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2014 ; 20
(17
): 2667-80
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Electrophilic fatty acid species inhibit 5-lipoxygenase and attenuate
sepsis-induced pulmonary inflammation
#MMPMID24206143
Awwad K
; Steinbrink SD
; Frömel T
; Lill N
; Isaak J
; Häfner AK
; Roos J
; Hofmann B
; Heide H
; Geisslinger G
; Steinhilber D
; Freeman BA
; Maier TJ
; Fleming I
Antioxid Redox Signal
2014[Jun]; 20
(17
): 2667-80
PMID24206143
show ga
AIMS: The reaction of nitric oxide and nitrite-derived species with
polyunsaturated fatty acids yields electrophilic fatty acid nitroalkene
derivatives (NO2-FA), which display anti-inflammatory properties. Given that the
5-lipoxygenase (5-LO, ALOX5) possesses critical nucleophilic amino acids, which
are potentially sensitive to electrophilic modifications, we determined the
consequences of NO2-FA on 5-LO activity in vitro and on 5-LO-mediated
inflammation in vivo. RESULTS: Stimulation of human polymorphonuclear leukocytes
(PMNL) with nitro-oleic (NO2-OA) or nitro-linoleic acid (NO2-LA) (but not the
parent lipids) resulted in the concentration-dependent and irreversible
inhibition of 5-LO activity. Similar effects were observed in cell lysates and
using the recombinant human protein, indicating a direct reaction with 5-LO.
NO2-FAs did not affect the activity of the platelet-type 12-LO (ALOX12) or
15-LO-1 (ALOX15) in intact cells or the recombinant protein. The NO2-FA-induced
inhibition of 5-LO was attributed to the alkylation of Cys418, and the exchange
of Cys418 to serine rendered 5-LO insensitive to NO2-FA. In vivo, the systemic
administration of NO2-OA to mice decreased neutrophil and monocyte mobilization
in response to lipopolysaccharide (LPS), attenuated the formation of the 5-LO
product 5-hydroxyeicosatetraenoic acid (5-HETE), and inhibited lung injury. The
administration of NO2-OA to 5-LO knockout mice had no effect on LPS-induced
neutrophil or monocyte mobilization as well as on lung injury. INNOVATION:
Prophylactic administration of NO2-OA to septic mice inhibits inflammation and
promotes its resolution by interfering in 5-LO-mediated inflammatory processes.
CONCLUSION: NO2-FAs directly and irreversibly inhibit 5-LO and attenuate
downstream acute inflammatory responses.
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