Inflammatory response induced in pulmonary embolic lung: Evaluation usinga reproducible murine pulmonary embolism model.

Abstract

BackgroundSince previously established models of pulmonary embolism showed a large variability in the degree of ischemia, it is difficult to assess the pathophysiological response in the lung after embolization. Here, we established a model of pulmonary embolism by certain amount of relatively small thrombi, in which the degree of ischemia was reproducible. MethodsThrombi with a maximum diameter of 100 m or 500 m were administered intravenously under anesthesia, and the survival ratio at 4 hours was evaluated. The location of thrombi in the lung was visualized by administration of fluorescent-labeled thrombus, and the hemodynamics of the lung after administration of thrombi was evaluated. CT angiography was also performed to evaluate the ratio of the embolized vessels. In addition, cytokine mRNAs was quantified 4 hours in embolized lung. Immunohistochemical analysis for interleukin (IL)-6 and CD68 as a marker of macrophages were also performed. ResultsIt was found that mice with 100 m clots, but not with 500 m clots, showed a dose-dependence of survival between 2.3 L/g and 3.0 L/g at 4 hours from embolization induction. In mice treated with 2.5 L/g of 100 m thrombus, thrombi were located in the peripheral region of the lung, which was consistent with the disruption of blood circulation the peripheral region. In addition, about 60% of the vessels with a diameter of less than 100 m were occluded in these mice. In the lungs after 4 hours of embolization, IL-6 mRNA and tumor necrosis factor (TNF)- mRNA were significantly higher and lower than control lungs. IL-6 was expressed in CD68-positive macrophages in both embolized and control lungs after 4 hours of embolization, and the number of each positive cells were comparable in both embolized and control lungs. ConclusionsThese results show that the pulmonary embolization model induced by a certain amount of small thrombus is useful for evaluating the pathological responses in the embolized lung. Furthermore, it was found that IL-6 expression was increased in macrophages in the embolized lung, indicating that inflammatory responses may contribute to the pathogenesis of pulmonary embolism.