CONICET | Buscador de Institutos y Recursos Humanos

According to the World Health Organization, 9 out of 10 people worldwide breathe low-quality air. Consequently, more than 9 million premature deaths occur every year due to the effects of ambient air pollution exposure. Recently, it has been estimated that the exposure to polluted air in urban environments reduces life expectancy by almost 3 years globally. Increased incidence of respiratorydiseases, such as pneumonia, chronic obstructive pulmonary disease (COPD), and lung cancer, is frequently associated with air pollution exposure. However, cardiovascular diseases largely account for most of the increase in morbidity and mortality rates. In fact, according to the Global Burden of Disease study, air pollution is responsible for one-fourth of the total death count from ischemicheart disease and stroke. Besides the well demonstrated toxicity of air pollution gaseous components, epidemiological studies indicate that particulate matter (PM) is the main responsible for pollution exposure adverse effects. PM derived from anthropogenic emissions is a complex mixture of particles of variable sizes and chemical composition. Motor vehicle emissions and fossil fuel combustion during industrial processes and power generation are the main sources of PM in urban areas, as a result from incomplete oxidation of carbonaceous materials. Following PM inhalation, the activation of oxidative stress and inflammatory pathways largely account for PM biological effects, both locally as well as systemically and in secondary organs, such as the heart and brain. In the lung, increased levels of pro-inflammatory cytokines, including interleukin (IL) -1β, tumor necrosis factor-α, IL-6, and monocyte chemoattractant protein-1, are a frequent finding after PM exposure. Therefore, lung inflammatory cell recruitment is usually observed following PM exposure, both in humans and in different animal models. Increased plasma levels of these inflammatory mediators are a common finding, indicating that PM exposure triggers an inflammatory response that is not only confined to the lung, but is also systemic. As a result, metabolism is impaired in distant organs. We and others have studied the role of the exposure toair pollution PM over lung and heart redox metabolism, in which altered mitochondrial respiration together with enhanced NADPH oxidase 2 (NOX2) activity plays a central role as shown. Interestingly, NOX2 seems to account for increased reactive oxygen species (ROS) production in the lung following PM exposure, while mitochondrial mild uncoupling, characterized as increased oxygen consumption rate and decreased inner membrane potential, together with decreased ATP production rate and lower efficiency of the oxidative phosphorylation process (lower P/O ratio), may prevent further ROS release from this organelle. When increasing electron transport rate at the respiratory chain complexes, mitochondrial ROS production is attenuated by different mechanisms: First, mitochondria can significantly reduce O2.- production by decreasing oxygen tension in the mitochondrial microenvironment; Second, by favoring more oxidized levels of respiratory chain intermediates; Third, by lowering NADH levels that could be used by mitochondrial matrix flavoenzymes; Forth, by preventing reverse electron transfer due to lower membrane potential. Alveolar macrophages play a central role in maintaining lung homeostasis through the removal of exogenous materials and microorganisms from the respiratory surface by phagocytosis, including PM. However, PM usually overwhelms cell capacity for foreign material removal, leading to uncontrolled cell activation and ROS production, as well as an exaggerated inflammatory responseand pro-inflammatory cytokine release. Activation of the NLRP3 inflammasome following PM uptake seems to represent a central step in the cellular inflammatory response to PM in alveolar macrophages. Interestingly, PM has been also shown to accumulate inside mitochondria, suggesting a specific direct effect of PM over this organelle. Accordingly, PM exposure induces altered mitochondrial ultrastructure in alveolar macrophages, including swelling, cristae disorder, and organelle fragmentation at high doses, as well as modulation of mitochondrial fission/fusion gene expression. In an experimental model tested in our laboratory, an increased mitochondrial production of O2⦁- in intact cells exposed to PM was measured, which may be a consequence ofimpaired mitochondrial function. These findings suggest that mitochondria are important mediators in the events that follow PM exposure in macrophages. Interestingly, recently published evidence suggests that mitochondria are not only a source of ROS, but also a target of oxidative damage in the context of PM exposure. In this sense, the relevance of NOX2 as a source of O2⦁- in inflammatory macrophages is suggested, which encouraged the search for such contribution in this model. Indeed, an increase in NOX activity was found, which may contribute to the development of a crosstalk between the observed oxidative response and mitochondrial dysfunction. Consideringthese findings, it is proposed that mitochondria and NOX are the main sources of O2⦁-, which is converted into H2O2 by superoxide dismutase, and ultimately acts as an effector molecule in redox signaling and oxidative damage to macromolecules, following PM exposure in macrophages. Impaired cardiac mitochondrial function also arises as a central feature of air pollution PM toxicology. Mechanistically, an acute exposure to PM induces a decrease in active, but not rest, state oxygen consumption rate, together with inner membrane depolarization and reduced mitochondrial ATP production. Consequently, deficient contractile and lusitropic reserve is observed in PM-exposed mice, as the heart fails to properly increase cardiac contractility after a β-adrenergic stimulus with isoproterenol. Blunted mitochondrial ATP supply in mice breathing PM may account for this effect, as decreased ATP levels are a frequent finding in the failing heart. Interestingly, this cardiac mitochondrial bioenergetic dysfunction seems to be partially mediated by an inflammatoryresponse triggered by PM exposure, since impaired mitochondrial respiration and cardiac contractility is attenuated by pretreatment with a chimeric anti-TNF-α antibody (Infliximab) in PM-exposed mice. The central nervous system is also a target of air pollution, causing tissue damage and functional alterations, with oxidative stress and neuroinflammation as possible mechanisms mediating these effects. Glutathione levels, assessed as GSH/GSSG ratio, were found to be decreased in cerebral cortex after exposure to urban air, and at later time points in the olfactory bulb (OB). Activation of NOX was also observed. Increased GFAP expression levels showed reactive astrocytes in OB, probably associated with the altered olfactory function observed by a behavioral test. Interestingly, impaired mitochondrial function, due to reduction in O2 consumption in active state, a decrease in ATP production rate and an increase of H2O2 production was found, accompanied by decreased activities of the respiratory complexes I-III and II-III.Taken together, impaired mitochondrial respiration, enhanced ROS release, and deficient ATP supply, play a central role in the adverse health effects reported after air pollution PM exposure in the lungs and distant organs, such as the heart and brain. In this context, the modulation of mitochondrial function (e.g. by mitochondrial targeted antioxidants) arises as a potential therapeutic target to prevent excessive lung inflammatory response, as well as the alterations observed in cardiac and brain tissues in PM-exposed individuals at particular high risk.