Hypercapnic acidosis affects in vitro lung infection response in a pathogen-specific manner

Hypercapnic acidosis (HCA) is a hallmark of acute hypercapnic respiratory failure, often triggered by respiratory infections. Its role in lung injury remains controversial, with both protective and detrimental effects reported. However, the specific impact on pulmonary immune responses to lung infections remain poorly understood. To investigate the impact of HCA on alveolar response during infection, we developed an in vitro model combining human alveolar epithelial cells (type I and II) and macrophage-like THP-1 cells.

The co-culture and monocultures were infected with Pseudomonas aeruginosa or Streptococcus pneumoniae under normocapnic or HCA conditions. At 1 hour and 24 hours post-infection, we assessed inflammatory cytokine expression (IL-1β, CCL2, IL-8), tight junction protein levels (occludin, ZO-1) and bacterial survival.

HCA modulated inflammation in pathogen-specific manner: IL-1β induction by S. pneumoniae was mainly CO₂-driven, while P. aeruginosa triggered strong IL-1β regardless of CO₂. Tight junction proteins were upregulated at 1 hour under HCA, particularly with macrophages, but occludin declined at 24 hours, potentially impairing epithelial repair. While extracellular bacterial loads were unaffected by CO₂, HCA promoted intracellular replication of P. aeruginosa in macrophages, without affecting intracellular survival in epithelial cells or overall bacterial burden in S. pneumoniae-infected cultures.

HCA condition differentially influence host responses depending on the infectious pathogen, compromising the barrier function and prolonging lung inflammation with differences according to time culture, which could benefit bacterial persistence.