The Effect of glucocorticoids and mineralocorticoids in a Sedated and Ventilated Model of Canine Sepsis

肾上腺是内分泌腺，在危重疾病时会同时产生糖皮质激素和盐皮质激素。主要的糖皮质激素是皮质醇，而主要的盐皮质激素是醛固酮。皮质醇具有重要的心血管、代谢、免疫和止血功能。相比之下，醛固酮对盐和水的调节很重要，因此对维持血管内容量和血压至关重要。急性肾上腺功能不全是指肾上腺不能对生理应激做出适当反应，如感染。急性肾上腺功能不全的临床表现是由于盐皮质激素活性不足，而不是糖皮质激素活性不足。 因此，患有急性肾上腺功能不全的危重患者可能会出现低血压和严重脱水。因此，有人推测盐皮质激素缺乏可能导致感染性休克的发展和严重程度。虽然许多研究人员已经研究了糖皮质激素活性在感染性休克中的重要性，但盐皮质激素活性和醛固酮在感染性休克中的重要性仍不清楚。 肾上腺产生醛固酮，通过对阿米洛利敏感的上皮钠通道(ENaC)的活动，导致肾脏对钠的重吸收增加。钠的重吸收增加会导致血管内容量的扩大和血压的升高。阿米洛利是一种节省钾的利尿剂，它可以阻断ENaC，从而抑制钠在肾远端曲管、连接小管和集合管中的重吸收。氢氯噻嗪(HCT)是一种著名的利尿剂，将与阿米洛利联合使用，以确保对ENAC功能产生最大效果。ENAC在许多器官的顶端质膜上表达，包括肾脏、肺、膀胱、远端结肠、汗腺和唾液管。1出于本方案的目的，我们将集中讨论ENaC在肾脏和肺中的重要性。 利用败血症休克的犬模型，我们实验室先前进行的实验表明，通过醛固酮的盐皮质激素活性可能在感染性休克的病理生理学中起重要作用。我们证明，在脓毒症发作前72小时给予醋酸脱氧皮质酮(DOCA)，这是一种具有类似于醛固酮的生理效应的选择性矿物皮质激素，可以更快地逆转休克并提高存活率。在这些实验中没有测量到对钠重吸收或ENaC活性的直接影响，但这些结果表明，DOCA的给药导致肾脏钠重吸收增加和血管内容量的保存，从而减轻严重休克和改善生存。 作为一个基本的生理学问题，这项研究将扩大我们对肾脏和肺中的钠通道以及盐皮质激素在危重疾病期间管理液体平衡中所起的作用的理解。这项研究还将展示这些渠道的表达如何受到影响以提高存活率。从临床角度来看，如果预防性治疗被证明能提高存活率，这将立即使外科手术(如腹部手术)感染风险较高的患者受益。此外，这些结果将确定钠通道的哪些成分可以作为药物开发的靶点。 这一系列研究调查了糖皮质激素和盐皮质激素在镇静和通风的脓毒症模型中的独立作用。我们首先在ICU环境中定义了脓毒症期间正常的肾上腺功能(Sweeney，JID 2010)。然后，我们确定了脓毒症期间选择性皮质类固醇激动剂的疗效(Hicks CCM 2012)以及皮质类固醇在细菌清除中的作用(Hicks ICM 2012)。然后，我们研究了致死性金黄色葡萄球菌肺炎的下丘脑-垂体-肾上腺轴(Corts-Puch AJP，2014)。目前的研究将扩大我们对水处理背后的机制以及在危重疾病期间如何影响生存的理解。

The adrenal glands are endocrine glands which produce both glucocorticoid and mineralocorticoid hormones in response to critical illness. The primary glucocorticoid hormone is cortisol, whereas the primary mineralocorticoid hormone is aldosterone. Cortisol has important cardiovascular, metabolic, immunologic, and hemostatic functions. In comparison, aldosterone is important in salt and water regulation and therefore critical to the maintenance of intravascular volume and blood pressure. Acute adrenal insufficiency is the failure of the adrenal gland to respond appropriately to physiologic stress, such as infection. The clinical presentation of acute adrenal insufficiency is due to insufficient mineralocorticoid activity rather than inadequate glucocorticoid activity. As such, critically ill patients with acute adrenal insufficiency can present with low blood pressure and severe dehydration. Thus, it has been hypothesized that mineralocorticoid deficiency may contribute to the development and severity of septic shock. Although many researchers have studied the importance of glucocorticoid activity in septic shock, the importance of mineralocorticoid activity and aldosterone in septic shock remains unclear. Aldosterone is produced in the adrenal gland and causes increased renal sodium reabsorption via the activity of an amiloride-sensitive epithelial sodium (Na) channel (ENaC). Increased reabsorption of sodium leads to expansion of intravascular volume and increased blood pressure. Amiloride is a potassium sparing diuretic that blocks ENaC thereby inhibiting sodium reabsorption in the late distal convoluted tubules, connecting tubules, and collecting ducts in the kidney. Hydrochlorothiazide (HCT), a well described diuretic, will be used in conjunction with amiloride to ensure maximal effect on eNaC function. ENaC is expressed on the apical plasma membrane of many organs including the kidneys, lungs, urinary bladder, distal colon, sweat glands, and salivary ducts.1 For the purpose of this protocol, we will concentrate on the importance of ENaC in the kidneys and the lungs Using a canine model of septic shock, our lab has previously conducted experiments suggesting mineralocorticoid activity via aldosterone may be important to the pathophysiology of septic shock. We demonstrated that administration of desoxycorticosterone acetate (DOCA), a selective mineralocorticoid with physiologic effects similar to aldosterone given 72h before the onset of sepsis, led to a more rapid reversal of shock and improved survival. The direct effect on sodium reabsorption or ENaC activity was not measured in these experiments but these results suggest that the administration of DOCA leads to increased renal sodium reabsorption and preservation of intravascular volume resulting in less severe shock and improved survival. As a basic physiologic question, this study will expand our understanding of sodium channels in the kidney and lung and the role mineralocorticoids plays in managing fluid balance during critical illness. This study will also show how the expression of these channels can be influenced to improve survival. From a clinical perspective, if prophylactic treatment is shown to improve survival this would immediately benefit patients subject to high risk for infection surgical procedures, ie, abdominal. In addition, these results will define which components of the sodium channel could be targeted for drug development. This series of studies investigates the independent roles of glucocorticoids and mineralocorticoids in a sedated and ventilated model of sepsis. We began by defining normal adrenal function during sepsis in an ICU setting (Sweeney, JID 2010). We then determined the efficacy of selective corticosteroid agonists during sepsis (Hicks CCM 2012) and the role of corticosteroids on bacterial clearance (Hicks ICM 2012). We then investigated the Hypothalamic-Pituitary-Adrenal Axis in Lethal Canine Staphylococcus aureus Pneumonia (Corts-Puch AJP, 2014). The current study will expand our understanding of the mechanisms behind water handling and how survival is affected during critical illness