• Research Summary of Lusha Xiang, MD

    Trauma-Induced Lung Injury in Obesity

    Obese and Type II diabetic patients with orthopedic trauma exhibit higher risk of multiple organ failure as compared to lean patients.  Pulmonary edema is the earliest and most frequent outcome and a major cause of mortality. However, the mechanisms responsible for increased risk of pulmonary edema following orthopedic trauma in obese and type II diabetic patients are unclear, providing difficulties in prevention and treatment of these complications. 

    Hyperglycemia in obese and Type II diabetic subjects increases sensitivity and vulnerability to orthopedic trauma via elevated reactive oxygen species (ROS). As compared with lean patients, obese individuals with orthopedic trauma exhibit increased ROS, systemic inflammation, and complications, more strongly correlated to plasma glucose levels in a dose dependent manner than BMI or dyslipidemia. My published data shows in the obese Zucker rat (OZ), a model of obesity with hyperglycemia and elevated ROS, that orthopedic trauma exacerbates inflammation and increases pulmonary capillary permeability leading to a protein-rich pulmonary edema.  The pulmonary edema in OZ with orthopedic trauma (OZT) is associated with elevated circulating prostaglandin E2 (PGE2).   Treatment of PGE2   in isolated lungs results in a larger increase in capillary permeability in OZ as compared with lean rats.  Additionally, preliminary studies show that OZ exhibits an increased basal pulmonary vascular permeability, with this high permeability improved following anti-superoxide treatment. These results suggest that OZ is more vulnerable to develop pulmonary edema in response to orthopedic trauma. The overall goal of my research is therefore to determine that in obesity and Type II diabetics, hyperglycemia and resultant ROS increase basal lung vascular permeability which exacerbates trauma-induced inflammation leading to increases in COX-2-dependent PGE2, further increasing the pulmonary permeability and causing pulmonary edema (Figure).

    The Impaired Hyperemic Response in Obesity 

    Obese individuals exhibit a blunted increase in blood flow in response to exercise (functional hyperemia), which prevents patients from adequate exercise, a useful therapy for weight control, metabolic disorders and cardiovascular disease. We have demonstrated that the functional vasodilation is attenuated in OZ.  This blunted hyperemic response is associated with a decreased prostacyclin synthesis, elevated thromboxane receptor activation, and impaired K ATP channel function.  In addition, we found that the adipocyte-derived relaxing factors (ADFs) can decrease the vasodilator capacity of skeletal muscle arterioles due to a K ATP-dependent loss of basal arteriolar tone.  Although the nature of ADFs is unclear, our study suggests that they are unlikely proteins (at lease structure dependent on their vasodilator function) or lipids.   We also showed that these altered vascular function and responses in OZ are related to insulin resistance, hyperglycemia, and elevated ROS.  Exercise training or insulin sensitizer not only improves the insulin resistance but also increases the functional vasodilation and exercise capacity in OZ.