THE SPHERE PROJECT
In spite of more than two decades of mechanistic research, the recent statement of air pollution and Cardio Vascular Diseases (CVD) from the American Heart Association remarked that at front of high degree of consistency of the epidemiology findings showing increased air pollution related CVD risk, the evidence on intermediate mechanisms remains moderate or weak.
Ambient particles have been shown to produce a strong inflammatory reaction, however inflammatory and oxidative responses have little specificity and can be activated by a multitude of trigger, thus limiting our capability to correlate them to air pollution exposure. Beside proinflammatory mediators, cell-derived membrane vesicles (microvesicles/ exosomes, MV/EX) are also released, representing another mode of intercellular communication that has recently become the subject of increasing interest. MV/EX might be the ideal candidate to mediate the effects of air pollution, since potentially they could be produced by the respiratory system, reach the systemic circulation and lead to the development of endothelial dysfunction.
The project SPHERE (Susceptibility to Particle Health Effects, miRNAs and Exosomes) granted by the European Research Council and hosted by the “Università degli Studi”, Milan, Italy, is aimed at investigating whether exposure to air particles and PM-associated metals can modify MV/EX (as quantity, size, membrane molecules, procoagulant activity and miRNAs content) in plasma of human subjects and to investigate whether these alterations may be linked to CVD risk factors and outcomes. The study population includes 2000 overweighed/obese subjects presenting at the Center for Obesity and Weight Control (Fondazione IRCCS Ca’Granda – Ospedale Maggiore Policlinico) in the period 2011-2014. Obese subjects have been shown to be particularly susceptible to the effects of air pollution. Exposure to air pollutants is being assessed using multiple tools: a) use of daily PM10 concentration series from air quality monitors; b) use of daily PM10 concentration estimates by the FARM model (the flexible air quality regional model), a three-dimensional Eulerian grid model for dispersion, transformation and deposition of particulates, capable to simulate PM10 concentration using a 4 km–dispersion grid; c) Metals determination in urine and hair; d) Personal passive samplers (to measure PM), on a subgroup of subjects (n=200). To identify altered MV/EX -associated miRNAs , we are following a two-stage, split sample study design. The first (discovery) stage involves genome-wide miRNA expression profiling among 1000 of the aforementioned 2000 participants using the OpenArray technology. The second (replication) stage involves a replication analysis of the top 50 miRNAs that resulted from the first stage. The proposed research will help to shed light on the chain of events that from air pollution exposure leads to CVD trying to explore a new mechanism which involves alteration of MV/EX production and content.
Our findings, if confirmed, could lead to the identification of potentially-reversible alterations that might be also considered as potential target for new diagnostic and therapeutic interventions.