ERRATA: Berberine protects against lung injury induced by liver transplantation through upregulating PPARγ and suppressing NF-κB-mediated pyroptosis pathway

ABSTRACTPurpose:We builted a orthotopic autologous liver transplantation (OALT) model in rats to evaluate the possible mechanisms of berberine against lung injury.Methods:Forty clean grade Sprague-Dawley rats (male, healthy, 250–280 g) were divided into five groups (n = 8): sham-operated group (group S), orthotopic autologous liver transplantation group (group T), berberine group (group B), peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor GW9662 group (group G), and berberine + GW9662 group (group B+G). In group S, the relevant tissues around the liver were dissociated only. Orthotopic autologous liver transplantation was used in other groups, berberine 200 mg/kg/day was given one week before surgery in group B and group B+G. GW9662 1 mg/kg was intraperitoneally injected in group G and group B+G 4 hours before surgery. Blood samples were obtained for detecting PaO2 and the concentration of serum clam cell protein (CC16), surfactant protein-D (SP-D), interleukin (IL)-1β and IL-18. The immunohistochemical method detects the expression of PPARγ and nuclear factor-kappa B (NF-κB) in lung tissues. The expression of PPARγ, NF-κBand pyroptosis-related proteins were analysed by western blotting.Results:Rats exhibited increased histological lung injury following OALT. Liver transplantation caused upregulated CC16, SP-D, IL-18 and IL-1β levels, reduced PaO2 and the PPARγ expression, upregulated the NF-κB and pyroptosis-related protein expressions. BBR pretreatment greatly alleviates these lung damages induced by OALT. However, administration of GW9662 partially reversed the beneficial effects of BBR on lung injury.Conclusion:Berberine may play protective capacities against lung injury by upregulating PPARγ to downregulate the NF-κB-mediated pyroptosis pathway.

Ghrelin protects against ischemia/reperfusion-induced hepatic injury via inhibiting Caspase-11-mediated noncanonical pyroptosis

Isopropyl 3-(3, 4-dihydroxyphenyl)-2-hydroxypropanoate protects lipopolysaccharide-induced acute lung injury in mice by attenuating pyroptosis

This study aims to investigate the therapeutic effects of the Coptidis Rhizoma-Scutellariae Radix on cytokine storm secondary lung injury(CSSLI) induced by CpG1826 in mice, and to elucidate the potential molecular mechanisms by which its major active components, i.e., coptisine and wogonin, alleviate CSSLI by inhibiting the mitochondrial permeability transition pore(mPTP)/nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3) inflammasome pyroptosis pathway. In vivo, a mouse model of CSSLI was established by CpG1826 induction. Pulmonary edema was assessed by lung wet-to-dry weight ratio(W/D), lung injury was evaluated by hematoxylin-eosin(HE) staining, and ultrastructural changes in lung tissue were observed by transmission electron microscopy(TEM). The levels of interleukin(IL)-1β, high mobility group box 1 protein(HMGB1), IL-18, and IL-1α in bronchoalveolar lavage fluid were measured by enzyme-linked immunosorbent assay(ELISA). The results showed that the decoction of the Coptidis Rhizoma-Scutellariae Radix significantly reduced pulmonary edema, alleviated lung injury, and decreased the concentrations of related cytokines in BALF more effectively than either single herb alone, thereby improving CSSLI. In vitro, a CpG1826-induced CSSLI model was established in mouse alveolar macrophage MH-S cells. Calcein-AM quenching was used to screen for the most effective monomer components from the herb pair in inhibiting mPTP opening. Coptisine(5, 10, 20 μmol·L~(-1)) and wogonin(10, 20, 40 μmol·L~(-1)) markedly inhibited mPTP opening, with optimal effects and a clear dose-dependent pattern. These components suppressed mPTP opening, thereby reducing the release of mitochondrial DNA(mtDNA) and the accumulation of reactive oxygen species(ROS), effectively reversing the CpG1826-induced decrease in mitochondrial membrane potential(MMP). Further studies revealed that both coptisine and wogonin inhibited pyroptosis and downregulated the expression of key proteins in the NLRP3/Caspase-1/gasdermin D(GSDMD) pathway. In conclusion, the Coptidis Rhizoma-Scutellariae Radix improves CpG1826-induced CSSLI in mice, and this effect is associated with the inhibition of the mPTP/NLRP3 pyroptosis pathway, providing scientific evidence for its clinical application and further development.

Duration of Invasive Mechanical Ventilation Post-Liver Transplantation: Does One Size Fit All?

Epidemiological studies have shown that particulate matters with diameter less than 2.5μm (PM2.5) play an important role in inducing and promoting respiratory diseases, but its underlying mechanism remains to be explored. The air-blood barrier, also known as the alveolar-capillary barrier, is the key element of the lung, working as the site of oxygen and carbon dioxide exchange between pulmonary vasculatures. In this study, a mouse PM2.5 exposure model was established, which leads to an induced lung injury and air-blood barrier disruption. Oxidative stress and pyroptosis were observed in this process. After reducing the oxidative stress by N-acetyl-L-cysteine (NAC) treatment, the air-blood barrier function was improved and the effect of PM2.5 was alleviated. The level of pyroptosis and related pathway were also effectively relieved. These results indicate that acute PM2.5 exposure can cause lung injury and the alveolar-capillary barrier disruption by inducing reactive oxygen species (ROS) with the participation of pyroptosis pathway.

Fudosteine attenuates acute lung injury in septic mice by inhibiting pyroptosis via the TXNIP/NLRP3/GSDMD pathway

The stimulator of interferon genes (STING) pathway serves as a crucial nexus in inflammatory responses and cell death. Despite its role in Mitochondria-Endoplasmic Reticulum Contact (MERC), the mechanistic contributions to inflammatory outcomes remain poorly understood. In clinical acute respiratory distress syndrome (ARDS) models of COVID-19 infection and animal models of LPS-induced acute lung injury (ALI), the STING pathway is closely associated with the pyroptosis pathway. The macrophage STING-N-GSDMD-mtDNA positive feedback loop, upon LPS challenge, induces inflammatory responses and pyroptosis. The GSDMD inhibitor disulfiram (DSF) specifically abrogates the N-terminal portion of GSDMD anchored to the mitochondrial membrane. Furthermore, macrophage STING mediates the direct interaction between Drp1 and N-GSDMD on mitochondrial membrane by regulating mitochondrial calcium, linking mitochondrial fission to the induction of inflammatory responses. Targeting STING-mediated mitochondrial homeostasis, both genetically and pharmacologically, may play a protective role in preventing and treating sepsis-induced acute lung injury. Overall, our study posits that STING deficiency mitigates the cooperative interaction between N-GSDMD and Drp1 in mediating mitochondrial permeabilization and rupture following LPS challenge, paving the way for further investigations into inflammation and pyroptosis.Graphical abstractSupplementary InformationThe online version contains supplementary material available at 10.1007/s00018-025-05774-x.

Black ginseng extract alleviates particulate matter-induced airway inflammation by suppressing the ROS/NLRP3/caspase-1 pathway in macrophages.

BackgroundMechanical ventilation of preterm newborns causes lung injury and is associated with poor neurodevelopmental outcomes. However, the mechanistic links between ventilation-induced lung injury (VILI) and brain injury is not well defined. Since circulating extracellular vesicles (EVs) are known to link distant organs by transferring their cargos, we hypothesized that EVs mediate inflammatory brain injury associated with VILI.MethodsNeonatal rats were mechanically ventilated with low (10 mL/kg) or high (25 mL/kg) tidal volume for 1 h on post-natal day 7 followed by recovery for 2 weeks. Exosomes were isolated from the plasma of these rats and adoptively transferred into normal newborn rats. We assessed the effect of mechanical ventilation or exosome transfer on brain inflammation and activation of the pyroptosis pathway by western blot and histology.ResultsInjurious mechanical ventilation induced similar markers of inflammation and pyroptosis, such as increased IL-1β and activated caspase-1/gasdermin D (GSDMD) in both lung and brain, in addition to inducing microglial activation and cell death in the brain. Isolated EVs were enriched for the exosomal markers CD9 and CD81, suggesting enrichment for exosomes. EVs isolated from neonatal rats with VILI had increased caspase-1 but not GSDMD. Adoptive transfer of these EVs led to neuroinflammation with microglial activation and activation of caspase-1 and GSDMD in the brain similar to that observed in neonatal rats that were mechanically ventilated.ConclusionsThese findings suggest that circulating EVs can contribute to the brain injury and poor neurodevelopmental outcomes in preterm infants with VILI through activation of GSDMD.

In patients with acute respiratory distress syndrome, mechanical ventilation often leads to ventilation-induced lung injury (VILI), which is attributed to unphysiological lung strain (UPLS) in respiratory dynamics. Platelet endothelial cell adhesion molecule-1 (PECAM-1), a transmembrane receptor, senses mechanical signals. The Src/STAT3 pathway plays a crucial role in the mechanotransduction network, concurrently triggering pyroptosis related inflammatory responses. We hypothesized that the mechanical stretch caused by UPLS can be sensed by PECAM-1 in the lungs, leading to VILI via the Src/STAT3 and pyroptosis pathway. A VILI model was established in rats through UPLS. The link between lung strain and VILI as well as the change in the activation of PECAM-1, Src/STAT3, and pyroptosis was firstly being explored. Then, the inhibitors of PECAM-1, Src, STAT3 were adopted respectively, the effect on VILI, inflammation, the Src/STAT3 pathway, and pyroptosis was evaluated. In vitro, human umbilical vein endothelial cells (HUVECs) were used to validate the findings in vivo. UPLS activated PECAM-1, Src/STAT3 signaling pathway, inflammation, and pyroptosis in the VILI model with rats, whereas inhibition of PECAM-1 or the Src/STAT3 signaling pathway decreased lung injury, inflammatory responses, and pyroptosis. Inhibition of PECAM-1 also reduced activation of the Src/STAT3 signaling pathway. The mechanism was validated with HUVECs exposed to overload mechanical cyclic stretch. This study suggests that UPLS contributes to VILI by activating the PECAM-1/Src/STAT3 pathway and inducing inflammatory responses as well aspyroptosis.

Objective To study the effects of ischemia-reperfusion in liver transplantation on the pathophysiological changes of the lung and mechanisms of lung injury. Methods We studied 23 patients who received liver transplantation at Fuzhou General Hospital of PLA. We cut a small piece of the right lung for pathological study and for L-1β and TNF-a immunohistochemistry studies at 5 minutes after the beginning of operation (Ta), 5 minutes before the portal vein was opened (Tb) and three hours after the new liver was transplanted (Tc). We also collected peripheral blood to study the concentration of IL-1β and TNF-a in the plasma at the beginning of operation (T1), the portal vein 5 minutes before opening, the portal vein (T2) ten minutes after the opening (T3) , and one hour after the new liver was transplanted (T4), three hours after the new liver was transplanted (T5), and 12 hours after operation (T6). Results The cytokines TNF-a and IL-1β in peripheral blood were not obviously increased in the portal vein before it was opened, but were significantly increased after the portal vein was opened. Comparison of T1 and T2 separately with T3, T4 and T5 showed significant differences (P<0. 01). In light and electron microscopy, the structures of the lung tissues were normal at Ta and did not change significantly at Tb. There were significant abnormalities at Tc. The average positive points of TNF-a and IL-1β expressions in the lung tissues at Tc were significantly higher than Ta and Tb(P<0. 01). Conclusion Ischemia-reperfusion in liver transplantation led to a serious systemic inflammatory syndrome,and acute lung injury. TNF-a and IL-1β were involved in acute lung injury. Key words: Liver transplantation; Ischemia-reperfusion; TNF-a; IL-1β; Lung injury

Alcohol abuse and high-fat diet–induced liver diseases have been the most prevalent chronic liver diseases and the leading reasons for liver transplantation around the world. Cannabidiol (CBD) is a botanical component extracted from marijuana plants without psychoactive impact. In our previous reports, we found that CBD can prevent fatty liver induced by Lieber–DeCarli ethanol diet or non-alcoholic fatty liver disease (NAFLD) induced by high-fat high-cholesterol diet. The current work is a further study on whether CBD can alleviate liver injuries induced by ethanol plus high-fat high-cholesterol diet (EHFD), which is a model simulating heavy alcohol drinkers in a Western diet. A mice liver injury model induced by EHFD for 8 weeks was applied to explore the protective properties of CBD and the underlying mechanisms. We found that CBD prevented liver steatosis and oxidative stress induced by EHFD. CBD treatment inhibited macrophage recruitment and suppressed activation of NFκB–NLRP3–pyroptosis pathway in mice livers. The hepatoprotective property of CBD in the current model might be a result of inhibition of inflammation via alleviating activation of the hepatic NFκB–NLRP3 inflammasome–pyroptosis pathway by CBD.

Objective To investigate the correlation between perioperative fluid therapy and ear-ly pulmonary complications after liver transplantation, and provide a reasonable fluid therapy in the perioperative period of liver transplantation. Methods Sixty-two patients undergoing liver transplan-tation at the First Affiliated Hospital of Guangxi Medial University from July 1996 to December 2005 were enrolled and analyzed retrospectively. Based on early phase prognosis after liver transplantation, the 62 patients were divided into the none-pulmonary complication group and the pulmonary complica-tion group (including pulmonary edema, acute lung injury, pneumonia and acute respiratory distress syndrome). Twenty-three perioperative variables in both groups were analyzed by monofaetorial analysis and logistic multivariate regression analysis to screen out several variables affecting the early pul-monary complications, and the parameters reflecting postoperative recovery were analyzed in these var-iables. Results Using monofactorial analysis for each variable, there were significant differences be-tween the two groups in the following variables: preoperative lung function; the volume of intraopera-tire transfusion (ml/kg) ; the volume of intraoperative bleeding (ml/kg) ; the volume of intraoperative net fluid retention (ml/kg) ; the transfusion volume at the first day after operation (ml/kg) ; fluid bal-ance (≤ - 14 ml/kg) at the first day after operation and fluid balance (≤- 14 ml/kg) at the first and another days of the first 3 days after operation. Analysis of the relationship between multivariate fac-tors and pulmonary complication after liver transplantation by logistic multivariate regression analysis revealed that preoperative lung function, the volume of intraoperative net fluid retention (ml/kg), the transfusion volume at the first day after operation (ml/kg) and fluid balance (≤- 14 ml/kg) at the first and another days of the first 3 days after operation were influential factors. Conclusions It is im-portant to maintain fluid balance during the perioperative period of liver transplantation. If haemody-namics is stable, appropriate negative fluid balance at the first 3 days after operation apparently de-crease the incidence of early pulmonary complications after liver transplantation. These measures were associated with better postoperative recovery. Key words: Liver transplantation; Perioperative care; Water-electrolyte balance

Effect of post-operative goal-directed fluid therapy (GDFT) on organ function after orthotopic liver transplantation: Secondary outcome analysis of the COLT randomised control trial