Date of Graduation
School of Pharmacy
S Jamal Mustafa
Epidemiological studies have established that people who have lung diseases such as asthma and COPD are likely to develop adverse cardiovascular events. While the reason for this has not been elucidated, it is believed that inflammation could be the key component linking the two conditions. Adenosine, an endogenous purine nucleoside, has been strongly implicated in asthma pathophysiology and also has potent effects on the cardiovascular system. This work was undertaken to gain a better understanding of the relationship between asthma and its cardiovascular effects, and more specifically the possible role adenosine plays under these conditions.;We hypothesize that asthmatic lung inflammation translates into systemic inflammation and alters vascular responses where adenosine plays an important role. Therefore, this study investigated the effects of aerosolized adenosine, used to elevate lung adenosine levels, on vascular reactivity and inflammation in a well established mouse model of allergic asthma established in our lab. We found that allergic mice had poor vasorelaxation to adenosine and systemic inflammation, in addition to lung inflammation, and aerosolized adenosine exacerbated these effects. Data indicated a possible role for A1 adenosine receptor (AR) in altered vascular reactivity and inflammation. Based on these findings, we next studied the effects of adenosine using genetically modified mice in which the A1 AR gene was deleted (A1KO) and corresponding A1 wild-type (A1WT) mice, in which the A1 receptor was present.;Allergic A1KO mice had no systemic inflammation, and the adenosine-mediated vasorelaxation responses obtained were comparable to non-allergic mice. Aerosolized adenosine also did not have any effect in A1KO mice. On the other hand, allergic A1WT mice had lower aortic relaxation response to non-selective adenosine analog NECA, presence of significantly higher levels of inflammatory cytokines in plasma and higher airway responsiveness to NECA, compared to non-allergic A1WT controls and all groups of A 1KO mice, with aerosolized adenosine exacerbating all these responses. From these data, it can be concluded that asthmatic mice had poor vascular responses and inflammation, possibly mediated through the A1 AR.
Ponnoth, Dovenia S., "Involvement of adenosine A1 receptors in systemic inflammation and altered vascular reactivity in allergic mice" (2008). Graduate Theses, Dissertations, and Problem Reports. 4416.