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-1? 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-1? 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.
Acute respiratory distress syndrome (ARDS) is the primary cause of death in ICU hospitalized COVID-19 patients. The risk of SARS-CoV-2 infections progressing to ARDS is greatly increased by obesity, diabetes and fatty liver diseases (NASH, TASH). We will assess the ability of metformin-loaded nanoparticles to mitigate the effect of these risk factors, including exposure to the environmental toxicant triclosan, and prevent the onset of ARDS, thereby reducing COVID-19 mortality and morbidity.
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