Pulmonary exposure to diesel exhaust particles promotes cerebral microvessel thrombosis: protective effect of a cysteine prodrug l-2-oxothiazolidine-4-carboxylic acid.
Inhaled particulate matter is associated with increased cerebro- and cardiovascular events. However, the systemic mechanisms underlying these effects remain unclear. In the present study, we investigated the mechanisms underlying the relationship between airway and systemic inflammation and pial cerebral venular thrombosis, 24h after intratracheal (i.t.) instillation of diesel exhaust particles (DEP; 15 or 30 microg/mouse) or saline (control). Doses of 15 and 30 microg/mouse induced a dose-dependent macrophage and neutrophil influx into the bronchoalveolar lavage (BAL) fluid with elevation of total proteins and Trolox equivalent antioxidant capacity (TEAC), but without IL-6 release. Similarly, in plasma, IL-6 concentrations did not increase but the TEAC was significantly and dose-dependently decreased. The number of platelets and the tail bleeding time were both significantly reduced after exposure to DEP (30 microg). Interestingly, the same dose showed platelet proaggregatory effect in mouse pial cerebral venules. Pretreatment with the cysteine prodrug l-2-oxothiazolidine-4-carboxylic acid (OTC, 80 mg/kg) 24 and 1h before i.t. DEP (30 microg), abolished the DEP-induced macrophage and neutrophil influx, and the increase of TEAC in BAL. Lung histopathology confirmed the protective effect of OTC on DEP-induced lung inflammation. OTC also reversed the decrease of TEAC concentrations in plasma, the shortening of the bleeding time, and the thrombotic effect of DEP in pial cerebral venules. We conclude that pulmonary exposure to DEP cause oxidative stress responsible, at least partially, for the pulmonary and systemic inflammation and thrombotic events in the pial cerebral microvessels of mice. OTC pretreatment abrogated these effects through its ability to balance oxidant-antioxidant status.
Nemmar
Abderrahim
A
Department of Physiology, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates. anemmar@uaeu.ac.ae
Al-Salam
Suhail
S
Dhanasekaran
Subramanian
S
Sudhadevi
Manjusha
M
Ali
Badreldin H
BH
D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D020767:Intracranial Thrombosis / Q000473:pathology*; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D055806:Microvessels / Q000473:pathology; D010316:Particle Size; D011355:Prodrugs; D020011:Protective Agents / Q000378:metabolism*; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism*; D053778:Thiazolidines / Q000378:metabolism*; D001335:Vehicle Emissions / Q000633:toxicity*
D000393:Air Pollutants; D011355:Prodrugs; D020011:Protective Agents; D053778:Thiazolidines; D001335:Vehicle Emissions; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid