DETECTION AND MODELS OF TOXICANT EXPOSURE

摘要 新型SARS-CoV-2冠状病毒，新冠肺炎的病原体，可以建立致命的下呼吸道 感染。在某些情况下，这种感染可能受到各种风险因素和共病的强烈影响， 可进展为急性呼吸窘迫综合征(ARDS)，这是导致死亡的主要医疗条件 导致失控的肺部炎症和损伤，并可能导致代谢崩溃和多器官衰竭。反- 有效防止ARDS启动和传播的炎症治疗应降低高水平的 与新冠肺炎相关的发病率和死亡率，从而挽救了许多人的生命和数十亿医疗保健资金。 除了糖皮质激素，还没有开发出这样的治疗方法。此外，当糖皮质激素抑制 炎症它们具有很强的免疫抑制活性，因此可以防止长时间感染 持久的抗病毒免疫力。新冠肺炎急性呼吸窘迫综合征是由病毒诱导的对肺上皮细胞的杀伤和 IL-1α激活巨噬细胞的损伤相关分子模式的释放 NLRP3炎性小体的组装和激活，是ARDS启动的关键事件。NLRP3炎症体 激活调节IL-1β和IL-18的处理和分泌，这两种有效的炎性细胞因子 ICU入院的新冠肺炎患者循环水平升高。新冠肺炎相关性急性呼吸窘迫综合征和急性呼吸窘迫综合征 所有原因都与年龄有关，在老年人(65岁及以上)中，它们的风险可能会增加20倍 他们占新冠肺炎死亡人数的80%。ARDS和新冠肺炎的风险因并存而进一步增加， 如肥胖、II型糖尿病(T2D)和脂肪肝疾病，如NAFLD，包括非酒精性和 中毒性脂肪性肝炎(分别为NASH和TASH)。急性呼吸窘迫综合征风险的显著增加 肥胖、T2D和NAFLD可能是COVID-29发病率和发病率社会经济差异的主要原因 死亡率。我们最近发现，常用的处方、安全、廉价的抗糖尿病药物二甲双胍可以 在体内外抑制NLRP3炎症体的激活。然而，二甲双胍的半衰期很短， 巨噬细胞不表达肝细胞上存在的二甲双胍转运体。增加二甲双胍的释放量 对于肺泡巨噬细胞，我们将产生负载二甲双胍的纳米颗粒，并首先测试它们的抑制作用。 或改善脂多糖诱导的急性呼吸窘迫综合征。当雾化吸入二甲双胍的疗效得到确认时， 和快速模型，我们将检测其在SARS-CoV-2感染的hACE2转基因小鼠中的效果，这为我们提供了一个 适合于新冠肺炎相关ARDS的研究。我们还将检查肥胖、过量果糖 食用和接触环境毒物三氯生，一种有效的TASH诱导，增加ARDS 两种模型的严重程度以及吸入二甲双胍是否减轻这些影响。

ABSTRACT The novel SARS-CoV-2 coronavirus, the causative agent of COVID-19, can establish fatal lower airway infections. Such infections can in some cases, strongly affected by a variety of risk factors and co-morbidities, can progress to acute respiratory distress syndrome (ARDS), the major cause of death medical condition the entails uncontrolled lung inflammation and injury and can lead to metabolic collapse and multiorgan failure. Anti- inflammatory treatment that effectively prevent ARDS initiation and propagation should reduce the high levels of morbidity and mortality associated with COVID-19 and thereby save many lives and billions of healthcare dollars. Other than glucocorticoids, no such treatments have been developed. Moreover, while glucocorticoids inhibit inflammation they have strong immunosuppressive activity and can therefore prevent the acquisition of long lasting anti-viral immunity. COVID-19 ARDS is initiated by viral-induced killing of lung epithelial cells and the release of damage associated molecular patterns (DAMP) of which IL-1α primes macrophages, ATP triggers NLRP3 inflammasome assembly and activation, a key event in the initiation of ARDS. NLRP3 inflammasome activation mediates the processing and secretion of IL-1β and IL-18, two potent inflammatory cytokines, whose circulating levels are elevated in ICU-admitted COVID-19 patients. COVID-19 associated ARDS and ARDS of all causes are age dependent and their risk can increase by up to 20-fold in older adults (65 years and above) who account for 80% of COVID-19 deaths. ARDS and COVID-19 risk are further increased by co-morbidities, such as obesity, type II diabetes (T2D) and fatty liver diseases as NAFLD, including both non-alcoholic and toxicant induced steatohepatitis (NASH and TASH, respectively). The marked increase in ARDS risk posed by obesity, T2D and NAFLD may account for most of the socio-economic disparity in COVID-29 morbidity and mortality. We recently found that the commonly prescribed, safe and cheap anti-diabetic drug metformin can inhibit NLRP3 inflammasome activation in vitro and in vivo. Metformin, however, has a short half-life and macrophages do not express the metformin transporter present on hepatocytes. To increase metformin delivery to alveolar macrophages, we will generate metformin-loaded nanoparticles and will first test them for inhibition or amelioration of LPS-induced ARDS. When the efficacy of inhalation metformin will be confirmed in that simple and rapid model, we will examine its efficacy in SARS-CoV-2 infected hACE2 transgenic mice, which provide a suitable model for studying COVID-19 related ARDS. We will also examine whether obesity, excessive fructose consumption and exposure to the environmental toxicant triclosan, a potent induce of TASH, increase ARDS severity in both models and whether inhalation metformin mitigates these effects.