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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: 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.

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

Lipoxin A4 biosynthesis by trans-cellular cooperation in the airways. The neutrophil donates LTA4 intermediate formed by the action of 5 lipoxygenase (5-LO) on arachidonic acid (AA) to the acceptor airway epithelial cell or alveolar macrophage whereby 15 lipoxygenase (15-LO) catalyses LXA4 formation (brown arrows). Airway epithelial cell or alveolar macrophage 15-LO activity catalyses the conversion of AA to 15S-HETE which is donated to the acceptor neutrophil and converted to LXA4 by 5-LO catalysis (blue arrows).
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fig1: Lipoxin A4 biosynthesis by trans-cellular cooperation in the airways. The neutrophil donates LTA4 intermediate formed by the action of 5 lipoxygenase (5-LO) on arachidonic acid (AA) to the acceptor airway epithelial cell or alveolar macrophage whereby 15 lipoxygenase (15-LO) catalyses LXA4 formation (brown arrows). Airway epithelial cell or alveolar macrophage 15-LO activity catalyses the conversion of AA to 15S-HETE which is donated to the acceptor neutrophil and converted to LXA4 by 5-LO catalysis (blue arrows).

Mentions: Two main pathways will result in LXA4 synthesis. One involves lipoxygenation of arachidonic acid by 15-LO in macrophages and epithelial cells. The 5-LO expressed by neutrophils can then utilise the 15(S)-hydroxyeicosatetranoic acid (15S-HETE) released as a substrate to synthesize LXA4 [7] (Figure 1, blue arrows). Alternatively, platelet 12-LO [10] and macrophage or epithelial 15-LO [13, 14] are each able to transform Leukotriene A4, released by neutrophils, into LXA4 (Figure 1, brown arrows). The activity of 15-LO promotes LXA4 biosynthesis and blocks leukotriene biosynthesis, both as a result of 15-LO products competing for flux at the 5-LO level and by diversion of the intermediate Leukotriene A4 away from LTB4 towards LXA4 biosynthesis [1, 11, 15].


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)

Lipoxin A4 biosynthesis by trans-cellular cooperation in the airways. The neutrophil donates LTA4 intermediate formed by the action of 5 lipoxygenase (5-LO) on arachidonic acid (AA) to the acceptor airway epithelial cell or alveolar macrophage whereby 15 lipoxygenase (15-LO) catalyses LXA4 formation (brown arrows). Airway epithelial cell or alveolar macrophage 15-LO activity catalyses the conversion of AA to 15S-HETE which is donated to the acceptor neutrophil and converted to LXA4 by 5-LO catalysis (blue arrows).
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Lipoxin A4 biosynthesis by trans-cellular cooperation in the airways. The neutrophil donates LTA4 intermediate formed by the action of 5 lipoxygenase (5-LO) on arachidonic acid (AA) to the acceptor airway epithelial cell or alveolar macrophage whereby 15 lipoxygenase (15-LO) catalyses LXA4 formation (brown arrows). Airway epithelial cell or alveolar macrophage 15-LO activity catalyses the conversion of AA to 15S-HETE which is donated to the acceptor neutrophil and converted to LXA4 by 5-LO catalysis (blue arrows).
Mentions: Two main pathways will result in LXA4 synthesis. One involves lipoxygenation of arachidonic acid by 15-LO in macrophages and epithelial cells. The 5-LO expressed by neutrophils can then utilise the 15(S)-hydroxyeicosatetranoic acid (15S-HETE) released as a substrate to synthesize LXA4 [7] (Figure 1, blue arrows). Alternatively, platelet 12-LO [10] and macrophage or epithelial 15-LO [13, 14] are each able to transform Leukotriene A4, released by neutrophils, into LXA4 (Figure 1, brown arrows). The activity of 15-LO promotes LXA4 biosynthesis and blocks leukotriene biosynthesis, both as a result of 15-LO products competing for flux at the 5-LO level and by diversion of the intermediate Leukotriene A4 away from LTB4 towards LXA4 biosynthesis [1, 11, 15].

Bottom Line: 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.

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