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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-?, TNF-?, interferons, or IL-1? 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.

SUBMITTER: Peteranderl C

PROVIDER: S-EPMC5394420 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Inflammatory Responses Regulating Alveolar Ion Transport during Pulmonary Infections.

Peteranderl Christin C Sznajder Jacob I JI Herold Susanne S Lecuona Emilia E

Frontiers in immunology 20170418

The respiratory epithelium is lined by a tightly balanced fluid layer that allows normal O<sub>2</sub> and CO<sub>2</sub> 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 a ...[more]

PMID: 28458673

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Project description:BACKGROUND AND PURPOSE:Epithelial surface hydration is critical for proper gut function. However, colonic tissues from individuals with inflammatory bowel disease or animals with colitis are hyporesponsive to Cl(-) secretagogues. The Cl(-) secretory responses to the muscarinic receptor agonist bethanechol are virtually absent in colons of mice with dextran sodium sulphate (DSS)-induced colitis. Our aim was to define the mechanism underlying this cholinergic hyporesponsiveness. EXPERIMENTAL APPROACH:Colitis was induced by 4% DSS water, given orally. Epithelial ion transport was measured in Ussing chambers. Colonic crypts were isolated and processed for mRNA expression via RT-PCR and protein expression via immunoblotting and immunolocalization. KEY RESULTS:Expression of muscarinic M(3) receptors in colonic epithelium was not decreased during colitis. Short-circuit current (I(SC)) responses to other Ca(2+)-dependent secretagogues (histamine, thapsigargin, cyclopiazonic acid and calcium ionophore) were either absent or severely attenuated in colonic tissue from DSS-treated mice. mRNA levels of several ion transport molecules (a Ca(2+)-regulated Cl(-) channel, the intermediate-conductance Ca(2+)-activated K(+) channel, the cystic fibrosis transmembrane conductance regulator, the Na(+)/K(+)-ATPase pump or the Na(+)/K(+)/2Cl(-) co-transporter) were not reduced in colonic crypts from DSS-treated mice. However, protein expression of Na(+)/K(+)-ATPase alpha1 subunits was decreased twofold during colitis. Activation of Ca(2+)-activated K(+) channels increased I(SC) significantly less in DSS colons compared with control, as did the protein kinase C activator, phorbol 12-myristate 13-acetate. CONCLUSIONS AND IMPLICATIONS:Decreased Na(+)/K(+)-ATPase expression probably contributes to overall epithelial hyporesponsiveness during colitis, while dysfunctional K(+) channels may account, at least partially, for lack of epithelial secretory responses to Ca(2+)-mediated secretagogues.

Project description:OBJECTIVE:Pulmonary rehabilitation is a cornerstone treatment in the management of chronic obstructive pulmonary disease (COPD). Acute bouts of exercise can lead to short bursts of inflammation in healthy individuals. However, it is unclear how COPD patients respond to acute bouts of exercise. This study assessed inflammatory responses to exercise in COPD patients at the start (phase 1) and end (phase 2) of pulmonary rehabilitation. METHODS:Blood samples were collected before and after an acute exercise bout at the start (phase 1, n?=?40) and end (phase 2, n?=?27) of pulmonary rehabilitation. The primary outcome was change in fibrinogen concentrations. Secondary outcomes were changes in CRP concentrations, total/differential leukocyte counts, markers of neutrophil activation (CD11b, CD62L and CD66b), and neutrophil subsets (mature, suppressive, immature, progenitor). RESULTS:Acute exercise (phase 1) did not induce significant changes in fibrinogen (p?=?0.242) or CRP (p?=?0.476). Total leukocyte count [mean difference (MD), 0.5?±?1.1 (109 L-1); p?=?0.004], neutrophil count [MD, 0.4?±?0.8 (109 L-1); p?<?0.001], and immature neutrophils (MD, 0.6?±?0.8%; p?<?0.001) increased post-exercise. Neutrophil activation markers, CD11b (p?=?0.470), CD66b (p?=?0.334), and CD62L (p?=?0.352) were not significantly altered post-exercise. In comparison to the start of pulmonary rehabilitation (phase 2), acute exercise at the end of pulmonary rehabilitation led to a greater fibrinogen response (MD, 84 mg/dL (95% CI -?14, 182); p?=?0.045). CONCLUSION:An acute bout of exercise does not appear to induce significant alterations in the concentrations of inflammatory mediators but can increase white blood cell subsets post-exercise. A greater fibrinogen response to acute exercise is seen at the end of pulmonary rehabilitation when compared to the start. Further research is required to understand the clinical context of these acute inflammatory responses to exercise.

Dataset Information

Inflammatory Responses Regulating Alveolar Ion Transport during Pulmonary Infections.

Publications

Inflammatory Responses Regulating Alveolar Ion Transport during Pulmonary Infections.

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