Hypercapnia as a Double-Edged Modulator of Innate Immunity and Alveolar Epithelial Repair: A PRISMA-ScR Scoping Review

Lung-protective ventilation and other experimental conditions raise arterial carbon dioxide tension (PaCO₂) and alter pH. Short-term benefits are reported in non-infectious settings, whereas infection and/or prolonged exposure are typically harmful. This scoping review systematically maps immune-mediated effects of hypercapnia on innate immunity and alveolar epithelial repair. Scoping review per Levac et al. and PRISMA Extension for Scoping Reviews (Open Science Framework protocol: 10.17605/OSF.IO/WV85T; post hoc). We searched original preclinical studies (in vivo/in vitro) in PubMed, Web of Science, ScienceDirect, Cochrane Reviews, and SciELO (2008-2023). PaCO₂ (mmHg) was prioritized; %Fraction of inspired Carbon Dioxide (%FiCO₂) was recorded when PaCO₂ was unavailable; pH was classified as buffered/unbuffered. Data were organized by context, PaCO₂, and exposure duration; synthesis used heat maps (0-120 h) and a narrative description for >120 h. Mechanistic axes extracted the following: NF-κB (canonical/non-canonical), Bcl-2/Bcl-xL-Beclin-1/autophagy, AMPK/PKA/CaMKKβ/ERK1/2 and ENaC/Na,K-ATPase trafficking, Wnt/β-catenin in AT2 cells, and miR-183/IDH2/ATP. Thirty-five studies met the inclusion criteria. In non-infectious models, a "protective window" emerged, with moderate PaCO₂ and brief exposure (65-95 mmHg; ≤4-6 h), featuring NF-κB attenuation and preserved epithelial ion transport. In infectious models and/or with prolonged exposure or higher PaCO₂, harmful signals predominated: reduced phagocytosis/autophagy (Bcl-2/Bcl-xL-Beclin-1 axis), AMPK/PKA/ERK1/2-mediated internalization of ENaC/Na,K-ATPase, depressed β-catenin signaling in AT2 cells, impaired alveolar fluid clearance, and increased bacterial burden. Chronic exposures (>120 h) reinforced injury. Hypercapnia is a context-, dose-, time-, and pH-dependent double-edged modulator. The safe window is narrow; standardized, parallel reporting of PaCO₂ and pH-with explicit comparisons of buffered vs. unbuffered hypercapnia-is essential to guide clinical translation.