Lipoxin A4 Preconditioning Attenuates Intestinal Ischemia Reperfusion Injury through Keap1/Nrf2 Pathway in a Lipoxin A4 Receptor Independent Manner

Abstract

Oxidative stress plays a critical role in the pathogenesis of intestinal ischemia reperfusion (IIR) injury. Enhancement in endogenous Lipoxin A4 (LXA4), a potent antioxidant and mediator, is associated with attenuation of IIR. However, the effects of LXA4 on IIR injury and the potential mechanisms are unknown. In a rat IIR (ischemia 45 minutes and subsequent reperfusion 6 hours) model, IIR caused intestinal injury, evidenced by increased serum diamine oxidase, D-lactic acid, intestinal-type fatty acid-binding protein, and the oxidative stress marker 15-F2t-Isoprostane. LXA4 treatment significantly attenuated IIR injury by reducing mucosal 15-F2t-Isoprostane and elevating endogenous antioxidant superoxide dismutase activity, accompanied with Keap1/Nrf2 pathway activation. Meanwhile, LXA4 receptor antagonist Boc-2 reversed the protective effects of LXA4 on intestinal injury but failed to affect the oxidative stress and the related Nrf2 pathway. Furthermore, Nrf2 antagonist brusatol reversed the antioxidant effects conferred by LXA4 and led to exacerbation of intestinal epithelium cells oxidative stress and apoptosis, finally resulting in a decrease of survival rate of rat. Meanwhile, LXA4 pretreatment upregulated nuclear Nrf2 level and reduced hypoxia/reoxygenation-induced IEC-6 cell damage and Nrf2 siRNA reversed this protective effect of LXA4 in vitro. In conclusion, these findings suggest that LXA4 ameliorates IIR injury by activating Keap1/Nrf2 pathway in a LXA4 receptor independent manner.

Lipoxin A4 inhibits UV radiation-induced skin inflammation and oxidative stress in mice

“…LXA 4 induced GSH release and Nrf2 expression by cortical astrocytes exposed to oxygen-glucose deprivation/reperfusion insults in cell culture [17]. LXA 4 activates ERK/Nrf2 signaling pathway in experimental models such as intestinal ischemia reperfusion injury in rats [13], cerebral ischaemia/reperfusion injury in rats [15], and hypoxia/reoxygenation injury of cardiomyocytes [16]. Additionally, LXA 4 methyl ester ameliorates cognitive deficits induced by chronic cerebral hypoperfusion through enhancing Nrf2 and Nqo1 [14].…”

“…Lipoxin A 4 (LXA 4 ) is an anti-inflammatory and pro-resolution lipid mediator derived from arachidonic acid metabolism by lipoxygenases 5 and 12. LXA 4 reduces inflammation by inhibiting inflammatory cell recruitment [6][7][8], cytokine production [8][9][10][11], NADPH oxidase function [12], and inducing the expression of Nrf2 [13][14][15][16][17]. Pro-resolution-inducing agents can induce remission and restore normal physiological function of the target tissues [18].…”

“…Pro-resolution-inducing agents can induce remission and restore normal physiological function of the target tissues [18]. LXA 4 limits inflammation and induces resolution in varied models of disease such as inflammatory bowel disease [18], rheumatoid arthritis [19], Alzheimer's disease [20], asthma [21,22], ischemia [13,23] and atherosclerosis [24]. Furthermore, up-regulation of LXA 4 promotes the resolution of phorbol myristate acetate (PMA)induced acute skin inflammation [25].…”

“…Although LXA 4 is known to have anti-inflammatory and to reduce oxidative stress [6][7][8][13][14][15][16][17]19], whether it can protect the skin against UV-induced damage has not been reported. Thus, the effects of LXA 4 on UV-induced skin inflammation and oxidative stress in hairless mice were investigated in this study.…”

İntestinal İskemi/Reperfüzyon Modelinde Tiroid Hormon Ön Koşullanmasının İnce Bağırsak Ve Akciğer Hasarı Üzerine Etkisi

“…Artan oksidan hasar intestinal mukozada hasara, mikrovasküler dolaşım bozukluğu, mukozal ve vasküler permeabilite artışı ile sistemik sepsis ve çoklu organ yetmezliği ile sonuçlanmaktadır. Bu durum yoğun bakım koşullarında yüksek mortaliteye neden olmakta ve etkili ve koruyucu bir tedavi yöntemi de yoktur (20).…”