The exposure to air pollution particulate matter aggravates experimental myocardial infarction in mice by potentiating cytokine secretion from lung macrophages

MARCHINI, TIMOTEO; WOLF, DENNIS; ANTO MICHEL, NATHALY; BECKERT, JESSICA; DUFNER, BIANCA; HOPPE, NATALIE; JÄEKEL, MARKUS; MAULER, MAXIMILIAN; MAGNANI, NATALIA; DUERSCHMIED, DANIEL; HILGENDORF, INGO; TASAT, DEBORAH; ALVAREZ, SILVIA; REINÖHL, JOCHEN; VON ZUR MUHLEN, CONSTANTIN; IDZKO, MARCO; BODE, CHRISTOPH; EVELSON, PABLO; ZIRLIK, ANDREAS

Friburgo

Simposio; 1st Atherothrombosis Winter School; 2016

Sociedad Alemana de Cardiología (DGK)

Background. The exposure to environmental particulate matter (PM) is associated with increased morbidity and mortality rates, including myocardial infarction (MI) and its complications. We hypothesize that alveolar macrophages orchestrate a local inflammatory response in the lung following PM inhalation, which afterwards leads to systemic inflammation that affects disease progression. In the present work, we aimed to describe mechanisms and consequences of PM exposure in an experimental model of MI. Methods and results. C57BL/6J mice were exposed to a PM surrogate (Residual Oil Fly Ash, ROFA) by intranasal installation, prior to permanent ligation of the left anterior descending coronary artery. Histological analysis of the myocardium at 7 days after MI showed increased infarct area and enhanced inflammatory cell recruitment in ROFA-exposed mice. Time-course evaluation of cell populations in infarcted tissue by flow cytometry revealed increased numbers of Ly6Chigh monocytes at day 3 after MI, as well as increased macrophages numbers at day 7. Mechanistically, the ROFA instillation increased plasma TNF-α levels 3-fold. Moreover, the ROFA exposure induced the activation and expression of adhesion molecules in myeloid and endothelial cells, respectively, and enhanced leukocyte recruitment in models of sterile peritonitis and intravital microscopy. Notably, the observed effects over endothelial cells and circulating leukocytes could be prevented in vitro by a blocking TNF-α antibody. We identified alveolar macrophages as the primary source of elevated cytokine production after PM exposure. Accordingly, in vivo depletion of lung macrophages by an intranasal instillation of clodronate liposomes completely inhibited ROFA-mediated cytokine secretion. On the other hand, lymphocyte-free Rag1-/- mice where still susceptible to ROFA and its complications, indicating that macrophages, but not lymphocytes, mediate inflammation after PM inhalation. Conclusion. Taken together, our data demonstrate that the exposure to environmental PM worsens MI healing in mice. These findings provide a novel link between air pollution and inflammatory pathways, and emphasize the importance of environmental factors in cardiovascular disease.