Grant: CIHR Fellowship

Due to climate change, the number of annual forest fires over the past 40 years has continued to rise. Although cigarette smoke is one of the greatest risk factors for cardiovascular disease, the effect of wood smoke is currently unknown. Firefighters have been found to be at a higher risk for having a cardiovascular event as compared to other emergency response personal. In fact, firefighters are at greater risk of dying from cardiovascular disease than from burn injury. Although smoke exposure is thought to play a role in firefighter deaths, the mechanisms by which wood smoke promotes cardiovascular disease is unknown. Granzyme B is an enzyme that degrades extracellular matrix and adhesion proteins that are important in sustaining tissue structure and function. Human and mouse models of abdominal aortic aneurysms have demonstrated increased Granzyme B expression and aneurysm rupture. Granzyme B inhibition prevents aneurysm rupture and increases survival in mouse models. Cigarette smoke is the number one risk factor for abdominal aortic aneurysms. While smoking is associated with increased Granzyme B levels in COPD, the link between wood smoke, Granzyme B, and aneurysms is not known. Likewise, while Granzyme B expression is seen in pro-inflammatory mast cells in aneurysms, the mechanism by which Granzyme B is induced in such cells is unknown. Our objective is to investigate the role of wood smoke on Granzyme B expression in mast cells in the onset and progression of abdominal aortic aneurysms. We will use the ApoE-/- angiotensisn II mouse model and determine what, if any, effect that wood smoke has on aneurysm formation and progression. In isolated primary human peripheral blood mast cells, we will examine the effect that epigenetic and microRNA regulation has on Granzyme B expression in mast cells, cells which do not normally express Granzyme B. This research may lead to the development of new drugs to target Granzyme B and treat abdominal aortic aneurysm.