# DETECTION AND MODELS OF TOXICANT EXPOSURE

> **NIH NIH P42** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $408,869

## Abstract

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.

## Key facts

- **NIH application ID:** 10200528
- **Project number:** 3P42ES010337-19S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Robert H Tukey
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $408,869
- **Award type:** 3
- **Project period:** 2000-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200528

## Citation

> US National Institutes of Health, RePORTER application 10200528, DETECTION AND MODELS OF TOXICANT EXPOSURE (3P42ES010337-19S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10200528. Licensed CC0.

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