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.

Mechanisms of Severe Mortality-Associated Bacterial Co-infections Following Influenza Virus Infection

“…These exposed areas can be covered by basement membrane elements such as fibrin and fibrinogen deposition, laminin, or type I and IV collagen. This phenomenon has been observed in the clinics; patients can be easily infected by bacteria while recovering from primary illness (Louria et al, 1959 ; Peteranderl et al, 2017 ). In addition, many bacterial virulence factors can attach to elements of the extracellular matrix or basement membrane (Foster and Hook, 1998 ; McCullers and Tuomanen, 2001 ).…”

An interferon-independent lncRNA promotes viral replication by modulating cellular metabolism

“…To check if lncRNA-ACOD1 functions through apoptosis and autophagy, which are reported to be involved in viral clearance (25,26), we tested the effect of lncRNA-ACOD1 with flow cytometry and immunoblot assay and found that host-cell apoptosis and autophagy were not influenced by lncRNA-ACOD1 ( fig. S13).…”

Cytokine–Ion Channel Interactions in Pulmonary Inflammation

“…The activation of TNF receptor 1 by TNF modulates the integrity of the alveolar barrier, in addition to its direct effects on ion channels and pumps of the alveolar epithelium. TNF increases the endothelial expression of chemo-attractants and adhesion molecules including IL-8 (formerly called neutrophil chemotactic factor), the IL-8- receptor 2, the intercellular adhesion molecule-1 (ICAM-1), platelet endothelial cell adhesion molecule-1 (PECAM-1), and vascular adhesion molecule-1, thus promoting excessive recruitment of mononuclear phagocytes and neutrophils during lung inflammation ( 71 , 369 – 371 ).…”