang Y, Bose S, Ma SF, Kim JS, Schwab A, et al. Proteomic Biomarkers of Survival in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2024;209(9):1111-20.

26. Organ LA, Duggan AR, Oballa E, Taggart SC, Simpson JK, Kang'ombe AR, et al. Biomarkers of collagen synthesis predict progression in the PROFILE idiopathic pulmonary fibrosis cohort. Respir Res. 2019;20(1):148.

27. Lavis P, Garabet A, Cardozo AK, Bondue B. The fibroblast activation protein alpha as a biomarker of pulmonary fibrosis. Front Med (Lausanne). 2024;11:1393778.