Dissecting the Role of Arachidonic Acid Metabolic Pathways Involved in Resolution Versus Progression of PM-Induced Cardiometabolic Toxicity

ABSTRACT
Epidemiological and experimental data have shown that chronic exposure to ambient particulate matter (PM)
leads to exacerbation of atherosclerosis, and increased cardiovascular morbidity and mortality. We have shown
that mouse exposures to diesel exhaust and ultrafine particles (PM< 0.18 µm) lead to increased lipid peroxidation
in the lungs and systemic tissues, accompanied by effects on plasma lipoproteins, disturbances in lipid
metabolism, liver steatosis, and atherosclerosis, all components of the so-called cardiometabolic syndrome. PM-
induction of these disorders is thought to involve chronic and persistent activation of inflammatory pathways.
However, while chronic exposure to PM < 2.5 µm (PM2.5) has been reported to result in steatohepatitis, we have
shown that chronic exposure to diesel exhaust also leads to triglyceride accumulation in the liver (steatosis) but
without the inflammatory component, suggesting that PM with different compositions could have different abilities
to activate inflammatory pathways after chronic exposures. This project has been designed to dissect molecular
pathways involved in the development and progression versus inhibition or resolution of inflammation. Our
central hypothesis is that PM exposure promotes cardiometabolic toxicity via prooxidant and proinflammatory
effects that lead to wide dysregulation of arachidonic acid metabolic pathways, with activation of 5-lipoxygenase,
overpowering the counteracting actions of homeostatic protective responses when that activation is persistent.
We will test this hypothesis via three specific aims: 1) Determine molecular pathways involved in the inhibition
of steatohepatitis after exposure to diesel exhaust. 2) Dissect molecular pathways and toxic constituents
involved in the development and progression of steatohepatitis and atherosclerosis after exposure to ultrafine
particles. 3) Determine whether PM-induced chronic inflammation is mediated by the persistent activation of the
5-lipoxygenase (5-LO) pathway, and explore the therapeutic potential of blocking this pathway to mitigate the
cardiometabolic toxicity and resolve inflammation induced by PM. In aims 1 and 2, LDL-R KO mice will be
exposed to whole diesel exhaust or ultrafine concentrated ambient particles, respectively, to evaluate the effect
of different PMs on the development of fatty liver disease and atherosclerosis in experimental protocols of
continuous or intermittent exposures to PM. Intervening molecular pathways will be analyzed in various tissues
(lungs, blood, liver, aorta), especially those involving arachidonic acid metabolism and antioxidant homeostatic
responses. Data will be integrated with inflammatory endpoints obtained in various tissues, alveolar and systemic
macrophages. Comparison among contrasting effects observed in both aims will enable identification of critical
pathways responsible for development versus resolution of chronic inflammation. In aim 3, LDL-R KO mice
deficient in 5-LO or treated with pharmacological inhibitors of the 5-LO pathway will be tested to evaluate the
role of 5-LO activation in mediating PM-induced inflammation. This project will help in better understanding of
PM-induced toxicity with prophylactic or therapeutic implications.

Grant Number: 5R01ES033703-05
NIH Institute/Center: NIH
Principal Investigator: Jesus Araujo