Pretreatment with Propofol Reduces Pulmonary Injury in a Pig Model of Intestinal Ischemia-Reperfusion via Suppressing the High-Mobility Group Box 1 Protein (HMGB1)/Toll-Like Receptor 4 (TLR4)/Protein Kinase R (PKR) Signaling Pathway

Abstract

Background Propofol improves rodent pulmonary injury after intestinal ischemia-reperfusion (IIR). However, its effect and underlying mechanisms in large animals remain unclear. Here, we examined whether pretreatment with propofol could relieve lung injury during IIR in pigs, then investigated the underlying mechanism. Material/Methods A porcine model of IIR-induced lung injury was built by clamping the super mesenteric artery for 2 h and loosening the clamp for 4 h. Randomized grouping was used, and pigs were assigned to a sham-operated group, an IIR with saline pretreatment group, and an IIR with propofol pretreatment group. Pulmonary histopathologic changes, permeability, and oxygenation were assessed to evaluate the effect of propofol. We assessed levels of methane dicarboxylic aldehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO), high-mobility group box 1 protein (HMGB1), Toll-like receptor 4 (TLR4), and double-stranded RNA activated protein kinase R (PKR) to investigate the underlying mechanism. Results IIR caused severe lung damage, including morphological changes, high permeability, airway resistance, low static compliance, hypoxemia, and acidemia. Pulmonary and plasma MDA content and MPO activity increased, whereas SOD activity decreased. The HMGB1/TLR4/PKR signaling pathway was activated following IIR. Pretreatment with propofol markedly attenuated lung injury (such as reducing the lung edema and permeability), increased MDA content and MPO activity, and restored SOD activity induced by IIR, accompanied by inhibiting the effect of the HMGB1/TLR4/PKR signaling pathway. Conclusions IIR caused acute lung injury in pigs. Pretreatment with propofol alleviated the lung injury, which was related to its suppression of the HMGB1/TLR4/PKR signaling pathway.

Effects of butyrate on intestinal ischemia-reperfusion injury via the HMGB1-TLR4-MyD88 signaling pathway

“…Moreover, the interplay between HMGB1-TLR4-MyD88 and ischemia-reperfusion signaling pathways has been studied [ 53 , 54 ]. Propofol pretreatment alleviated IRI-induced lung injury in pigs by inhibiting the HMGB1-TLR4-PKR signaling pathway [ 55 ]. Given the interactions among HMGB1, TLR4, and MyD88 identified in previous research, this study analyzed the effects of butyrate intervention on their proteins.…”

Attenuation of intestinal ischemia-reperfusion-injury by anesthetics: a potentially protective effect of anesthetic management in experimental studies

“…Some studies proved mucosal mast cell (IMMC) activation is critical in intestinal IRI by secreting many mediators to induce intestinal epithelial injury and integrity disruption. Propofol preconditioning can suppress IMMC activation, and it can explain why propofol can attenuate Intestinal IRI, restore intestinal epithelial cell integrity, and prevent intestinal IRI-induced lung injury in rodents and even pigs from other perspectives ( Zhao et al, 2014 ; Gan et al, 2015 ; Bian et al, 2021 ; Li et al, 2022a ). The above findings showed propofol may provide a meaningful anesthetic management regimen for preventing intestinal IRI and organ injury following major surgery and is worthy of a further clinical study to examine the clinical significance.…”

Advancements in the study of acute lung injury resulting from intestinal ischemia/reperfusion

“…Researchers have employed various animal species to establish II/R models in order to fulfil the requirements for detecting corresponding indicators. For example, Li et al ( 9 ) utilized C57BL/6J mice, Chen et al ( 10 ) employed Sprague-Dawley rats, Bian et al ( 11 ) utilized pigs, and Anderson et al ( 12 ) utilized horses. Moreover, the timing of sample collection for intestinal tissue ischemia and reperfusion varies.…”

“…Blocking HMGB1 reverses these effects, protecting lung tissue from inflammation ( 6 ). In a porcine II/R model, propofol pretreatment decreased inflammatory factor and oxidative stress-related substance levels in lung tissue, improved II/R-induced hypoxemia and acidemia, reduced airway resistance, and protected lung function by inhibiting the expression of the HMGB1/TLR4/PKR signaling pathway ( 11 ). In the oxygen and glucose deprivation/reoxygenation (OGD/R) model of mouse lung epithelial cells, silencing Nrf2 increased OGD/R-induced upregulation of TLR4 and MyD88, and exacerbated apoptosis and autophagy, revealing the role of the Nrf2/TLR4/MyD88 axis in inflammation-related lung injury ( 25 ).…”