Ischemia-reperfusion (IR) lung injury, a common cause of lung transplant failure, is characterized by hypoxemia, alveolar damage, inflammation, and edema. As novel lung preservation techniques could have a significant clinical impact in this setting, we employed an animal model of IR injury to investigate the potential therapeutic role of simvastatin, an agent we have previously characterized as a potent vascular barrier protectant (Jacobson JR et al, 2004 and 2005). Ischemia was induced in anesthetized Sprague-Dawley rats by ligation of the left pulmonary artery for a period of 1 hour followed by 4 hours of reperfusion. Indices of inflammation and vascular leak, including bronchoalveolar lavage (BAL) cell counts and protein content and lung tissue myeloperoxidase activity, were then assessed. Similar to the protective effects we previously observed with sphingosine 1-phosphate in this model (Moreno L, 2004), BAL from animals pretreated with simvastatin (20 mg/kg, intraperitoneal injection, 16 hours prior to ischemia) demonstrated a reduced number of total cells (48.3% decrease), neutrophils (33% decrease), and albumin concentration (20.7% decrease) compared to controls. A single dose of simvastatin also resulted in reduced (49% decrease) lung tissue MPO. These data indicate that simvastastin significantly attenuates the protein leakage and inflammation associated with IR lung injury in our animal model. Ultimately, our results could have profound clinical implications as simvastatin treatment may represent a potential agent to reduce the incidence and severity of IR injury associated with lung transplantation.
Funded by Parker B Francis Foundation.