{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T05:08:48Z","timestamp":1778476128719,"version":"3.51.4"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>To elucidate the role of complement component C5a in pulmonary hypoperfusion (PHypo)-induced alveolar hypoplasia, given its centrality in sterile inflammation and the recent implication of immune activation in a neonatal rat PHypo model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>PHypo was induced in postnatal day 1 (P1) rats via pulmonary artery banding (PAB). Bulk RNA sequencing of lung tissues was performed at P7 and P14, and Single-cell RNA sequencing was conducted at P7. Alveolar development was assessed histologically (H&amp;amp;E) at P14. PHypo rats were treated with a C5a receptor 1(C5aR1) antagonist (C5aR1 ant) at P1. Key molecular changes (IL-1\u03b2, NF-\u03baB, SEMA3a) and alveolar cell number were evaluated. Serum C5a levels were measured in children with PHypo versus controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Bulk RNA-sequencing of P7 lungs identified the complement cascade in the top 20 pathway enrichment, with C5aR1 as the most significantly upregulated gene. Single-cell RNA sequencing revealed that C5aR1 and IL-11\u03b2 are predominantly expressed in monocytes\/macrophages, and immunofluorescence further demonstrated cytoplasmic localization of C5aR1. PHypo induced notable alveolar hypoplasia at P14. RNA-sequencing of P14 lungs showed downregulation of genes associated with alveolar formation and upregulation of those related to immune responses in PHypo lungs. Treatment with C5aR1 ant rescued PHypo-induced alveolar hypoplasia. Mechanistically, C5a-induced IL-1\u03b2 activated NF-\u03baB, inhibiting SEMA3a, crucial for alveolar budding. C5aR1 ant downregulated IL-1\u03b2\/NF-\u03baB axis and upregulated SEMA3a; direct inhibition of IL-1\u03b2 replicated these effects and improved alveologenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study defines a C5a\u2013IL-1\u03b2\u2013NF-\u03baB\u2013SEMA3a axis driving PHypo-induced alveolar hypoplasia. C5aR1 antagonist and IL-1\u03b2 inhibitors demonstrate therapeutic efficacy, may offer novel strategies to improve long-term outcomes in affected children.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1802250","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T04:24:14Z","timestamp":1778473454000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Complement C5a receptor 1 antagonist attenuates alveolar hypoplasia induced by pulmonary hypoperfusion and its underlying mechanisms"],"prefix":"10.3389","volume":"17","author":[{"given":"Chenxi","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Immunology, Shanghai Children\u2019s Medical Center, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, 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