Inhibitory action of Lipoxins on Superoxide production in
Deregulated neutrophilic inflammation and chronic infection lead to progressive
destruction of the airways in cystic fibrosis (CF). In normal tissues, the lipoxins are
endogenous anti-inflammatory lipid mediators that are important regulators of
neutrophilic inflammation . In CF, the generation of lipoxins is impaired
In response to infection or tissue injury, arachidonic acid produces proinflammatory
Leukotriene B4 that leads to neutrophil recruitment and
acute inflammation , , .
Arachidonic acid also produces antiinflammatory lipoxins. Lipoxins mediate switch to
chronic inflammation and promote resolution , , . In CF, inflammatory response remains persistently neutrophilic (acute
inflammation) that leads to tissue injury and further infection. This may be attributed
to a documented defect in the generation of lipoxins , , .
Lipoxins are bioactive eicosanoids derived from arachidonic acid. In contrast to
proinflammatory leukotrienes and prostaglandins, lipoxins (Lipoxin
A4, 15-epi-LXA4 and its stable synthetic
analog 15-epi-p-fluoro-phenoxy-LXA4) display potent
antiinflammatory actions, including attenuation of neutrophil respiratory burst and
transendothelial migration , .
Leukotriene B4 and Lipoxins (Lipoxin
A4, 15-epi-LXA4 and
15-epi-p-fluoro-phenoxy-LXA4) interact with highly specific
and distinct G protein-coupled membrane receptors , , , to evoke opposing leukocyte responses, including Lipoxin
A4 inhibition of Leukotriene B4-initiated
respiratory burst, chemotaxis, adhesion, and transmigration .
Leukotriene B4 binds to the Leukotriene B4 receptor
(LTBR1) which activates both Phospholipase C beta 2
(PLC-beta2) and Phosphatidylinositol 3-kinase
(PI3K reg class IB (p101) and PI3K cat class
IB (p110-gamma)) signaling via G-protein alpha-i
family, G-protein alpha-15 and
G-protein beta/gamma subunits , , , , , , .
PLC-beta2 catalyzes the hydrolysis of
phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to
inositol 1,4,5-trisphosphate (IP3) and diacylglycerol
(DAG). IP3 stimulates
Ca(2+) release from endoplasmic reticulum.
Ca(2+) and DAG, in turn,
activate Protein kinase C alpha (PKC-alpha).
Phosphatidylinositol 3-kinase phosphorylates the membrane lipid
PtdIns(4,5)P2 to phosphatidylinositol 3,4,5-trisphosphate
(PtdIns(3,4,5)P3) , , , , .
PtdIns(3,4,5)P3 recruits and activates diverse cytosolic
effectors, including Phospholipase D1 (PLD1) , 3-phosphoinositide dependent protein kinase-1
(PDPK1) , , Protein kinase C
zeta (PKC-zeta)  and Phosphatidylinositol
3,4,5-trisphosphate-dependent RAC exchanger 1 (PREX1) , . PREX1 is the main guanine
nucleotide exchange factor for the Ras-related C3 botulinum toxin substrate 2
(RAC2) in neutrophils , , .
Interleukin-8 (IL-8) is probably involved in the release
of reactive oxygen species (ROS) by neutrophils. IL-8-induced activation of the
respiratory burst is exclusively mediated by Interleukin 8 receptor alpha
(IL8RA), and does not involve PLC-beta and calcium signaling
, , .
Lipoxin A4, 15-epi-LXA4 and
15-epi-p-fluoro-phenoxy-LXA4 interact with the Formyl
peptide receptor-like 1 (FPRL1) , , ,  that transduces counter-regulatory signals
in part via intracellular polyisoprenyl phosphate remodeling. Presqualene
diphosphate is a polyisoprenyl phosphate in human neutrophils that is
rapidly converted to Presqualene monophosphate upon cell
activation. Phosphatidic acid phosphatase type 2 domain containing 2
(PPAPDC2) is a presqualene diphosphate phosphatase that
converts Presqualene diphosphate to
Presqualene monophosphate . In human,
neutrophils leukotriene-induced LTBR1 signaling initiates a
rapid decrease in Presqualene diphosphate levels, probably
through PPADC2 activation, to promote proinflammatory cell
response, whereas lipoxin-induced FPRL1 signaling
dramatically blocks Presqualene diphosphate turnover to
Presqualene monophosphate, probably through
PPADC2 inhibition, to prevent neutrophil activation , .
Presqualene diphosphate, but not
Presqualene monophosphate, directly inhibits
PI3K cat class IB (p110-gamma) and Phospholipase D1
(PLD1), preventing subsequent NADPH oxidase assembly and
superoxide anion generation , , , , , .
Downstream of Phosphatidylinositol 3-kinase signaling
PDPK1 can phosphorylate and activate
PKC-zeta and PKC-alpha , , , , .
PLD1 hydrolyzes membrane
Phosphatidylcholines to generate Phosphatidic
acid that is a powerful activator of
PKC-zeta, which is, together with
PKC-alpha, involved in phosphorylation of NADPH oxidase
complex subunits , , , , .
The NADPH oxidase is a multicomponent enzyme in which cytosolic regulatory components
(Neutrophil cytosolic factors 1, 2 and 4 (p47-phox,
p67-phox and p40-phox)) must
assembly with membrane-ancored Cytochrome b-558 that is
composed of two transmembrane catalytic subunits, alpha
(p22-phox) and beta
(gp91-phox). The NADPH oxidase catalyzes the NADPH-dependent
one electron reduction of O(2) to form superoxide anion
(O(2)(-), from which other reactive oxygen species,
including hydrogen peroxide, hydroxyl radical, and hypochlorous acid, are derived .
The neutrophil NADPH oxidase assembly is directly regulated by
PKC-zeta, PKC-alpha , , , RAC2 ,  and its effector, p21/Cdc42/Rac1-activated kinase 1
(PAK1) , , .
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