From Alveolar Injury to Precision Perioperative Care: Integrating Molecular Biomarkers and Technology-Enabled Strategies for Prolonged Air Leak After Lung Resection.

Prolonged air leak (PAL) remains one of the most frequent and clinically consequential complications after lung resection, prolonging chest tube duration, delaying recovery, increasing postoperative morbidity, and expanding healthcare resource utilization. Although traditionally approached as a mechanical failure of alveolar-pleural sealing or surgical technique, PAL is increasingly understood as a heterogeneous postoperative syndrome in which persistent air leak dynamics intersect with impaired inflammatory and reparative biology. Surgical manipulation, one-lung ventilation, parenchymal injury, and patient-specific vulnerability may activate cytokine signaling, epithelial barrier disruption, oxidative stress, extracellular matrix remodeling, glycocalyx degradation, and delayed wound repair. This narrative review synthesizes clinical, translational, and experimental evidence on the pathogenesis of PAL, with particular emphasis on inflammatory mediators and biomarker-defined mechanisms relevant to failed closure of alveolar-pleural fistulas (APFs). Candidate biomarkers are discussed according to the biological domains they reflect, including systemic inflammatory burden and poor healing reserve (C-reactive protein [CRP], IL-6, and serum albumin), epithelial injury and damage-associated signaling (high-mobility group box 1 [HMGB1]/receptor for advanced glycation end products [RAGE] and sRAGE), oxidative epithelial stress (4-hydroxynonenal [4-HNE] and malondialdehyde [MDA]), protease-mediated matrix and junctional remodeling (matrix metalloproteinase [MMP]-9), glycocalyx and barrier disruption (syndecan [SDC]-1), and upstream inflammatory regulation (histone deacetylase 6 [HDAC6]-related pathways). The review also considers how quantitative digital chest drainage parameters may complement molecular biomarkers by capturing the physiologic expression of persistent air leak. By integrating these mechanistic and technological signals, this review proposes a conceptual framework for biomarker-informed perioperative risk stratification, PAL phenotyping, and individualized prevention and management. Because most biomarker-driven strategies remain investigational, prospective validation is required before routine clinical implementation.