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Physiological impact of abnormal lipoxin A₄ production on cystic fibrosis airway epithelium and therapeutic potential.

Higgins G, Ringholz F, Buchanan P, McNally P, Urbach V - Biomed Res Int (2015)

Bottom Line: In CF, the loss of chloride transport caused by the mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel gene results in dehydration, mucus plugging, and reduction of the airway surface liquid layer (ASL) height which favour chronic lung infection and neutrophil based inflammation leading to progressive lung destruction and early death of people with CF.The report points out novel aspects of the cellular mechanism involved in the physiological response to LXA4, including release of ATP from airway epithelial cell via pannexin channel and subsequent activation of and P2Y11 purinoreceptor.Therefore, inadequate endogenous LXA4 biosynthesis reported in CF exacerbates the ion transport abnormality and defective mucociliary clearance, in addition to impairing the resolution of inflammation, thus amplifying the vicious circle of airway dehydration, chronic infection, and inflammation.

View Article: PubMed Central - PubMed

Affiliation: National Children's Research Centre, Crumlin, Dublin 12, Ireland ; Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.

ABSTRACT
Lipoxin A4 has been described as a major signal for the resolution of inflammation and is abnormally produced in the lungs of patients with cystic fibrosis (CF). In CF, the loss of chloride transport caused by the mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel gene results in dehydration, mucus plugging, and reduction of the airway surface liquid layer (ASL) height which favour chronic lung infection and neutrophil based inflammation leading to progressive lung destruction and early death of people with CF. This review highlights the unique ability of LXA4 to restore airway surface hydration, to stimulate airway epithelial repair, and to antagonise the proinflammatory program of the CF airway, circumventing some of the most difficult aspects of CF pathophysiology. The report points out novel aspects of the cellular mechanism involved in the physiological response to LXA4, including release of ATP from airway epithelial cell via pannexin channel and subsequent activation of and P2Y11 purinoreceptor. Therefore, inadequate endogenous LXA4 biosynthesis reported in CF exacerbates the ion transport abnormality and defective mucociliary clearance, in addition to impairing the resolution of inflammation, thus amplifying the vicious circle of airway dehydration, chronic infection, and inflammation.

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Related in: MedlinePlus

In normal airways the airway surface liquid layer (ASL) provides an adequate mucociliary clearance which is maintained by a combination of Cl− secretion through the cystic fibrosis transmembrane conductance regulator (CFTR), Na+ absorption via the epithelial sodium channel (ENaC), and water transport through a paracellular pathway and membrane bound aquaporins (Aq). In CF, a defective CFTR leads to loss of Cl− secretion and Na+ hyperabsorption. The concomitant dehydration of the airway lumen favours bacterial infection and inflammation (mainly neutrophilic). LXA4 mediates an increase in ASL height and restores it to normal levels in CF bronchial epithelium. LXA4 also increase tight junction formation, reestablishing the epithelial barrier function. Taken together this work provides evidence for LXA4 as potentially a new therapy for CF patients.
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fig2: In normal airways the airway surface liquid layer (ASL) provides an adequate mucociliary clearance which is maintained by a combination of Cl− secretion through the cystic fibrosis transmembrane conductance regulator (CFTR), Na+ absorption via the epithelial sodium channel (ENaC), and water transport through a paracellular pathway and membrane bound aquaporins (Aq). In CF, a defective CFTR leads to loss of Cl− secretion and Na+ hyperabsorption. The concomitant dehydration of the airway lumen favours bacterial infection and inflammation (mainly neutrophilic). LXA4 mediates an increase in ASL height and restores it to normal levels in CF bronchial epithelium. LXA4 also increase tight junction formation, reestablishing the epithelial barrier function. Taken together this work provides evidence for LXA4 as potentially a new therapy for CF patients.

Mentions: The lung must continually defend itself against bacteria that deposit on the airway surfaces during normal tidal breathing. Mucus clearance is a primary form of pulmonary defence and the efficiency of mucociliary clearance in large part depends upon the volume of the airway surface liquid layer (ASL). The ASL allows for mucus containing foreign bodies to be transported away from the lung to the oropharynx where it is either expelled from the body or swallowed and destroyed by the gut. The ASL provides a low viscosity solution allowing free ciliary beat and mucus transport [59]. The normal hydration of the airway surface is maintained (in the highly water permeable airway epithelium) by active ion-transport controlling the quantity of salt (NaCl) delivered to airway surfaces, with water following passively by osmosis [60]. The NaCl concentration of the airway surface liquid is tightly regulated in normal airway epithelia by the epithelial sodium channel (ENaC) mediated Na+ absorption and Cl− secretion. Cl− is secreted by epithelial cells via the apical CFTR Cl− channel and calcium activated Cl− channels, with Cl− entering the cell through the Na+–K+–2Cl− cotransporter located in the basolateral membrane. Regulation of Cl− secretion determines the net transport of ions across the epithelium and hence the mass of salt on the epithelial surfaces. CFTR was also found to regulate ENaC suggesting that CFTR acted both as a Cl− channel and as a regulator of other ion transport processes. In CF, mutations of the CFTR gene result in defective Cl− secretion and Na+ hyperabsorption by airway epithelia [61, 62]. Studies in CF airway epithelium cultures, transgenic mice, and people with CF suggest that the initiating event in CF airway disease is a reduced ASL volume resulting from dehydration. This dehydration leads to reduced mucus clearance, adhesion of mucus to airway surfaces, and chronic bacterial infection of the lung (Figure 2). The chronic bacterial infection leads to an aggravated immune response, bronchial epithelial remodelling, and ultimately lung destruction [59, 63–70].


Physiological impact of abnormal lipoxin A₄ production on cystic fibrosis airway epithelium and therapeutic potential.

Higgins G, Ringholz F, Buchanan P, McNally P, Urbach V - Biomed Res Int (2015)

In normal airways the airway surface liquid layer (ASL) provides an adequate mucociliary clearance which is maintained by a combination of Cl− secretion through the cystic fibrosis transmembrane conductance regulator (CFTR), Na+ absorption via the epithelial sodium channel (ENaC), and water transport through a paracellular pathway and membrane bound aquaporins (Aq). In CF, a defective CFTR leads to loss of Cl− secretion and Na+ hyperabsorption. The concomitant dehydration of the airway lumen favours bacterial infection and inflammation (mainly neutrophilic). LXA4 mediates an increase in ASL height and restores it to normal levels in CF bronchial epithelium. LXA4 also increase tight junction formation, reestablishing the epithelial barrier function. Taken together this work provides evidence for LXA4 as potentially a new therapy for CF patients.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4383482&req=5

fig2: In normal airways the airway surface liquid layer (ASL) provides an adequate mucociliary clearance which is maintained by a combination of Cl− secretion through the cystic fibrosis transmembrane conductance regulator (CFTR), Na+ absorption via the epithelial sodium channel (ENaC), and water transport through a paracellular pathway and membrane bound aquaporins (Aq). In CF, a defective CFTR leads to loss of Cl− secretion and Na+ hyperabsorption. The concomitant dehydration of the airway lumen favours bacterial infection and inflammation (mainly neutrophilic). LXA4 mediates an increase in ASL height and restores it to normal levels in CF bronchial epithelium. LXA4 also increase tight junction formation, reestablishing the epithelial barrier function. Taken together this work provides evidence for LXA4 as potentially a new therapy for CF patients.
Mentions: The lung must continually defend itself against bacteria that deposit on the airway surfaces during normal tidal breathing. Mucus clearance is a primary form of pulmonary defence and the efficiency of mucociliary clearance in large part depends upon the volume of the airway surface liquid layer (ASL). The ASL allows for mucus containing foreign bodies to be transported away from the lung to the oropharynx where it is either expelled from the body or swallowed and destroyed by the gut. The ASL provides a low viscosity solution allowing free ciliary beat and mucus transport [59]. The normal hydration of the airway surface is maintained (in the highly water permeable airway epithelium) by active ion-transport controlling the quantity of salt (NaCl) delivered to airway surfaces, with water following passively by osmosis [60]. The NaCl concentration of the airway surface liquid is tightly regulated in normal airway epithelia by the epithelial sodium channel (ENaC) mediated Na+ absorption and Cl− secretion. Cl− is secreted by epithelial cells via the apical CFTR Cl− channel and calcium activated Cl− channels, with Cl− entering the cell through the Na+–K+–2Cl− cotransporter located in the basolateral membrane. Regulation of Cl− secretion determines the net transport of ions across the epithelium and hence the mass of salt on the epithelial surfaces. CFTR was also found to regulate ENaC suggesting that CFTR acted both as a Cl− channel and as a regulator of other ion transport processes. In CF, mutations of the CFTR gene result in defective Cl− secretion and Na+ hyperabsorption by airway epithelia [61, 62]. Studies in CF airway epithelium cultures, transgenic mice, and people with CF suggest that the initiating event in CF airway disease is a reduced ASL volume resulting from dehydration. This dehydration leads to reduced mucus clearance, adhesion of mucus to airway surfaces, and chronic bacterial infection of the lung (Figure 2). The chronic bacterial infection leads to an aggravated immune response, bronchial epithelial remodelling, and ultimately lung destruction [59, 63–70].

Bottom Line: In CF, the loss of chloride transport caused by the mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel gene results in dehydration, mucus plugging, and reduction of the airway surface liquid layer (ASL) height which favour chronic lung infection and neutrophil based inflammation leading to progressive lung destruction and early death of people with CF.The report points out novel aspects of the cellular mechanism involved in the physiological response to LXA4, including release of ATP from airway epithelial cell via pannexin channel and subsequent activation of and P2Y11 purinoreceptor.Therefore, inadequate endogenous LXA4 biosynthesis reported in CF exacerbates the ion transport abnormality and defective mucociliary clearance, in addition to impairing the resolution of inflammation, thus amplifying the vicious circle of airway dehydration, chronic infection, and inflammation.

View Article: PubMed Central - PubMed

Affiliation: National Children's Research Centre, Crumlin, Dublin 12, Ireland ; Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.

ABSTRACT
Lipoxin A4 has been described as a major signal for the resolution of inflammation and is abnormally produced in the lungs of patients with cystic fibrosis (CF). In CF, the loss of chloride transport caused by the mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel gene results in dehydration, mucus plugging, and reduction of the airway surface liquid layer (ASL) height which favour chronic lung infection and neutrophil based inflammation leading to progressive lung destruction and early death of people with CF. This review highlights the unique ability of LXA4 to restore airway surface hydration, to stimulate airway epithelial repair, and to antagonise the proinflammatory program of the CF airway, circumventing some of the most difficult aspects of CF pathophysiology. The report points out novel aspects of the cellular mechanism involved in the physiological response to LXA4, including release of ATP from airway epithelial cell via pannexin channel and subsequent activation of and P2Y11 purinoreceptor. Therefore, inadequate endogenous LXA4 biosynthesis reported in CF exacerbates the ion transport abnormality and defective mucociliary clearance, in addition to impairing the resolution of inflammation, thus amplifying the vicious circle of airway dehydration, chronic infection, and inflammation.

Show MeSH
Related in: MedlinePlus