Dexmedetomidine ameliorates acute lung injury following orthotopic autologous liver transplantation in rats probably by inhibiting Toll-like receptor 4–nuclear factor kappa B signaling

Chi, Xinjin; Wei, Xiaoxia; Gao, Wanling; Guan, Jianqiang; Yu, Xiaofan; Wang, Yiheng; Li, Xi; Cai, Jun

doi:10.1186/s12967-015-0554-5

Cited by 44 publications

(29 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In correspondence with previous electronmicroscopic and functional studies (Aoki et al, 1998;Hutchinson et al, 2011), we also found immunopositive staining in reactive astrocytes in the lesioned regions, which was most prominent during the 1 st month after post-TBI. This led us to investigate whether ATI affects the release of inflammatory cytokines, as suggested by previous studies in models of brain, lung, and kidney injury (Chi et al, 2015;Yao et al, 2015;Ren et al, 2016). Moreover, whether the alleviation of inflammation-related odema by ATI could explain some of the enhanced somatomotor recovery.…”

Section: Target Expression and Mechanisms Of Action Of Atimentioning

confidence: 86%

Disease-modifying effect of atipamezole in a model of post-traumatic epilepsy

et al. 2017

View full text Add to dashboard Cite

Treatment of TBI remains a major unmet medical need, with 2.5 million new cases of traumatic brain injury (TBI) each year in Europe and 1.5 million in the USA. This single-center proof-of-concept preclinical study tested the hypothesis that pharmacologic neurostimulation with proconvulsants, either atipamezole, a selective α-adrenoceptor antagonist, or the cannabinoid receptor 1 antagonist SR141716A, as monotherapy would improve functional recovery after TBI. A total of 404 adult Sprague-Dawley male rats were randomized into two groups: sham-injured or lateral fluid-percussion-induced TBI. The rats were treated with atipamezole (started at 30min or 7 d after TBI) or SR141716A (2min or 30min post-TBI) for up to 9 wk. Total follow-up time was 14 wk after treatment initiation. Outcome measures included motor (composite neuroscore, beam-walking) and cognitive performance (Morris water-maze), seizure susceptibility, spontaneous seizures, and cortical and hippocampal pathology. All injured rats exhibited similar impairment in the neuroscore and beam-walking tests at 2 d post-TBI. Atipamezole treatment initiated at either 30min or 7 d post-TBI and continued for 9 wk via subcutaneous osmotic minipumps improved performance in both the neuroscore and beam-walking tests, but not in the Morris water-maze spatial learning and memory test. Atipamezole treatment initiated at 7 d post-TBI also reduced seizure susceptibility in the pentylenetetrazol test 14 wk after treatment initiation, although it did not prevent the development of epilepsy. SR141716A administered as a single dose at 2min post-TBI or initiated at 30min post-TBI and continued for 9 wk had no recovery-enhancing or antiepileptogenic effects. Mechanistic studies to assess the α-adrenoceptor subtype specificity of the disease-modifying effects of atipametzole revealed that genetic ablation of α-noradrenergic receptor function in Adra2A mice carrying an N79P point mutation had antiepileptogenic effects after TBI. On the other hand, blockade of α-adrenoceptors using the receptor subtype-specific antagonist ORM-12741 had no favorable effects on the post-TBI outcome. Finally, to assess whether regulation of the post-injury inflammatory response by atipametzole in glial cells contributed to a favorable outcome, we investigated the effect of atipamezole on spontaneous and/or lipopolysaccharide-stimulated astroglial or microglial cytokine release in vitro. We observed no effect. Our data demonstrate that a 9-wk administration of α2A-noradrenergic antagonist, atipamezole, is recovery-enhancing after TBI.

show abstract

Section: Target Expression and Mechanisms Of Action Of Atimentioning

confidence: 86%

Disease-modifying effect of atipamezole in a model of post-traumatic epilepsy

et al. 2017

View full text Add to dashboard Cite

show abstract

“…In our study, we demonstrated that the limb I/R‐induced remote overexpression of TNF‐α, IL‐1, and IL‐6 in the lungs was attenuated by DEX preadministration. Previous studies demonstrated that DEX lowered mortality, reduced pulmonary inflammation, and inhibited TLR4/MyD88 expression and NF‐κB activation in the lung tissues of septic rats . DEX pretreatment downregulated TLR4 and NF‐κB proteins in the liver and inhibited the release of the pro‐inflammatory cytokines TNF‐α and IL‐1β in the serum .…”

Section: Discussionmentioning

confidence: 96%

Dexmedetomidine protects against lung injury induced by limb ischemia‐reperfusion via the TLR4/MyD88/NF‐κB pathway

Xue

Chen

Tang

et al. 2019

The Kaohsiung J of Med Scie

View full text Add to dashboard Cite

Dexmedetomidine (DEX) can protect the lung from ischemia-reperfusion (I/R) injury, but the underlying mechanisms are not fully understood. The aims of this study were to determine whether DEX attenuates lung injury following lower extremity I/R and to investigate the related toll-like receptor 4 (TLR4) signaling pathway. Twenty-eight SD rats were divided into four groups (n = 7): Sham, I/R, I/R + DEX (25 μg/kg prior to ischemia), and I/R + DEX + Atip (250 μg/kg atipamezole before DEX treatment). Lower extremity I/R was induced by left femoral artery clamping for 3 hours and followed by 2 hours reperfusion. Quantitative alveolar damage and the wet/dry (W/D) ratio were calculated. Interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)α in the bronchoalveolar lavage fluid (BALF) and serum and myeloperoxidase (MPO) in the lung were measured. The TLR4 and MyD88 mRNA expression levels were measured by RT-PCR, nuclear factor (NF)-κB, and phosphorylated NF-κB by western blot, respectively. Quantitative alveolar damage, W/D ratio, MPO, BALF and serum IL-1, IL-6, and TNF-α, and TLR4, MyD88, NF-κB, and p-NF-κB expression significantly increased in the I/R group relative to the Sham group. DEX preconditioning significantly reduced lung edema, and histological injury relative to the I/R group. Serum and BALF IL-1, IL-6, and TNF-α levels, MPO activity and TLR4, MyD88, NF-κB, and p-NF-κB expression were also significantly reduced in the I/R + DEX group compared with the I/R group. Atipamezole partially reversed all the aforementioned effects. DEX preconditioning protects the lungs against lower extremity I/R injury via α2-adrenoceptor-dependent and α2-adrenoceptor-independent mechanisms. It also suppresses the TLR4 pathway and reduces inflammation. K E Y W O R D S acute lung injury, dexmedetomidine, limb ischemia/reperfusion injury, toll-like receptor 4

show abstract

“… Rats in the M group (model group, established OALT model) underwent OALT operation including portal vein (PV) and inferior vena cava (IVC) occlusion for 20 minutes, followed by reperfusion for eight hours. Based on the previous studies 48 49 50 , rats in the D1 group (10 μg/kg of Dex + OALT group) received 10 μg/kg of Dex injected intraperitoneally (i.p.) 30 minutes prior to OALT.…”

Section: Methodsmentioning

confidence: 99%

Dexmedetomidine Inhibits TLR4/NF-κB Activation and Reduces Acute Kidney Injury after Orthotopic Autologous Liver Transplantation in Rats

Yao

Chi

Jin

et al. 2015

Sci Rep

Self Cite

View full text Add to dashboard Cite

Patients who undergo orthotopic liver transplantation often sustain acute kidney injury(AKI). The toll-like receptor 4(TLR4)/Nuclear factor-кB(NF-кB) pathway plays a role in AKI. Dexmedetomidine(Dex) has been shown to attenuate AKI. The current study aimed to determine whether liver transplantation-induced AKI is associated with inflammatory response, and to assess the effects of dexmedetomidine pretreatment on kidneys in rats following orthotopic autologous liver transplantation(OALT). Seventy-seven adult male rats were randomized into 11 groups. Kidney tissue histopathology and levels of blood urea nitrogen(BUN) and serum creatinine(SCr) were evaluated. Levels of TLR4, NF-κB, tumor necrosis factor-α, and interleukin-1β levels were measured in kidney tissues. OALT resulted in significant kidney functional impairment and tissue injury. Pre-treatment with dexmedetomidine decreased BUN and SCr levels and reduced kidney pathological injury, TLR4 expression, translocation of NF-κB, and cytokine production. The effects of dexmedetomidine were reversed by pre-treatment with atipamezole and BRL44408, but not ARC239. These results were confirmed by using α2A-adrenergic receptor siRNA which reversed the protective effect of dexmedetomidine on attenuating NRK-52E cells injury induced by hypoxia reoxygenation. In conclusion, Dexmedetomidine-pretreatment attenuates OALT-induced AKI in rats which may be contributable to its inhibition of TLR4/MyD88/NF-κB pathway activation. The renoprotective effects are related to α2A-adrenergic receptor subtypes.

show abstract

Dexmedetomidine ameliorates acute lung injury following orthotopic autologous liver transplantation in rats probably by inhibiting Toll-like receptor 4–nuclear factor kappa B signaling

Cited by 44 publications

References 34 publications

Disease-modifying effect of atipamezole in a model of post-traumatic epilepsy

Disease-modifying effect of atipamezole in a model of post-traumatic epilepsy

Dexmedetomidine protects against lung injury induced by limb ischemia‐reperfusion via the TLR4/MyD88/NF‐κB pathway

Dexmedetomidine Inhibits TLR4/NF-κB Activation and Reduces Acute Kidney Injury after Orthotopic Autologous Liver Transplantation in Rats

Contact Info

Product

Resources

About