Inflammatory Responses Regulating Alveolar Ion Transport during Pulmonary Infections

Abstract

The respiratory epithelium is lined by a tightly balanced fluid layer that allows normal O₂ and CO₂ exchange and maintains surface tension and host defense. To maintain alveolar fluid homeostasis, both the integrity of the alveolar-capillary barrier and the expression of epithelial ion channels and pumps are necessary to establish a vectorial ion gradient. However, during pulmonary infection, auto- and/or paracrine-acting mediators induce pathophysiological changes of the alveolar-capillary barrier, altered expression of epithelial Na,K-ATPase and of epithelial ion channels including epithelial sodium channel and cystic fibrosis membrane conductance regulator, leading to the accumulation of edema and impaired alveolar fluid clearance. These mediators include classical pro-inflammatory cytokines such as TGF-β, TNF-α, interferons, or IL-1β that are released upon bacterial challenge with Streptococcus pneumoniae, Klebsiella pneumoniae, or Mycoplasma pneumoniae as well as in viral infection with influenza A virus, pathogenic coronaviruses, or respiratory syncytial virus. Moreover, the pro-apoptotic mediator TNF-related apoptosis-inducing ligand, extracellular nucleotides, or reactive oxygen species impair epithelial ion channel expression and function. Interestingly, during bacterial infection, alterations of ion transport function may serve as an additional feedback loop on the respiratory inflammatory profile, further aggravating disease progression. These changes lead to edema formation and impair edema clearance which results in suboptimal gas exchange causing hypoxemia and hypercapnia. Recent preclinical studies suggest that modulation of the alveolar-capillary fluid homeostasis could represent novel therapeutic approaches to improve outcomes in infection-induced lung injury.

Keywords: Na-K-ATPase; cystic fibrosis membrane conductance regulator; cytokines; edema; epithelial sodium channel; ion channel; ion pumps; lung injury.

Figure 1

Mediators released in pulmonary infection and their effects on ion homeostasis. Ion transport of the lung epithelial cell is mediated by various ion channels and pumps. Sodium enters the epithelial cell via the apical cyclic nucleotide-gated cation channel (CNG) or the epithelial sodium channel (ENaC), that can be downregulated by reactive oxygen and nitrogen species (RONS) and ATP, transforming growth factor beta (TGF-β) or interleukin-1 beta (IL-1β) upon Streptococcus pneumoniae and influenza A virus (IAV) infection. Sodium is secreted at the basolateral side by the Na,K-ATPase (NKA), which is modulated in lipopolysaccharide (LPS)-induced lung injury as well as upon Mycoplasma pulmonis, IAV, coronavirus (CoV), or adenovirus challenge. RONS, interferon-alpha (IFN-α), and TNF-related apoptosis-inducing ligand (TRAIL) lead to a decrease in NKA abundance or activity. In parallel, chloride is taken up (alveolar epithelium) or secreted (airway) by the cystic fibrosis membrane conductance regulator (CFTR) and secreted by apical Ca²⁺-activated ion channels (CaCC), supported by basolateral potassium channels (not shown) and Na⁺/K⁺/2Cl⁻ cotransporters (NKCC). While extracellular ATP enhances chloride secretion by CaCC, CFTR action is reduced by IFN-γ and interleukin-8 (IL-8) in CoV, IAV, respiratory syncytial virus (RSV), or Mycoplasma pneumoniae infection.