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Inflammatory Response Induced in Pulmonary Embolic Lung: Evaluation Using a Reproducible Murine Pulmonary Embolism Model

Honoka Okabe, Haruka Kato, Momoka Yoshida, Mayu Kotake, Ruriko Tanabe, Yasuki Matano, Masaki Yoshida, Shintaro Nomura, Atsushi Yamashita, Nobuo Nagai*

Background: To assess the pathophysiological response in pulmonary embolism, we established a novel model using a certain volume of relatively small thrombi in mice.

Methods: Thrombi with a maximum diameter of 100 μm or 500 μm were administered intravenously under anesthesia, and the survival ratio was evaluated at 4 hours. The thrombus location, hemodynamics and Computed Tomography (CT) angiography was assessed after thrombus administration. In addition, quantification of cytokine mRNAs and immunohistochemical analysis for interleukin (IL)-6 and CD68 as a macrophage marker were also performed in normal and embolized lungs at 4 hours.

Results: Mice with 100 μm clots showed a dose-dependent survival between 2.3 μL/g and 3.0 μL/g 4 hours after embolization. The thrombi were located at the peripheral region of the lung, which was consistent with the disruption of blood circulation. In CT angiography analysis, approximately 60% of vessels with a diameter of less than 100 μm was occluded in these mice. IL-6 and tumor necrosis factor alpha mRNA were significantly higher and lower, respectively, in embolized lungs than in normal lungs at 4 hours. In both the normal and embolized lungs, IL-6 was expressed in CD68-positive macrophages, and their numbers were comparable.

Conclusion: These results show that the pulmonary embolism model induced by a certain amount of small clot is highly reproducible and useful for evaluating pathophysiological responses in the embolized lung. Furthermore, it was found that inflammatory responses shown by IL-6 increase may contribute to the pathogenesis in early stage of pulmonary embolism.