Effects of urban coarse particles inhalation on oxidative and inflammatory parameters in the mouse lung and colon.

BACKGROUND: Air pollution is a recognized aggravating factor for pulmonary diseases and has notably deleterious effects on asthma, bronchitis and pneumonia. Recent studies suggest that air pollution may also cause adverse effects in the gastrointestinal tract. Accumulating experimental evidence shows that immune responses in the pulmonary and intestinal mucosae are closely interrelated, and that gut-lung crosstalk controls pathophysiological processes such as responses to cigarette smoke and influenza virus infection. Our first aim was to collect urban coarse particulate matter (PM) and to characterize them for elemental content, gastric bioaccessibility, and oxidative potential; our second aim was to determine the short-term effects of urban coarse PM inhalation on pulmonary and colonic mucosae in mice, and to test the hypothesis that the well-known antioxidant N-acetyl-L-cysteine (NAC) reverses the effects of PM inhalation. RESULTS: The collected PM had classical features of urban particles and possessed oxidative potential partly attributable to their metal fraction. Bioaccessibility study confirmed the high solubility of some metals at the gastric level. Male mice were exposed to urban coarse PM in a ventilated inhalation chamber for 15 days at a concentration relevant to episodic elevation peak of air pollution. Coarse PM inhalation induced systemic oxidative stress, recruited immune cells to the lung, and increased cytokine levels in the lung and colon. Concomitant oral administration of NAC reversed all the observed effects relative to the inhalation of coarse PM. CONCLUSIONS: Coarse PM-induced low-grade inflammation in the lung and colon is mediated by oxidative stress and deserves more investigation as potentiating factor for inflammatory diseases.

Role of mitochondria-associated endoplasmic reticulum membrane (MAMs) interactions and calcium exchange in the development of type 2 diabetes.

Glucotoxicity-induced ß-cell dysfunction in type 2 diabetes is associated with alterations of mitochondria and the endoplasmic reticulum (ER). Mitochondria and ER form a network in cells that controls cell function and fate. Mitochondria of the pancreatic ß cell play a central role in the secretion of insulin in response to glucose through their ability to produce ATP. Both organelles interact at contact sites, defined as mitochondria-associated membranes (MAMs), which were recently implicated in the regulation of glucose homeostasis. Here, we review MAM functions in the cell and we focus on the crosstalk between the ER and Mitochondria in the context of T2D, highlighting the pivotal role played by MAMs especially in ß cells through inter-organelle calcium exchange and glucotoxicity-associated ß cell dysfunction.

Differential Effect of Glucose on ER-Mitochondria Ca2+ Exchange Participates in Insulin Secretion and Glucotoxicity-Mediated Dysfunction of ß-Cells.

Glucotoxicity-induced ß-cell dysfunction in type 2 diabetes is associated with alterations of mitochondria and the endoplasmic reticulum (ER). Both organelles interact at contact sites, defined as mitochondria-associated membranes (MAMs), which were recently implicated in the regulation of glucose homeostasis. The role of MAMs in ß-cells is still largely unknown, and their implication in glucotoxicity-associated ß-cell dysfunction remains to be defined. Here, we report that acute glucose treatment stimulated ER-mitochondria interactions and calcium (Ca2+) exchange in INS-1E cells, whereas disruption of MAMs altered glucose-stimulated insulin secretion (GSIS). Conversely, chronic incubations with high glucose of either INS-1E cells or human pancreatic islets altered GSIS and concomitantly reduced ER Ca2+ store, increased basal mitochondrial Ca2+, and reduced ATP-stimulated ER-mitochondria Ca2+ exchanges, despite an increase of organelle interactions. Furthermore, glucotoxicity-induced perturbations of Ca2+ signaling are associated with ER stress, altered mitochondrial respiration, and mitochondria fragmentation, and these organelle stresses may participate in increased organelle tethering as a protective mechanism. Last, sustained induction of ER-mitochondria interactions using a linker reduced organelle Ca2+ exchange, induced mitochondrial fission, and altered GSIS. Therefore, dynamic organelle coupling participates in GSIS in ß-cells, and over time, disruption of organelle Ca2+ exchange might be a novel mechanism contributing to glucotoxicity-induced ß-cell dysfunction.