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

Area of Science:

• Immunology
• Pulmonary Medicine
• Cell Biology

Background:

• Lung-protective ventilation strategies can increase arterial carbon dioxide tension (PaCO2) and alter pH.
• While short-term benefits of hypercapnia exist in non-infectious conditions, prolonged exposure or infection typically leads to harm.
• Understanding the immune-mediated effects of hypercapnia on innate immunity and alveolar epithelial repair is crucial for clinical applications.

Purpose of the Study:

• To systematically map the immune-mediated effects of hypercapnia on innate immunity and alveolar epithelial repair.
• To identify the conditions (PaCO2 levels, exposure duration, pH) under which hypercapnia is beneficial or detrimental.
• To synthesize findings from preclinical studies to inform clinical translation.

Main Methods:

• A scoping review methodology following Levac et al. and PRISMA Extension for Scoping Reviews was employed.
• Searched preclinical studies (in vivo/in vitro) from 2008-2023 in major scientific databases.
• Data were extracted on PaCO2, %Fraction of inspired Carbon Dioxide (%FiCO2), pH (buffered/unbuffered), context, and exposure duration (0-120 h and >120 h).

Main Results:

• A "protective window" for hypercapnia was identified in non-infectious models (65-95 mmHg, ≤4-6 h), characterized by NF-κB attenuation and preserved epithelial ion transport.
• In infectious models or with prolonged exposure/higher PaCO2, harmful effects predominated, including reduced phagocytosis/autophagy and impaired alveolar fluid clearance.
• Chronic exposures (>120 h) consistently exacerbated injury, highlighting the detrimental impact of sustained hypercapnia.

Conclusions:

• Hypercapnia acts as a double-edged sword, with its effects being highly dependent on context, dose, time, and pH.
• The narrow therapeutic window for hypercapnia necessitates careful consideration of these factors in clinical settings.
• Standardized reporting of PaCO2 and pH, including comparisons of buffered versus unbuffered conditions, is essential for guiding clinical translation of hypercapnia therapies.