Work

p300 exacerbates lung injury following cardiopulmonary bypass in AnxA1-deficient rats

Year: 2026

Type: article

Abstract: Acute lung injury (ALI) following cardiopulmonary bypass (CPB) is one of the most common postoperative complications, significantly impairing postoperative recovery and, in severe cases, endangering patient survival. CPB-induced ALI is predominantly associated with systemic inflammatory responses, although multiple factors contribute to this inflammation. Annexin A1 (AnxA1), a potent anti-inflammatory protein, is widely expressed in various organs and has been shown to mitigate lung injury by suppressing inflammatory responses in ALI. In contrast, p300, a histone acetyltransferase, promotes inflammation by enhancing the expression of pro-inflammatory mediators in ALI. These opposing roles suggest a critical regulatory interplay between AnxA1 and p300 in modulating pulmonary inflammation. This study establishes a clinically relevant cardiopulmonary bypass combined left lung ischemia-reperfusion (CPB-I/R) acute lung injury (ALI) rat model, distinct from widely used LPS-induced ALI models, to dissect the interactive regulatory relationship between AnxA1 and p300 in perioperative lung injury for the first time. CPB triggers systemic inflammatory priming, while unilateral left lung ischemia-reperfusion imposes localized pulmonary endothelial damage; the two insults together produce synergistic severe lung injury, which closely mimics clinical cardiac surgery-related perioperative lung dysfunction. In this study, we established CPB-induced ALI models in both wild-type (WT) and AnxA1-knockout rats. We observed upregulated p300 expression and exacerbated inflammatory responses in AnxA1-knockout rats compared to WT controls. Furthermore, co-expression and potential protein complex formation between AnxA1 and p300 were detected in WT animals; however, the current co-immunoprecipitation assay lacks critical IgG negative controls and reciprocal pull-down validation, limiting definitive confirmation of specific bidirectional protein binding.Notably, pharmacological inhibition of p300 with C646 partially alleviated lung injury in the CPB-induced ALI model. Intriguingly, C646 treatment reduced total p300 protein abundance in lung tissue despite functioning as a catalytic activity inhibitor, which we further interpret via potential transcriptional feedback and protein stability mechanisms. Our findings provide novel mechanistic insights into the pathogenesis of CPB-related ALI and highlight the AnxA1-p300 axis as a promising potential therapeutic target, offering a theoretical foundation for future clinical interventions.

Source: Scientific Reports

DOI: 10.1038/s41598-026-74447-x