Lipoxin A4 protects rat skin flaps against ischemia-reperfusion injury through inhibiting cell apoptosis and inflammatory response induced by endoplasmic reticulum stress

BACKGROUND: The ischemia-reperfusion (I/R) injury of skin flap is a complex pathophysiological process involving many cells and factors. Although endoplasmic reticulum (ER) stress-induced cell apoptosis and inflammatory response are of immense importance in the skin flap ischemia, the treatment for I/R injury induced by ER stress is barely reported. METHODS: Healthy male Wister rats were randomly divided into three groups: sham-operated group, I/R model group and I/R + LXA4 group. I/R-induced injury in skin flaps with or without pre-treatment of Lipoxin A4 (LXA4, 100 µg/kg) was tested by using HE and TUNEL staining. Related factors associated with oxidative stress, apoptosis, inflammatory response, and ER stress were tested by ELISA, biochemical assay, and western blotting, respectively. RESULTS: Our results showed that LXA4 treatment significantly promotes skin flap survival and attenuates I/R injury by inhibiting oxidative stress, apoptosis, and inflammatory factor release, evidenced by the decreased expression of malondialdehyde (MDA), lactate dehydrogenase (LDH), NF-κBp65, tumor necrosis factor α (TNF-α), ET, active Caspase-3 and Bax and up-regulated superoxide dismutase (SOD), glutathione (GSH) level and Bcl-2 expression. Moreover, LXA4 treatment also reverses the increased expression of GRP78, p-PERK, p-eIF2α, ATF4, and CHOP induced by I/R injury. CONCLUSIONS: In conclusion, we showed that ER stress causes cell apoptosis and inflammatory response, resulting in the skin flaps injury. LXA4 exhibits a protective effect on skin flaps against I/R injury through the inhibition of ER stress.