Cardiovascular disease is the leading cause of death worldwide. Approximately 80% of all aneurysms that form within the aorta (the major blood vessel that deliveries oxygenated blood to the body) occur in the abdominal region. These are classified as abdominal aortic aneurysms (AAA). AAA is associated with progressive weakening and, ultimately, rupture of the vessel wall, causing rapid and extreme blood loss and a high rate of mortality. Sadly, aneurysm rupture is often the first sign of the disease and many die before reaching a hospital. For those that are diagnosed, treatment is currently limited to open chest or endovascular surgical repair. However, surgical repair of AAA is a risky, complex procedure with a high mortality rate.
In the past 40 years there has been a worldwide increase in forest fires. Although cigarette smoke is known to induce and advance AAA, the effect of wood smoke on blood vessel remodelling and AAA is currently unknown. Interestingly, firefighters are at a four times greater risk for having a heart attack compared to other emergency response personnel. In fact, firefighters are at a greater risk of dying from cardiovascular disease than from on the job burn injury. Although smoke exposure is thought to play a major role in the majority of firefighter cardiovascular deaths, the processes by which wood smoke may promote cardiovascular disease and AAA is unknown.
Granzyme B (GzmB) is an enzyme that breaks down the protein-based scaffolding between cells that is important in sustaining tissue structure and function. Human and mouse models of AAA have shown that GzmB expression is increased within the blood vessel wall of aneurysms and its degree of expression is directly related with aneurysm rupture. In animal models, drugs that inhibit of GzmB prevent aneurysm rupture and increase survival. Although cigarette smoke is associated with increased GzmB levels in those with lung disease such as COPD, the link between wood smoke, GzmB and AAA is not known.
Dr. Zeglinski will examine the effect of repeated exposure to wood smoke on GzmB expression in the vessel wall and its effect on AAA progression. To explore this relationship, he will use a well-established mouse model of AAA and determine what, if any, effect that wood smoke has on aneurysm formation and rupture.
The results of this research could lead to the development of new drugs to treat AAA, a devastating disease with few treatment options. Should the results confirm that GzmB is involved in AAA, Dr. Zeglinski will team up with clinicians for a clinical study to assess the levels of GzmB in those who have been diagnosed or have died from an AAA. By translating findings from the bench to the clinic, Dr. Zeglinski will later be able to partner with drug companies to develop a novel therapeutic agent to block GzmB action to slow or stop the progression of AAA and prevent AAA ruptures.