Apolipoprotein E deficient mouse에서 clodronate liposomes가 저밀도 콜레스테롤과 carrageenan 피하조직 주입 시 발생되는 염증에 미치는 영향
(The) Effect of Clodronate Liposomes on the Inflammatory Reaction Provoked by Subcutaneous Injection of LDL-Cholesterol or Carrageenan in Apolipoprotein E Deficient Mouse
Apolipoprotein E deficient mouse clodronate liposomes 콜레스테롤 carrageenan 피하조직;
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Background: Inflammation is the main event in the initiation and progression of atherosclerosis, and each characteristic lesion of atherosclerosis represents a different stage in a chronic inflammatory process in the artery. Continued inflammation results in increased numbers of macrophages and lymphocytes, which both emigrate from the blood and multiply within the lesion. Mononuclear phagocytes and T-lymphocytes are the main inflammatory cells in the initiation and progression of atherosclerosis. Macrophage internalizes modified LDL-cholesterol through scavenger receptors, and these processes give rise to the foam cells. Modulation of this foam cell infiltration can be a great effect to the process of atherosclerosis, and clodronate liposomes are known to destroy phagocytic cells such as macrophages, thereby affecting the process of atherosclerosis. Objective: Monocytes and macrophages are recruited in response to subcutaneous injection of LDL-cholesterol and carrageenan in Apo E deficient mice, and the process of differentiation from macrophages to foam cells were observed. Subcutaneous injection of carrageenan can elicit acute inflammation, thereby recruiting inflammatory cells such as macrophages, and subcutaneous injection of LDL-cholesterol can provoke chronic inflammation. We want to find out the effect of clodronate liposomes injection on the macrophage-mediated inflammatory reaction provoked by subcutaneous injection of LDL-cholesterol or carrageenan in Apolipoprotein E deficient mouse. Methods: We used 48 apolipoprotein E deficient mice, and they were divided into 2 groups (clodronate liposomes group vs. vehicle liposomes group). In each group, they were further divided into carrageenan subgroup (n=12) and LDL-cholesterol subgroup (n=12). Proportions of circulating blood monocytes were calculated with Fluorescence Activated Cell Sorter (FACS) analysis after 24 hours, 1 week, and 2 weeks after the initiation of clodronate liposomes injections. The effect of circulating blood monocytes numbers in subcutaneous tissue of either carrageenan or LDL-cholesterol was observed. Seven and 14 days after subcutaneous injection of either carrageenan or LDL-cholesterol, histologic changes were compared between two groups by using H&E staining and immunohistochemistry with CD68 antibodies. Results: 1. FACS analysis of peripheral blood showed that more than 75% of peripheral monocytes were depleted 24 hours after intravenous injection of clodronate liposomes, and less than 1% of peripheral monocytes remained after 2 weeks of intravenous injection. No significant differences in numbers of peripheral monocytes were notes after peritoneal injection of clodronate liposomes. 2. After intravenous injection of clodronate liposomes, macrophages and foam cells decreased in number at the subcutaneous tissue of carrageenan injection (42±23 vs. 303±74, 2 weeks after clodronate liposomes vs. control liposomes, respectively). 3. Only intravenous injection of clodronate liposomes was effective in macrophage depletion compared with peritoneal injection. 4. Subcutaneous injection of LDL-cholesterol did not elicit acute inflammatory reactions. Conclusion: Macrophage infiltrations at the site of carrageenan injection decreased significantly after intravenous clodronate liposomes injection, and we suggest more applications in the research field of atherosclerosis to find out the effect of macrophage modulation in the initiation and progression of atherosclerosis.