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Abstract
The aim of the present study was to investigate whether TIPE2 participates in the protective actions of dexmedetomidine (DEX) in a mouse model of sepsis-induced acute lung injury (ALI). We administered TIPE2 adeno-associated virus (AAV-TIPE2) intratracheally into the lungs of mice. Control mice were infected with an adeno-associated virus expressing no transgene. Three weeks later, an animal model of caecal ligation-perforation (CLP)-induced sepsis was established. DEX was administered intravenously 30 min after CLP. Twenty-four hours after sepsis, lung injury was assayed by lung histology, the ratio of polymorphonuclear leukocytes (PMNs) to total cells in the bronchoalveolar lavage fluid (BALF), myeloperoxidase (MPO) activity, BALF protein content and the lung wet-to-dry (W/D) weight ratio. Proinflammatory factor levels in the BALF of mice were measured. The protein expression levels in lung tissues were analysed by Western blotting. The results showed that DEX treatment markedly mitigated sepsis-induced lung injury, which was characterized by the deterioration of histopathology, histologic scores, the W/D weight ratio and total protein levels in the BALF. Moreover, DEX markedly attenuated sepsis-induced lung inflammation, as evidenced by the decrease in the number of PMNs in the BALF, lung MPO activity and proinflammatory cytokines in the BALF. In addition, DEX dramatically prevented sepsis-induced pulmonary cell apoptosis in mice, as reflected by decreases in the number of TUNEL-positive cells, the protein expression of cleaved caspase-9 and cleaved caspase 3 and the Bax/Bcl-2 ratio. In addition, evaluation of protein expression showed that DEX blocked sepsis-activated JNK phosphorylation and NF-κB p65 nuclear translocation. Similar results were also observed in the TIPE2 overexpression group. Our study demonstrated that DEX inhibits acute inflammation and apoptosis in a murine model of sepsis-stimulated ALI via the upregulation of TIPE2 and the suppression of the activation of the NF-κB and JNK signalling pathways.
Highlights
Sepsis is a systemic inflammation condition triggered by severe infection and trauma [1]
We investigated the effects of DEX and TIPE2 overexpression on acute lung injury (ALI) mortality
TIPE2-deficient cells are hyper-responsive to the activation of toll-like receptor (TLR) and T cell receptor (TCR) signals [18]; in addition, TIPE2-knockout mice, unlike normal WT mice, have been found to exhibit septic shock responses [26]
Summary
Sepsis is a systemic inflammation condition triggered by severe infection and trauma [1]. Respiratory dysfunction, such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), is one of the most common and severe complications of sepsis [2]. ALI is characterized by increased permeability of the alveolar-capillary barrier, interstitial edema, neutrophil recruitment and inflammatory stress-induced cell apoptosis [3, 4]. The pathophysiological mechanisms of sepsis-induced ALI involve cell inflammation, cytokine production and abnormal apoptosis [5, 6]. Known as programmed cell death, is essential for the selective elimination of cells. The dysregulation of apoptosis pathways has been shown to contribute to epithelial and endothelial injury, which is characteristic of ALI [7]. Apoptosis might play a vital role in regulating pro- and antiinflammatory processes [8], and the apoptotic process is regulated by several intracellular signalling pathways, including the JNK pathway [9, 10]
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