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.
Original language | English (US) |
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Article number | 446 |
Journal | Frontiers in immunology |
Volume | 8 |
Issue number | APR |
DOIs | |
State | Published - Apr 18 2017 |
Funding
This work was supported by the German Research Foundation (SFB-TR84 B2, SFB1021 C05, KFO309 P2/P8, EXC147), by the German Center for Lung Research (DZL), by the German Center for Infection Research (DZIF), and by the National Institutes of Health (R37-HL48129 and HL071643).
Keywords
- Cystic fibrosis membrane conductance regulator
- Cytokines
- Edema
- Epithelial sodium channel
- Ion channel
- Ion pumps
- Lung injury
- Na-K-ATPase
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology