Interplay Between Macrophages, Lipid Oxidation and the Nrf2/HO-1 Axis in the Cardiometabolic Toxicity Induced by Ultrafine Particles

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
health effects, with the potential to aid in the design of therapeutic and/or prophylactic interventions against the
toxicity induced by air pollution.

Grant Number: 5R01ES032806-05
NIH Institute/Center: NIH
Principal Investigator: Jesus Araujo