Protective Effect of Dexmedetomidine on Acute Lung Injury via the Upregulation of Tumour Necrosis Factor-α-Induced Protein-8-like 2 in Septic Mice

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.KEY WORDS: acute lung injury; TIPE2; dexmedetomidine; apoptosis; inflammation.Qian Kong and Xiaojing Wu contributed equally to this work.

Analgesic effect of dexmedetomidine in rats after chronic constriction injury by mediating microRNA‐101 expression and the E2F2–TLR4–NF‐κB axis

“…The overexpression of spinal cord pro‐apoptotic genes has been established in the early stage of the development of NPP, as evidenced by a marked increase in caspase‐9 expression in the dorsal horn spinal cord and TUNEL‐positive cells 3 days after CCI induction of sciatic nerve (Siniscalco et al., 2007). Similarly, Dex prevented pulmonary cell apoptosis in mice and spinal cord cells, as reflected by declines in the number of TUNEL‐positive cells and the protein expression of cleaved caspase‐9 (Kong et al., 2020; Zhao et al., 2019). NPP is initiated by nerve injury and characterized by elevated activity in the peripheral and central nervous system, in which various inflammatory cytokines and other biomolecules induce different pathways that participate in the development and/or maintenance of pain (Mai, Zhu, Huang, He, & Fan, 2020).…”

Dexmedetomidine at a dose of 1 µM attenuates H9c2 cardiomyocyte injury under 3 h of hypoxia exposure and 3 h of reoxygenation through the inhibition of endoplasmic reticulum stress

“…Furthermore, in a notable review in 2019, Davidson et al (18) opined that multitargeted strategies are necessary to reduce MIRI, because any single approach has a limited capacity to overcome the complex state of MIRI. The highly selective α 2 adrenergic receptor agonist dexmedetomidine (DEX) is frequently used clinically, especially to provide protection to the heart and other organs during surgery (19)(20)(21)(22). Currently, most of the functions of DEX appear to be associated with its anti-inflammatory activity and ability to inhibit IRI.…”

“…The highly selective α 2 adrenergic receptor agonist dexmedetomidine (DEX) is frequently used clinically, especially to provide protection to the heart and other organs during surgery ( 19-22 ). Currently, most of the functions of DEX appear to be associated with its anti-inflammatory activity and ability to inhibit IRI.…”

<p>Dexmedetomidine Attenuates Cellular Injury and Apoptosis in H9c2 Cardiomyocytes by Regulating p-38MAPK and Endoplasmic Reticulum Stress</p>

“…DEX, a highly selective α 2 adrenergic receptor agonist, is frequently used in clinical practice, especially to protect the heart and other organs during surgery. [11][12][13][14] At this point, the most likely function of DEX in this application could be related to the anti-inflammatory response and inhibition of ischaemia-reperfusion injury. Regarding ERS, the effects of DEX on ERS and subsequent apoptosis have not been thoroughly illustrated.…”