Merz Tamara, Wepler Martin, Nußbaum Benedikt, Vogt Josef, Calzia Enrico, Wang Rui, Szabo Csaba, Radermacher Peter, McCook Oscar
Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinikum Ulm, Helmholtzstrasse 8-1, 89081, Ulm, Germany.
Klinik für Anästhesiologie, Universitätsklinikum Ulm, Ulm, Germany.
Intensive Care Med Exp. 2018 Oct 20;6(1):43. doi: 10.1186/s40635-018-0208-z.
Sepsis is associated with disturbed glucose metabolism and reduced mitochondrial activity and biogenesis, ultimately leading to multiple organ dysfunction, e.g., acute kidney injury (AKI). Cystathionine-γ-lyase (CSE), the major cardiovascular source of endogenous HS release, is implicated in the regulation of glucose metabolism and mitochondrial activity through a PGC1α-dependent mechanism, and critical for kidney function. Atherosclerosis is associated with mitochondrial dysfunction and reduced CSE expression. Thus, the aim of this post hoc study was to test the hypothesis whether there is an interplay between CSE expression and kidney dysfunction, mitochondrial activity, and oxidative/nitrosative stress in porcine septic AKI with underlying coronary artery disease.
This study is a post hoc analysis of material from anesthetized and instrumented swine with a high fat diet-induced hypercholesterolemia and atherosclerosis undergoing faecal peritonitis-induced septic shock or sham procedure and intensive care (comprising fluid resuscitation and continuous i.v. noradrenaline (NoA) infusion) for 24 h. Glucose metabolism was quantified from blood C-glucose and expiratory CO/CO isotope enrichment during C-glucose infusion. Mitochondrial activity was determined by high-resolution respirometry. CSE and PGC1α expression, as well as nitrotyrosine formation and albumin extravasation, were quantified by immunohistochemistry of formalin-fixed kidney paraffin sections.
Sepsis was associated with lactic acidosis (p = 0.004) and AKI (50% fall of creatinine clearance (CrCl), p = 0.019). While both whole-body glucose production (p = 0.004) and oxidation (p = 0.006) were increased, kidney tissue mitochondrial respiration was reduced (p = 0.028), coinciding with decreased CSE (p = 0.003) and PGC1α (p = 0.003) expression. Albumin extravasation (p = 0.011) and nitrotyrosine formation (p = 0.008) were increased in septic kidneys.
Sepsis-induced AKI is associated with disturbed mitochondrial respiration and biogenesis, which may be aggravated by oxidative and nitrosative stress. Our results confirm previous data in murine septic shock and porcine hemorrhage and resuscitation on the crucial role of CSE for barrier integrity and kidney function.
脓毒症与葡萄糖代谢紊乱、线粒体活性及生物合成减少有关，最终导致多器官功能障碍，如急性肾损伤（AKI）。胱硫醚-γ-裂解酶（CSE）是内源性硫化氢释放的主要心血管来源，通过一种依赖过氧化物酶体增殖物激活受体γ辅激活因子1α（PGC1α）的机制参与葡萄糖代谢和线粒体活性的调节，对肾功能至关重要。动脉粥样硬化与线粒体功能障碍和CSE表达降低有关。因此，本事后分析研究的目的是检验在伴有潜在冠状动脉疾病的猪脓毒症性AKI中，CSE表达与肾功能障碍、线粒体活性以及氧化/亚硝化应激之间是否存在相互作用这一假设。
本研究是对麻醉并安装监测仪器的猪的材料进行的事后分析，这些猪因高脂饮食诱导高胆固醇血症和动脉粥样硬化，接受粪便性腹膜炎诱导的脓毒症休克或假手术及重症监护（包括液体复苏和持续静脉输注去甲肾上腺素（NoA））24小时。在输注C-葡萄糖期间，通过血液C-葡萄糖和呼出的CO/CO同位素富集来定量葡萄糖代谢。通过高分辨率呼吸测定法测定线粒体活性。通过对福尔马林固定的肾脏石蜡切片进行免疫组织化学分析，定量CSE和PGC1α的表达，以及硝基酪氨酸的形成和白蛋白外渗情况。
脓毒症与乳酸酸中毒（p = 0.004）和AKI（肌酐清除率（CrCl）下降50%，p = 0.019）有关。虽然全身葡萄糖生成（p = 0.004）和氧化（p = 0.006）均增加，但肾脏组织线粒体呼吸减少（p = 0.028），同时CSE（p = 0.003）和PGC1α（p = 0.003）表达降低。脓毒症肾脏中白蛋白外渗（p = 0.011）和硝基酪氨酸形成（p = 0.008）增加。
脓毒症诱导的AKI与线粒体呼吸和生物合成紊乱有关，氧化和亚硝化应激可能会加重这种情况。我们的结果证实了先前在小鼠脓毒症休克以及猪出血和复苏研究中的数据，即CSE对屏障完整性和肾功能起关键作用。
