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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>The pathophysiological mechanisms underlying diabetic lung disease (DLD) remain poorly understood. Beyond hyperglycemia, dysregulated molecules such as adenosine may contribute to pulmonary inflammation and fibrosis. MRS1754, a selective antagonist of the A2B adenosine receptor (A2BAR), has demonstrated anti-inflammatory and antifibrotic effects, including reductions in macrophage (M\u03a6) infiltration in animal models of diabetes-associated complications; however, its effects on DLD remain unexplored. Here, diabetic Sprague-Dawley rats were treated with MRS1754, and pulmonary inflammation, fibrosis, M\u03a6 infiltration, and polarization were assessed in bronchoalveolar lavage fluid (BALF) and lung tissue using immunohistopathological and molecular approaches. According to data normality, one-way ANOVA\/Tukey\u2019s test or Kruskal\u2013Wallis\/Dunn\u2019s test were employed, as appropriate; ordinal data were analyzed using the Mann\u2013Whitney test with Bonferroni correction. Compared with controls, diabetic rats exhibited pulmonary inflammation and fibrosis, increased M\u03a6 infiltration, and an M1\/M2 polarization imbalance. MRS1754 attenuated these alterations, reducing Tumor necrosis factor-alpha (TNF-\u03b1) and Transforming growth factor-beta 1 (TGF-\u03b21) levels, decreasing M\u03a6 accumulation in BALF and lung tissue, and fully restoring the M1\/M2 balance to control levels. BALF M\u03a6 populations, particularly the M2 (Cluster of differentiation 163-positive; CD163+) subset, correlated strongly with TGF-\u03b21 and fibronectin (FN1) levels. Reanalysis of human fibrotic lung single-cell transcriptomic data further identified M\u03a6 as a major TGF-\u03b21-expressing cell population. Collectively, these findings suggest that A2BAR antagonism partially mitigates inflammation, fibrosis, and M\u03a6 infiltration while fully restoring M\u03a6 polarization balance in DLD, supporting its potential as a therapeutic strategy.<\/jats:p>","DOI":"10.3390\/ijms27188171","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:09:51Z","timestamp":1789387791000},"page":"8171","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A2BAR Antagonism Mitigates Pulmonary Inflammation and Fibrosis and Restores Macrophage M1\/M2 Balance in Diabetic Rats"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8956-6724","authenticated-orcid":false,"given":"\u00c1ngelo","family":"Torres-Ar\u00e9valo","sequence":"first","affiliation":[{"name":"Escuela de Medicina Veterinaria, Facultad de Recursos Naturales y Medicina Veterinaria, Sede Talca, Universidad Santo Tom\u00e1s, Talca 347-3620, Chile"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Sarah","family":"Montoya-Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Facultad de Salud, Instituci\u00f3n Universitaria Colegio Mayor de Antioquia, Medell\u00edn 050036, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Mateo","family":"Montes-Vanegas","sequence":"additional","affiliation":[{"name":"Escuela de Medicina Veterinaria, Facultad de Recursos Naturales y Medicina Veterinaria, Sede Talca, Universidad Santo Tom\u00e1s, Talca 347-3620, Chile"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Claudio","family":"Cappelli-Le\u00f3n","sequence":"additional","affiliation":[{"name":"Laboratorio de Inmunoepigen\u00e9tica, Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Universidad Austral de Chile, Valdivia 511-0566, Chile"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"given":"Ignacio","family":"\u00c1rias","sequence":"additional","affiliation":[{"name":"Laboratorio de Inmunoepigen\u00e9tica, Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Universidad Austral de Chile, Valdivia 511-0566, Chile"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Claudia Jara","family":"Cancino","sequence":"additional","affiliation":[{"name":"Laboratorio de Patolog\u00eda Molecular, Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Universidad Austral de Chile, Valdivia 511-0566, Chile"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Claudia","family":"Quezada","sequence":"additional","affiliation":[{"name":"Tumor Biology Laboratory, Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, Valdivia 511-0566, Chile"},{"name":"Millennium Institute on Immunology and Immunotherapy, Universidad Austral de Chile, Valdivia 511-0566, Chile"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8413-8028","authenticated-orcid":false,"given":"Sebasti\u00e1n","family":"Alarc\u00f3n","sequence":"additional","affiliation":[{"name":"Escuela de Medicina, Facultad de Medicina, Campus Tres Pascualas, Universidad San Sebasti\u00e1n, Lientur 1457, Concepci\u00f3n 407-0129, Chile"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Benjam\u00edn","family":"Guerrero","sequence":"additional","affiliation":[{"name":"Tumor Biology Laboratory, Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, Valdivia 511-0566, Chile"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1353-6280","authenticated-orcid":false,"given":"Pamela","family":"Silva","sequence":"additional","affiliation":[{"name":"Tumor Biology Laboratory, Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, Valdivia 511-0566, Chile"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3156-5130","authenticated-orcid":false,"given":"V\u00edctor","family":"Pola-V\u00e9liz","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Science (ICB), Faculty of Medicine, Universidad Andr\u00e9s Bello, Santiago 837-0183, Chile"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Rody","family":"San Mart\u00edn","sequence":"additional","affiliation":[{"name":"Laboratorio de Patolog\u00eda Molecular, Instituto de Bioqu\u00edmica y Microbiolog\u00eda, Universidad Austral de Chile, Valdivia 511-0566, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"ref_1","unstructured":"International Diabetes Federation (2024). 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