Role of IRE1α/XBP1 signaling pathway in endoplasmic reticulum in endotoxin-induced acute lung injury in mice: relationship with NLRP3 inflammasomes / 中华麻醉学杂志

ABSTRACT

Objective:To evaluate the role of inositol-requiring kinase 1α-X-box binding protein 1 (IRE1α/XBP1) signaling pathway in endoplasmic reticulumin in endotoxin-induced acute lung injury (ALI) in mice and the relationship with NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasomes.Methods:Thirty-six SPF-grade healthy male C57BL/6 mice, aged 6-8 weeks, weighing 25-30 g, were divided into 3 groups ( n=12 each) according to the random number table method: control group (group C), endotoxin-induced ALI group (group ALI) and endotoxin-induced ALI+ STF-083010 group (group ST). The ALI model was established by inhaling nebulized lipopolysaccharide (LPS) 3 mg/ml for 30 min in ALI and ST groups, while the equal volume of nebulized normal saline was given in group C. IRE1α/XBP1 signaling pathway inhibitor STF-083010 50 mg/kg was intraperitoneally injected at 1 h before inhaling LPS in group ST, while the remaining two groups received the equal volume of normal saline intraperitoneally. Mice were sacrificed at 24 h after inhaling nebulized LPS or normal saline, bronchoalveolar lavage fluid (BALF) were collected and lung tissues were removed for microscopic examination of the pathological changes (by HE staining) which were scored and for determination of wet/dry lung weight ratio (W/D ratio), concentrations of interleukin-1beta (IL-lβ) and IL-18 in BALF (by enzyme-linked immunosorbent assay) and expression of phosphorylated IRE1α (p-IRE1α), XBP1s, NLRP3, ASC and caspase-1 in lung tissues (by Western blot). Results:Compared with group C, the W/D ratio, lung injury score and concentrations of IL-1β and IL-18 in BALF were significantly increased, and the expression of p-IRE1α, XBP1s, NLRP3, ASC and caspase-1 in lung tissues was up-regulated in group ALI and group ST ( P<0.001). Compared with group ALI, the W/D ratio, lung injury score and concentrations of IL-1β and IL-18 in BALF were significantly decreased, and the expression of p-IRE1α, XBP1s, NLRP3, ASC and caspase-1 protein in lung tissues was down-regulated in group ST ( P<0.001). Conclusions:IRE1α/XBP1 signaling pathway is involved in LPS-induced ALI in mice, and the mechanism is related to activation of NLRP3 inflammasomes.