As the air is precious, it brings with it many potential causes of disease. The air of industrialized nations is contaminated by an unpleasant odor mixture of gaseous pollutants and particulates (CO, O3 , SO2, PM2.5, NO2), especially in the cities and in the vicinity of heavy industries. Ambient air contains a range of particles that vary in size over 5 orders of magnitude (from 0.001 to 100 μm). Larger particles (≥10 μm; PM10) are derived from windblown soil or dust or volcanic activity and often consist of sea salts, pollen, mold, and spores. Such particles are also generated by human activities such as mining or agriculture. Fine particles (0.1 to 2.5 μm; PM2.5) are generated from combustion emissions such as automobile exhaust or wood or coal burning and industrial emissions from smelters, paper and steel mills, or cement plants. Because fine and ultrafine (<2.5 μm) particles penetrate deeper in the lung and could potentially appear in the circulation, they are considered to be of greater health significance.
As are the lungs suffer the most adverse consequences, the pollutants can affect many organ systems, such as the cardiovascular system and the metabolic system.
Epidemiologic studies, that have attempted to investigate environmental factors that accentuate risk for development of cardiometabolic disorders, have uncovered a number of factors other than traditional suspects related to diet and exercise. These variables include factors such as stress (mental and emotional), cultural and socioeconomic variables, chronic low-grade infection, and environmental pollutants. In many instances, these factors are strongly correlated, rendering isolation of cause and effect difficult.
More recent observations have provided additional links between exposure to environmental factors in air/water and propensity to chronic diseases. This issue is of importance given the extraordinary confluence of high levels of airborne and water pollutants in urbanized environments. Multiple studies in China, India, and other rapidly urbanizing economies demonstrate a steep gradient in urban–rural prevalence. (Environmental contaminants as risk factors for developing diabetes. 2008 ). Diabetic patients have previously been shown to be more susceptible to air pollution–induced cardiovascular morbidity and mortality ( Associations between ambient air pollution and daily mortality among persons with diabetes and cardiovascular disease. 2006 ). A few studies have examined the underlying mechanisms. In a study in Boston-area residents, 6-day moving averages of PM2.5 and black carbon (BC) were associated with decreased vascular reactivity among patients with diabetes ( Diabetes enhances vulnerability to particulate air pollution-associated impairment in vascular reactivity and endothelial function, 2005 ). Effects were stronger in type 2 than type 1 DM. In another study in Boston involving patients participating in unrelated clinical trials who provided blood samples, BC concentrations from a regional monitoring station were significantly associated with increased levels of inflammatory markers (Air pollution and inflammation in type 2 diabetes: a mechanism for susceptibility,2007 ).
PM2.5 as a mediator of endothelial dysfunction and IR.
Air-pollution exposure alters endothelial function in both animals and humans (Long-term air pollution exposure and acceleration of atherosclerosis and vascular inflammation in an animal model, 2005 Diesel exhaust inhalation causes vascular dysfunction and impaired endogenous fibrinolysis. 2005 ).
Alterations in endothelial function often precede changes in IR and have been implicated in reduced peripheral glucose uptake. In the first experimental investigation directly linking inhalational exposure of PM2.5 with DM, exposure in conjunction with high-fat diet feeding, increased fasting, postprandial glucose, insulin, and Homeostasis Model Assessment-IR (HOMA-IR) measures. The changes in IR measures seen with PM2.5 were incremental to that of high-fat diet alone over a period of 24 weeks (Airborne particulate matter selectively activates endoplasmic reticulum stress response in the lung and liver tissues, 2010 ).
The mean concentration of PM2.5 was 60 ± 5 µg/m3 (∼10-fold concentration from ambient levels). Tumor necrosis factor (TNF)-α , interleukin-6 , resistin, and leptin levels were elevated following PM2.5 exposure, in keeping with a proinflammatory insulin-resistant state. PM exposure also resulted in elevations in prothrombotic adipokines such as plasminogen activator inhibitor 1 and increased circulating adhesion molecules such as intracellular adhesion molecule-1 and E-selectin. The latter are important in promoting leukocyte adherence in postcapillary venular endothelium. PM exposure was associated with impairment in phosphatidylinositol 3-kinase–Akt–endothelial nitric oxide synthase signaling in the aorta and decreased tyrosine phosphorylation of IRS-1 in the liver, providing evidence for abnormal insulin signaling in the vasculature. (Ambient air pollution exaggerates adipose inflammation and insulin resistance in a mouse model of diet-induced obesity, 2009 ) .In experimental animal models, PM2.5 exposure results in an increase in adipose tissue macrophages with a shift to a proinflammatory phenotype characterized by an increase in TNF-α and IL-6 and a decrease in IL-10 gene expression. The finding of increased innate immune cells in visceral adipose tissue (VAT) is a pathophysiologic hallmark of type 2 DM. To test the mechanism by which increased proinflammatory monocytes permeate VAT, a transgenic model of yellow fluorescent protein (YFP) expression, driven by a monocyte-lineage promoter was employed to follow the migration of cells into the VAT compartment. The animals were initially rendered insulin-resistant with a high-fat diet and then subject to air-pollution exposure. Intravital microscopic studies were conducted to detect leukocyte–endothelial interactions. Pollution exposure resulted in a doubling in the number of endothelial adherent YFP+ cells in mesenteric fat with a sixfold increase in monocytes within adipose (Ambient air pollution exaggerates adipose inflammation and insulin resistance in a mouse model of diet-induced obesity, 2009 ). Thus, PM mediated adhesion and migration of YFP+ cells into visceral fat depots. These changes in adipose occurred with concomitant low-grade inflammation in the lung ( Long-term Exposure to Ambient Fine Particulate Pollution Induces Insulin Resistance and Mitochondrial Alteration in Adipose Tissue, 2011 ).
How may signals perceived in the lung lead to metabolic abnormalities?
The notion that alteration in lung function may lead to metabolic dysfunction is not new. Chronic inflammation is a sine qua non for type 2 DM and obesity (metaflammation), is well known to occur with air-pollution exposure, and may represent a potential link between air-pollution exposure and metabolic dysfunction. Type 2 DM in humans and animal models is associated with increased levels of inflammatory cytokines and recruitment and/or activation of innate immune cells in depots such as visceral adipose. Animal models of type 2 DM/obesity have provided strong evidence that diet-induced oxidative stress/inflammation plays a critical role in the pathogenesis of type 2 DM (Inflammation and insulin resistance, 2006 ). In addition to classical inflammatory pathways, air pollutant–mediated alterations in autonomic balance may further exacerbate systemic insulin resistance via overactivity of the sympathetic nervous system. Numerous pulmonary receptors such as transient receptor potential ankyrin 1 can be stimulated by pollutant inhalation and prompt sympathetic activation through centrally mediated pathways (How irritating: the role of TRPA1 in sensing cigarette smoke and aerogenic oxidants in the airways, 2008 ).
Plausible mechanisms that could be impacted by air pollutants include activation of hypothalamic–pituitary–adrenal axis, impaired insulin-sensitive tissue perfusion due to endothelial dysfunction or vasoconstriction, dysfunctional activity of high-density lipoprotein particles, and/or epigenetic alterations of critical modulators of cellular insulin signaling.
To explain the link between the innate immune signals in the lung and systemic inflammatory status have been proposed the following pathways: 1) direct inflammatory/oxidative stress of cells such as alveolar macrophages particularly under conditions of overload typified by continual exposure to PM may release innate immune cytokines (Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury, 2008 ). 2) Uptake by macrophages of particulates may also lead to presentation via dendritic cells to T cells in secondary lymphoid organs resulting in adaptive immune responses (Pulmonary T cell activation in response to chronic particulate air pollution, 2012 ). In addition to this mechanism, alveolar macrophages continually exposed to PM may result in particle overload resulting in a state of perpetual low-grade inflammation. One of counterregulatory mechanisms that prevent excess TLR activation is represented by proteins and phospholipids in the bronchoalveolar fluid may also be rendered dysfunctional with chronic PM exposure and participate in inflammation. Oxidative modification of surfactants and phospholipid components has been reported that may lead to a facilitatory role in air pollution–mediated effects (Myeloperoxidase-dependent inactivation of surfactant protein D in vitro and in vivo, 2010 and Inhibition of human surfactant protein A function by oxidation intermediates of nitrite, 2002 ). 3) Finally, emerging data support a role for central mechanisms for inflammation via afferent pathways linking the lung with the brain provides a hypothetical framework for these interactions and illustrates how inhalational stimuli may interact with overnutrition to entrain a state of chronic oxidative stress and inflammation.
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I will conclude this discussion with the following quote from the article Could Dirty Air Cause Diabetes?2009 “The association between pollution and diabetes has significant public health implications and raises important questions regarding urbanization, diabetes, and obesity. Are obesity and diabetes outcomes of repeated and chronic exposure to pollution? Which individuals are likely to be most affected? To what extent does pollution contribute to the current explosion in diabetes and obesity in the developed and the developing world? Can we prevent diabetes by controlling the levels of pollution? And if so, which of the thousands of chemicals in PM should be regulated?”