ArticleFrontiers in immunology2026
Complement C5a receptor 1 antagonist attenuates alveolar hypoplasia induced by pulmonary hypoperfusion and its underlying mechanisms.
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: 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. Methods: 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&E) at P14. PHypo rats were treated with a C5a receptor 1(C5aR1) antagonist (C5aR1 ant) at P1. Key molecular changes (IL-1β, NF-κB, SEMA3a) and alveolar cell number were evaluated. Serum C5a levels were measured in children with PHypo versus controls. Results: 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-11β 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-1β activated NF-κB, inhibiting SEMA3a, crucial for alveolar budding. C5aR1 ant downregulated IL-1β/NF-κB axis and upregulated SEMA3a; direct inhibition of IL-1β replicated these effects and improved alveologenesis. Conclusions: This study defines a C5a-IL-1β-NF-κB-SEMA3a axis driving PHypo-induced alveolar hypoplasia. C5aR1 antagonist and IL-1β inhibitors demonstrate therapeutic efficacy, may offer novel strategies to improve long-term outcomes in affected children.
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