Covid 19 cytokine storm

摘要 新冠状病毒19大流行与高达40%的蛋白尿的发展有关 住院病人的数量。肾脏疾病的这种主要表现很可能与 这些患者广泛的细胞因子风暴对肾小球、肾小球滤过单位的影响 肾脏。利用五年研究与感冒相关的细胞因子风暴的经验 诱导某些形式的人类肾脏疾病复发，我们开发了四种新的细胞因子 COVID 19细胞因子风暴的“鸡尾酒”模型。这些细胞因子鸡尾酒含有多种成分 在特定的相加序列中的先天和获得性免疫反应，并诱导急性 小鼠的蛋白尿。鸡尾酒中还包括可溶性血管紧张素转换酶2 (SACE2)，人类COVID19受体的一种循环形式。高度重视的存在 足细胞表达转录因子亚型的小鼠肾脏疾病 在选择的人群中，zhx2可能为疾病的更严重程度提供了部分遗传基础。 利用细胞因子耗竭和细胞因子受体阻断，我们注意到有可能开发出 治疗COVID相关肾脏疾病的治疗策略。 在具体目标1中，我们将在足细胞中进行与作用相关的机制研究 细胞因子对白介素4受体、白介素13受体、肿瘤坏死因子α的影响 受体和跨膜ACE2。利用基因敲除小鼠的体内研究和体外研究 使用培养的足细胞将进行。 在特定的目标2中，我们将研究与COVID19致病相关的机制 相关的肾小球疾病，尤其是塌陷性肾小球疾病。肾小球缺陷小鼠 将使用内皮整合素β5表达，足细胞ZX2表达，或两者都使用。组合 整合素β5表达缺陷小鼠与足细胞细胞因子受体缺陷小鼠的比较 肿瘤坏死因子α受体将用于研究旁分泌和自分泌反馈 循环。 在特定的目标3中，我们将进行系统性的细胞因子耗竭和受体阻断。 策略，并结合使用它们来开发一种新的治疗模式 COVID19相关性肾小球疾病的治疗这些耗尽战略很可能会 惠及其他因COVID19细胞因子风暴造成的器官损害。

Abstract The COVID 19 pandemic has been associated with the development of proteinuria in up to 40% of hospitalized patients. This cardinal manifestation of kidney disease is most likely related to effects of the extensive cytokine storm in these patients on glomeruli, the filtering units of the kidney. Using five years of experience with studying cytokine storms related to Common Cold induced relapse of some forms of human kidney disease, we developed four novel “cytokine cocktail” models of the COVID 19 cytokine storm. These cytokine cocktails contain components of the Innate and Adaptive immune response in a specific additive sequence and induce acute albuminuria in mice. Also included in the cocktails is soluble Angiotensin Converting Enzyme 2 (sACE2), a circulating form of the receptor for COVID 19 in humans. The presence of heightened kidney disease in mice that are hypomorphs for the podocyte expressed transcriptional factor Zhx2 may provide a partial genetic basis for greater severity of disease in select populations. Using cytokine depletion and cytokine receptor blockage, we noted that it is possible to developed treatment strategies to treat COVID related kidney disease. In Specific Aim 1, we will conduct mechanistic studies in the podocyte related to the effect of cytokine cocktail on the Interleukin 4 receptor, Interleukin 13 receptor, Tumor Necrosis Factor α receptor, and transmembrane ACE2. In vivo studies using knockout mice and in vitro studies using cultured podocytes will be conducted. In Specific Aim 2, we will investigate mechanisms involved in the pathogenesis of COVID 19 related glomerular disease, especially collapsing glomerulopathy. Mice deficient in glomerular endothelial Integrin β5 expression, podocyte Zhx2 expression, or both will be used. Combination of Integrin β5 expression deficient mice with those also deficient in podocyte cytokine receptors and Tumor Necrosis Factor α receptor will be used to study paracrine and autocrine feedback loops. In Specific Aim 3, we will conduct systematic current cytokine depletion and receptor blockage strategies, and also use them in combination to develop a novel therapeutic paradigm for the treatment of COVID 19 related glomerular disease. It is likely that these depletion strategies will benefit other end organ damage caused by the COVID 19 cytokine storm.