RAGE deficiency attenuates the protective effect of Lidocaine against sepsis-induced acute lung injury
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ORIGINAL ARTICLE
RAGE deficiency attenuates the protective effect of Lidocaine against sepsis-induced acute lung injury Zhuo Zhang,1 Jie Zhou,2 Changli Liao,3 Xiaobing Li,1 Minghua Liu,1 Daqiang Song,1 and Xian Jiang3,4
Abstract—Lidocaine (Lido) is reported to suppress inflammatory responses and exhibit a therapeutic effect in models of cecal ligation and puncture (CLP)-induced acute lung injury (ALI). The receptor for advanced glycation end product (RAGE) exerts pro-inflammatory effects by enhancing proinflammatory cytokine production. However, the precise mechanism by which Lido confers protection against ALI is not clear. ALI was induced in RAGE WT and RAGE knockout (KO) rats using cecal ligation and puncture (CLP) operations for 24 h. The results showed that Lido significantly inhibited CLP-induced lung inflammation and histopathological lung injury. Furthermore, Lido significantly reduced CLP-induced upregulation of HMGB1 and RAGE expression and activation of the NF-κB and MAPK signaling pathways. With the use of RAGE KO rats, we demonstrate here that RAGE deficiency attenuates the protective effect of Lido against CLP-induced lung inflammatory cell infiltration and histopathological lung injury. These results suggest that RAGE deficiency attenuates the protective effect of Lido against CLP-induced ALI by attenuating the pro-inflammatory cytokines production. KEY WORDS: Lidocaine; CLP; HMGB1; RAGE; ALI.
INTRODUCTION Acute lung injury (ALI) is a clinical problem induced by acute and excessive pulmonary inflammation and continues to cause high rates of morbidity and mortality despite modern clinical practices in critical care medicine [1, 2]. Therefore, there is an urgent need to develop effective treatment for ALI. Multiple studies
1
Department of Pharmacology, Pharmacy College of Southwest Medical University, Luzhou, Sichuan, China 2 Department of Traditional Chinese Pharmacology, Pharmacy College of Southwest Medical University, Luzhou, Sichuan, China 3 Department of Anesthesiology, the First Affiliated Hospital of Southwest Medical University, No.319 Zhongshan Road, Luzhou, Sichuan, China 4 To whom correspondence should be addressed at Department of Anesthesiology, the First Affiliated Hospital of Sichuan Medical University, No.319 Zhongshan Road, Luzhou, Sichuan, China. E-mail: [email protected]
have found that lidocaine (Lido) confers tissue protection in animal models of ALI, including hyperoxic lung injury and sepsis-induced lung injury, and breast milk-induced lung injury [3–5]. Lido administration induces alterations in local production of cytokines, including reduced production of tumor necrosis factor (TNF)-α, IL-1β, and IL-6, increased production of IL10, and reduced histopathological lung injury [4]. The anti-inflammatory effects of Lido involve the modulation of several signaling pathways, including the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways [4, 6]. However, the precise mechanism by which Lido confers protection against ALI is not clear. T
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