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THE ROLE OF MICROVASCULAR THROMBOSIS IN PARTICULATE MATTER (PM) AND PM COMPONENT-INDUCED CARDIOVASCULAR EFFECTS: OXIDATIVE STRESS AS A MEDIATOR OF THROMBOSIS
Impact/Purpose:
This project will provide an important linkage to pulmonary and cardiovascular system whereby PM effects on cardiac physiology will be mechanistically explained. In addition, this project also will determine why humans with cardiovascular disease may be more susceptible to increased blood coagulation and how anticoagulation therapy may reduce their risk.
Description:
Particulate matter (PM) exposure has been associated with increased plasma fibrinogen. We have found that Spontaneously hypertensive rats respond to PM by increasing fibrinogen and plasminogen activator inhibitor -1 at PM concentration that would cause minimal changes in healthy Wistar Kyoto rats. Although increases in plasma fibrinogen have been reported in many studies, whether this effect is associated with increased clot formation or decreased clot degradation and how PM-induced oxidative-stress/inflammation may be involved in the mechanism of microvascular thrombosis is not investigated. Additionally, it is also not known how these pulmonary microvascular and endothelial changes trigger a systemic vascular response and affect cardiac physiology. We believe that SH rat is an appropriate model to investigate PM cardiovascular susceptibility and microvascular thrombosis. It is hypothesized that cardiac physiological changes are partly due to systemic response which involve increased microvascular thrombosis. Microvascular thrombosis is mediated by increased oxidative stress imposed by PM in the lung tissue. This research will use interventional approaches to determine if thrombogenic activity of PM can be modulatedand if so, are thrombomodulin and PAI-1 involved. The extent to which thrombomodulin receptor mediated cell signaling is involved and how oxidative stress mediate thrombomodulin and plasminogen activator inhibitor pathway will be determined.