# Interplay Between Macrophages, Lipid Oxidation and the Nrf2/HO-1 Axis in the Cardiometabolic Toxicity Induced by Ultrafine Particles > **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $395,381 ## Abstract PROJECT SUMMARY/ABSTRACT Cumulative epidemiological and experimental evidence have shown that exposure to air pollutants leads to increased cardiovascular morbidity and mortality. These associations have been mostly ascribed to the particulate matter (PM) components. We have found that exposures to ambient ultrafine particles (UFP), with an aerodynamic diameter less than 0.18 µm, and/or diesel exhaust, rich in ultrafine PM, lead to enhanced lipid peroxidation, metabolic derangements, liver steatosis and atherosclerosis. Inhalation of PM exerts prooxidant actions in the lungs but the mechanisms as to how pulmonary effects are translated into systemic toxicity are still unknown. PM exposure also triggers antioxidant responses in pulmonary and systemic tissues, including activation of transcription factor Nrf2 and upregulation of its target gene heme oxygenase 1 (HO-1), which attempt to counteract the ensuing harmful effects. The observations that particle uptake by alveolar macrophages significantly correlates with the development of atherosclerotic plaques strongly suggest that these cells are likely mediators in translating effects from the lungs to the systemic tissues. Our overarching hypothesis is that PM exposure promotes cardiometabolic toxicity starting with oxidative actions in the lungs that lead to prooxidant and proinflammatory effects in the circulating blood and systemic tissues via activation of alveolar macrophages, all modulated by the degree of myeloid anti-oxidant protection. We will test this hypothesis via the following three specific aims: 1) Assess the kinetics and mechanisms of lipid peroxidation in the lungs after ultrafine particle exposure, and their relation to prooxidant effects in the circulating blood and the development of atherosclerosis. We will use lipid peroxidation byproducts as tracking signals of PM-induced biological effects, and assess the kinetics of their appearance in various tissues such as the lungs, blood, liver, adipose tissue and aorta of ApoE KO mice exposed to ultrafine particles vs. filtered air for various times. 2) Determine if the myeloid antioxidant defense protects against UFP-induced lipid peroxidation, pulmonary and cardiometabolic toxicity. Myeloid-specific Nrf2 and HO-1 KO mice as well as myeloid-specific HO-1 Transgenic overexpresser mice in the ApoE null background, recently developed by us, will be used to test the effects of decreased or increased antioxidant defense, respectively, in the toxicity induced by UFP. 3) Evaluate whether alveolar macrophages carry UFP-induced oxidative effects from the lungs to the circulating blood. We will develop alveolar and lung macrophage chimeras with ablated HO-1 in their alveolar/interstitial macrophages to dissect their contribution in translating effects from the lungs into the systemic vessels. The proposed studies will aid in identifying mechanisms involved in PM-induced cardiovascular toxicity, and characterizing promising novel biomarkers of... ## Key facts - **NIH application ID:** 10576371 - **Project number:** 5R01ES032806-03 - **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES - **Principal Investigator:** Jesus Antonio Araujo - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2023 - **Award amount:** $395,381 - **Award type:** 5 - **Project period:** 2021-05-08 → 2026-02-28 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10576371 ## Citation > US National Institutes of Health, RePORTER application 10576371, Interplay Between Macrophages, Lipid Oxidation and the Nrf2/HO-1 Axis in the Cardiometabolic Toxicity Induced by Ultrafine Particles (5R01ES032806-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10576371. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*