Ambient particulate air pollution induces oxidative stress and alterations of mitochondria and gene expression in brown and white adipose tissues

<p>Abstract</p> <p>Background</p> <p>Prior studies have demonstrated a link between air pollution and metabolic diseases such as type II diabetes. Changes in adipose tissue and its mitochondrial content/function are closely associated with the development of insulin resistance and attendant metabolic complications. We investigated changes in adipose tissue structure and function in brown and white adipose depots in response to chronic ambient air pollutant exposure in a rodent model.</p> <p>Methods</p> <p>Male ApoE knockout (ApoE^-/-) mice inhaled concentrated fine ambient PM (PM < 2.5 μm in aerodynamic diameter; PM_2.5) or filtered air (FA) for 6 hours/day, 5 days/week, for 2 months. We examined superoxide production by dihydroethidium staining; inflammatory responses by immunohistochemistry; and changes in white and brown adipocyte-specific gene profiles by real-time PCR and mitochondria by transmission electron microscopy in response to PM_2.5exposure in different adipose depots of ApoE^-/-mice to understand responses to chronic inhalational stimuli.</p> <p>Results</p> <p>Exposure to PM_2.5induced an increase in the production of reactive oxygen species (ROS) in brown adipose depots. Additionally, exposure to PM_2.5decreased expression of uncoupling protein 1 in brown adipose tissue as measured by immunohistochemistry and Western blot. Mitochondrial number was significantly reduced in white (WAT) and brown adipose tissues (BAT), while mitochondrial size was also reduced in BAT. In BAT, PM_2.5exposure down-regulated brown adipocyte-specific genes, while white adipocyte-specific genes were differentially up-regulated.</p> <p>Conclusions</p> <p>PM_2.5exposure triggers oxidative stress in BAT, and results in key alterations in mitochondrial gene expression and mitochondrial alterations that are pronounced in BAT. We postulate that exposure to PM_2.5may induce imbalance between white and brown adipose tissue functionality and thereby predispose to metabolic dysfunction.</p

Air pollution and cardiac remodeling: a role for RhoA/Rho-kinase

Exposure to ambient air pollution has been associated with increases in blood pressure. We have previously demonstrated activation of the Rho/Rho kinase pathway in experimental hypertension in rats. In this investigation, we evaluated the effects of particulate matter of <2.5 μm (PM2.5) exposure on cardiovascular responses and remodeling and tested the effect of Rho kinase inhibition on these effects. C57BL/6 mice were exposed to concentrated ambient PM2.5 or filtered air for 12 wk followed by a 14-day ANG II infusion in conjunction with fasudil, a Rho kinase antagonist, or placebo treatment. Blood pressure was monitored, followed by analysis of vascular function and ventricular remodeling indexes. PM2.5 exposure potentiated ANG II-induced hypertension, and this effect was abolished by fasudil treatment. Cardiac and vascular RhoA activation was enhanced by PM2.5 exposure along with increased expression of the guanine exchange factors (GEFs) PDZ-RhoGEF and p115 RhoGEF in PM2.5-exposed mice. Parallel with increased RhoA activation, PM2.5 exposure increased ANG II-induced cardiac hypertrophy and collagen deposition, with these increases being normalized by fasudil treatment. In conclusion, PM2.5 potentiates cardiac remodeling in response to ANG II through RhoA/Rho kinase-dependent mechanisms. These findings have implications for the chronic cardiovascular health effects of air pollution

Inflammatory response to fine particulate air pollution exposure: neutrophil versus monocyte.

Studies have shown that chronic exposure to ambient fine particulate matter (less than 2.5 µm in aerodynamic diameter, PM₂.₅) pollution induces insulin resistance through alterations in inflammatory pathways. It is critical to study how the immune system responds to this stimulant, which has been linked to cardiovascular and autoimmune diseases, but few studies have been focused on such involvement of both neutrophils and monocytes in a timely manner. We hypothesized that the neutrophil was involved in the inflammatory response to air pollution.C57BL/6 mice were exposed to PM₂.₅ or filtered air (6 hours/day, 5 days/week) for 5, 14, and 21 days, respectively, in Columbus, OH. At the end of each of the exposure periods, we investigated the inflammatory response through flow cytometry, histology, intravital microscopy, and real-time PCR. PM₂.₅-exposed mice demonstrated a significant inflammatory response after 5 days of exposure. In the lung tissue and bronchoalveolar lavage fluid, monocytes/macrophages showed a transient response, while neutrophils showed a cumulative response. In addition, exposure to PM₂.₅ resulted in elevation of the monocyte chemoattractant protein 1 (MCP-1) cytokine, a monocyte/macrophage attractant in blood, at an early stage of exposure.These findings suggest that PM₂.₅ exposure induces the inflammatory responses from both macrophages and neutrophils involvement

Effect of PM_2.5 exposure on chemotactic migration.

<p>Chemotactic migration of macrophages (A) and neutrophils (B). N = 6. ***<i>P</i><0.0001 vs. FA group.</p

Primers Used for Real-time PCR.

<p>Primers Used for Real-time PCR.</p

Effect of PM_2.5 exposure on macrophages and neutrophils in the lung and visceral adipose tissue.

<p>Representative images (A) and statistical analysis (B) of the immunohistochemical staining for F4/80⁺ of macrophages in the lung. Statistical analysis of the immunohistochemical staining for neutrophils (NIMP-R14⁺) in the lung (C) and F4/80⁺ of macrophages in the epididymal adipose tissue (D). Arrows point to positive staining. Scale bar, 100 µm. N = 6. WAT, white adipose tissue. *<i>P</i><0.05, **<i>P</i><0.001.</p