Hepatic Estrogen Sulfotransferase Distantly Sensitizes Mice to Hemorrhagic Shock-Induced Acute Lung Injury.

Hemorrhagic shock (HS) is a potential life-threatening condition that may lead to injury to multiple organs, including the lung. The estrogen sulfotransferase (EST, or SULT1E1) is a conjugating enzyme that sulfonates and deactivates estrogens. In this report, we showed that the expression of Est was markedly induced in the liver but not in the lung of female mice subject to HS and resuscitation. Genetic ablation or pharmacological inhibition of Est effectively protected female mice from HS-induced acute lung injury (ALI), including interstitial edema, neutrophil mobilization and infiltration, and inflammation. The pulmonoprotective effect of Est ablation or inhibition was sex-specific, because the HS-induced ALI was not affected in male Est-/- mice. Mechanistically, the pulmonoprotective phenotype in female Est-/- mice was accompanied by increased lung and circulating levels of estrogens, attenuated pulmonary inflammation, and inhibition of neutrophil mobilization from the bone marrow and neutrophil infiltration to the lung, whereas the pulmonoprotective effect was abolished upon ovariectomy, suggesting that the protection was estrogen dependent. The pulmonoprotective effect of Est ablation was also tissue specific, as loss of Est had little effect on HS-induced liver injury. Moreover, transgenic reconstitution of human EST in the liver of global Est-/- mice abolished the pulmonoprotective effect, suggesting that it is the EST in the liver that sensitizes mice to HS-induced ALI. Taken together, our results revealed a sex- and tissue-specific role of EST in HS-induced ALI. Pharmacological inhibition of EST may represent an effective approach to manage HS-induced ALI.

Activation of Pregnane X Receptor Sensitizes Mice to Hemorrhagic Shock-Induced Liver Injury.

Hemorrhagic shock (HS) is a life-threatening condition associated with tissue hypoperfusion and often leads to injury of multiple organs including the liver. Pregnane X receptor (PXR) is a species-specific xenobiotic receptor that regulates the expression of drug-metabolizing enzymes (DMEs) such as the cytochrome P450 (CYP) 3A. Many clinical drugs, including those often prescribed to trauma patients, are known to activate PXR and induce CYP3A. The goal of this study is to determine whether PXR plays a role in the regulation of DMEs in the setting of HS and whether activation of PXR is beneficial or detrimental to HS-induced hepatic injury. PXR transgenic, knockout, and humanized mice were subject to HS, and the liver injury was assessed histologically and biochemically. The expression and/or activity of PXR and CYP3A were manipulated genetically or pharmacologically in order to determine their effects on HS-induced liver injury. Our results showed that genetic or pharmacological activation of PXR sensitized wild-type and hPXR/CYP3A4 humanized mice to HS-induced hepatic injury, whereas knockout of PXR protected mice from HS-induced liver injury. Mechanistically, the sensitizing effect of PXR activation was accounted for by PXR-responsive induction of CYP3A and increased oxidative stress in the liver. The sensitizing effect of PXR was attenuated by ablation or pharmacological inhibition of CYP3A, treatment with the antioxidant N-acetylcysteine amide, or treatment with a PXR antagonist. Conclusion: We have uncovered a function of PXR in HS-induced hepatic injury. Our results suggest that the unavoidable use of PXR-activating drugs in trauma patients has the potential to exacerbate HS-induced hepatic injury, which can be mitigated by the coadministration of antioxidative agents, CYP3A inhibitors, or PXR antagonists.

Development and evaluation of a training model for paracentetic suprapubic cystostomy and catheterization.

OBJECTIVES: Minimally invasive paracentetic suprapubic cystostomy is a technique that should be learned by all surgical trainees and residents. This study aimed to develop a self-made training model for paracentetic suprapubic cystostomy and placement of the suprapubic catheter and then to evaluate its effectiveness in training fourth-year medical students. METHODS: Medical students were divided into an experimental group receiving comprehensive training involving literature, video, and model use and a control group receiving all the same training protocols as the experimental group except without hands-on practice using the model. Each student's performance was video-recorded, followed by subjective and objective evaluations by urology experts and statistical analysis. RESULTS: All students completed the surgical procedures successfully. The experimental group's performance scores were significantly higher than those of the control group (median final performance scores of 91.0 vs. 86.8, respectively). Excellent scores were achieved by more students in the experimental group than in the control group (55% vs. 20%), and fewer poor scores were observed in the experimental group than in the control group (5% vs. 30%). CONCLUSIONS: Based on its cost-effectiveness, reusability, and training effectiveness, this paracentetic suprapubic cystostomy training model is able to achieve goals in teaching practice quickly and easily. Use of the model should be encouraged for training senior medical students and resident physicians who may be expected to perform emergent suprapubic catheter insertion at some time.

Development and evaluation of a training model for paracentetic suprapubic cystostomy and catheterization

OBJECTIVES: Minimally invasive paracentetic suprapubic cystostomy is a technique that should be learned by all surgical trainees and residents. This study aimed to develop a self-made training model for paracentetic suprapubic cystostomy and placement of the suprapubic catheter and then to evaluate its effectiveness in training fourth-year medical students. METHODS: Medical students were divided into an experimental group receiving comprehensive training involving literature, video, and model use and a control group receiving all the same training protocols as the experimental group except without hands-on practice using the model. Each student's performance was video-recorded, followed by subjective and objective evaluations by urology experts and statistical analysis. RESULTS: All students completed the surgical procedures successfully. The experimental group's performance scores were significantly higher than those of the control group (median final performance scores of 91.0 vs. 86.8, respectively). Excellent scores were achieved by more students in the experimental group than in the control group (55% vs. 20%), and fewer poor scores were observed in the experimental group than in the control group (5% vs. 30%). CONCLUSIONS: Based on its cost-effectiveness, reusability, and training effectiveness, this paracentetic suprapubic cystostomy training model is able to achieve goals in teaching practice quickly and easily. Use of the model should be encouraged for training senior medical students and resident physicians who may be expected to perform emergent suprapubic catheter insertion at some time.

Redox-dependent regulation of hepatocyte absent in melanoma 2 inflammasome activation in sterile liver injury in mice.

Sterile liver inflammation, such as liver ischemia-reperfusion, hemorrhagic shock after trauma, and drug-induced liver injury, is initiated and regulated by endogenous mediators including DNA and reactive oxygen species. Here, we identify a mechanism for redox-mediated regulation of absent in melanoma 2 (AIM2) inflammasome activation in hepatocytes after redox stress in mice, which occurs through interaction with cytosolic high mobility group box 1 (HMGB1). We show that in liver during hemorrhagic shock in mice and in hepatocytes after hypoxia with reoxygenation, cytosolic HMGB1 associates with AIM2 and is required for activation of caspase-1 in response to cytosolic DNA. Activation of caspase-1 through AIM2 leads to subsequent hepatoprotective responses such as autophagy. HMGB1 binds to AIM2 at a non-DNA-binding site on the hematopoietic interferon-inducible nuclear antigen domain of AIM2 to facilitate inflammasome and caspase-1 activation in hepatocytes. Furthermore, binding of HMGB1 to AIM2 is stronger with fully reduced all-thiol HMGB1 than with partially oxidized disulfide-HMGB1, and binding strength corresponds to caspase-1 activation. These data suggest that HMGB1 redox status regulates AIM2 inflammasome activation. CONCLUSION: These findings suggest a novel and important mechanism for regulation of AIM2 inflammasome activation in hepatocytes during redox stress and may suggest broader implications for how this and other inflammasomes are activated and how their activation is regulated during cell stress, as well as the mechanisms of inflammasome regulation in nonimmune cell types. (Hepatology 2017;65:253-268).