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This study compares two widely used animal models of SSc\u2014the bleomycin-induced fibrosis model and the collagen-V-induced autoimmune model\u2014to evaluate their ability to replicate key disease features. In the bleomycin model, consistent cardiac fibrosis was observed across treatment groups despite variability in fibrosis in the skin and lungs, suggesting organ-specific differences in susceptibility. The collagen-V model demonstrated robust autoantibody production against collagen-V, confirming its utility in studying immune activation, though fibrosis was largely confined to the heart. While the bleomycin model excels at mimicking rapid fibrosis and is suitable for testing antifibrotic therapies, the collagen-V model provides insights into antigen-specific autoimmunity. Both models highlight the dynamic nature of fibrosis, where ECM deposition and degradation occur concurrently, complicating its use as a quantitative disease marker. Cardiac fibrosis emerged as a consistent feature in both models, emphasizing its relevance in SSc pathophysiology. Combining these models or refining their design through hybrid approaches, extended timelines, or sex and age adjustments could enhance their translational utility. These findings advance understanding of SSc mechanisms and inform therapeutic development for this challenging disease.<\/jats:p>","DOI":"10.3390\/ijms26062618","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T07:02:16Z","timestamp":1741935736000},"page":"2618","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Comparative Evaluation of Bleomycin- and Collagen-V-Induced Models of Systemic Sclerosis: Insights into Fibrosis and Autoimmunity for Translational Research"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5278-1898","authenticated-orcid":false,"given":"L\u0151rinc","family":"Nagy","sequence":"first","affiliation":[{"name":"Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2943-2750","authenticated-orcid":false,"given":"G\u00e1bor","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0489-5676","authenticated-orcid":false,"given":"Tam\u00e1s","family":"Juh\u00e1sz","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Csaba","family":"Fill\u00e9r","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0958-9531","authenticated-orcid":false,"given":"Gabriella","family":"Sz\u0171cs","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7794-6844","authenticated-orcid":false,"given":"Zolt\u00e1n","family":"Szekanecz","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2157-3265","authenticated-orcid":false,"given":"Gy\u00f6rgy","family":"Vereb","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"},{"name":"HUN-REN-UD Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"},{"name":"Faculty of Pharmacy, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P\u00e9ter","family":"Antal-Szalm\u00e1s","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1rp\u00e1d","family":"Sz\u00f6\u0151r","sequence":"additional","affiliation":[{"name":"Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"},{"name":"HUN-REN-UD Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1056\/NEJMra0806188","article-title":"Scleroderma","volume":"360","author":"Gabrielli","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1038\/nrrheum.2014.222","article-title":"Systemic sclerosis in 2014: Advances in cohort enrichment shape future of trial design","volume":"11","author":"Allanore","year":"2015","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/s41572-018-0041-4","article-title":"Multiple sclerosis","volume":"4","author":"Filippi","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1046\/j.1523-1747.1999.00528.x","article-title":"Animal model of sclerotic skin. I: Local injections of bleomycin induce sclerotic skin mimicking scleroderma","volume":"112","author":"Yamamoto","year":"1999","journal-title":"J. Investig. Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.jid.2015.12.028","article-title":"The Antifibrotic Effect of alpha2AP Neutralization in Systemic Sclerosis Dermal Fibroblasts and Mouse Models of Systemic Sclerosis","volume":"136","author":"Kanno","year":"2016","journal-title":"J. Investig. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Tashiro, J., Rubio, G.A., Limper, A.H., Williams, K., Elliot, S.J., Ninou, I., Aidinis, V., Tzouvelekis, A., and Glassberg, M.K. (2017). Exploring Animal Models That Resemble Idiopathic Pulmonary Fibrosis. Front. Med., 4.","DOI":"10.3389\/fmed.2017.00118"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1172\/JCI93557","article-title":"Extracellular matrix as a driver of progressive fibrosis","volume":"128","author":"Herrera","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1513\/pats.201203-023AW","article-title":"The impact of TGF-beta on lung fibrosis: From targeting to biomarkers","volume":"9","author":"Fernandez","year":"2012","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1002\/art.38948","article-title":"Fibrosis, vascular activation, and immune abnormalities resembling systemic sclerosis in bleomycin-treated Fli-1-haploinsufficient mice","volume":"67","author":"Taniguchi","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1089\/ars.2012.5149","article-title":"Reactive oxygen species in inflammation and tissue injury","volume":"20","author":"Mittal","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Maria, A.T.J., Toupet, K., Maumus, M., Rozier, P., Vozenin, M.C., Le Quellec, A., Jorgensen, C., Noel, D., and Guilpain, P. (2018). Fibrosis Development in HOCl-Induced Systemic Sclerosis: A Multistage Process Hampered by Mesenchymal Stem Cells. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02571"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1186\/s13075-019-2052-2","article-title":"Proposition of a novel animal model of systemic sclerosis induced by type V collagen in C57BL\/6 mice that reproduces fibrosis, vasculopathy and autoimmunity","volume":"21","author":"Teodoro","year":"2019","journal-title":"Arthritis Res. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.jbspin.2014.03.009","article-title":"Antinuclear autoantibody profile in systemic sclerosis patients who are negative for anticentromere and anti-topoisomerase I specificities","volume":"82","author":"Caramaschi","year":"2015","journal-title":"Joint Bone Spine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1002\/art.21646","article-title":"DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti-topoisomerase I autoantibodies from systemic sclerosis patients","volume":"54","author":"Henault","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ko, J., Noviani, M., Chellamuthu, V.R., Albani, S., and Low, A.H.L. (2023). The Pathogenesis of Systemic Sclerosis: The Origin of Fibrosis and Interlink with Vasculopathy and Autoimmunity. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241814287"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1097\/BOR.0000000000000550","article-title":"An update on autoantibodies in scleroderma","volume":"30","author":"Mecoli","year":"2018","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kayser, C., and Fritzler, M.J. (2015). Autoantibodies in systemic sclerosis: Unanswered questions. Front. Immunol., 6.","DOI":"10.3389\/fimmu.2015.00167"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1111\/j.1365-2567.2007.02610.x","article-title":"Autoantibody profile in the experimental model of scleroderma induced by type V human collagen","volume":"122","author":"Callado","year":"2007","journal-title":"Immunology"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Pan, S.Y., Tian, H.M., Zhu, Y., Gu, W.J., Zou, H., Wu, X.Q., Cheng, R.J., and Yang, Z. (2022). Cardiac damage in autoimmune diseases: Target organ involvement that cannot be ignored. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1056400"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/s41584-019-0322-7","article-title":"Shared and distinct mechanisms of fibrosis","volume":"15","author":"Distler","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Morozan, A., Joy, S., Fujii, U., Fraser, R., Watters, K., Martin, J.G., and Colmegna, I. (2023). Superiority of systemic bleomycin to intradermal HOCl for the study of interstitial lung disease. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-47083-y"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Leong, E., Bezuhly, M., and Marshall, J.S. (2021). Distinct Metalloproteinase Expression and Functions in Systemic Sclerosis and Fibrosis: What We Know and the Potential for Intervention. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.727451"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1007\/s00296-024-05699-x","article-title":"Heart involvement in patients with systemic sclerosis-what have we learned about it in the last 5 years","volume":"44","author":"Nadel","year":"2024","journal-title":"Rheumatol. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3770","DOI":"10.1172\/JCI94753","article-title":"Fibroblast-specific TGF-beta-Smad2\/3 signaling underlies cardiac fibrosis","volume":"127","author":"Khalil","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1172\/JCI31139","article-title":"Systemic sclerosis: A prototypic multisystem fibrotic disorder","volume":"117","author":"Varga","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1126\/science.aaf6756","article-title":"Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease","volume":"353","author":"Ellebrecht","year":"2016","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/ncprheum0346","article-title":"Mechanisms of Disease: The role of immune cells in the pathogenesis of systemic sclerosis","volume":"2","author":"Sakkas","year":"2006","journal-title":"Nat. Clin. Pract. Rheumatol."},{"key":"ref_28","unstructured":"(2005). 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