Cell death mechanisms, DAMP release, and therapeutic targeting in sepsis-associated postoperative pneumonia.

BACKGROUND: Sepsis complicating postoperative pneumonia activates multiple programmed cell death pathways-pyroptosis, necroptosis, and ferroptosis-which release DAMPs that amplify systemic inflammation and worsen outcomes. This study aimed to characterize clinical correlates of these pathways, identify biomarkers predictive of ARDS and mortality, and evaluate relevant therapeutic strategies. METHODS: A single-center retrospective cohort of surgical patients over 12 years was analyzed. Patients developing postoperative pneumonia were stratified by sepsis and ARDS status. Systemic biomarkers, CT imaging, and survival outcomes were assessed using Cox regression, ROC analysis, and Kaplan-Meier modeling. Pathway-specific molecular assays were unavailable; all mechanistic interpretations are therefore hypothesis-generating. RESULTS: Inflammatory biomarkers escalated progressively across the pneumonia-sepsis-ARDS continuum. Procalcitonin and NLR demonstrated utility in identifying high-risk patients before sepsis onset. CT-quantified bilateral ground-glass opacities predicted ARDS development, though ARDS-specific estimates should be treated as exploratory given the small subgroup size. Mortality rose substantially at each stage of clinical severity, with sepsis, ARDS, CT severity score, and bilateral pulmonary involvement each identified as independent mortality predictors. CONCLUSION: Programmed cell death pathways provide a conceptually consistent framework for the observed clinical continuum, but require prospective molecular validation. Biomarker panels and CT-based stratification support early risk identification and may improve postoperative surveillance. Investigational agents targeting key cell death mediators remain hypothesis-driven and are not yet clinically actionable.