Role of the lipoxygenase pathway in RSV-induced alternatively activated macrophages leading to resolution of lung pathology.
Role of the lipoxygenase pathway in RSV-induced alternatively activated macrophages leading to resolution of lung pathology.
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呼吸道合胞病毒诱导的严重毛细支气管炎的缓解是由交替激活的巨噬细胞(AA-Mϕ)介导的，该细胞对抗环氧合酶(COX)-2诱导的肺病理。在此，我们报告呼吸道合胞病毒感染5-脂氧合酶(LO)−/−和15-LO−/−巨噬细胞或小鼠不能诱导AA-Mϕ分化，并伴随COX-2表达增加。此外，呼吸道合胞病毒感染5-LO−/−小鼠可导致肺组织病理加重。药物抑制5-LO或15-LO也可阻断呼吸道合胞病毒诱导的AA-Mϕ的分化，反之，5-LO−/−巨噬细胞的下游产物脂氧素A4(LXA4)和解决素E1(RvE1)可部分恢复AA-Mϕ标志物的表达。吲哚美辛阻断RSV感染的巨噬细胞COX活性可增加5-LO、15-LO以及精氨酸酶-1mRNA的表达。消炎痛治疗呼吸道合胞病毒感染的5-LO−/−小鼠，不仅可增加肺组织精氨酸酶-1mRNA的表达，降低环氧合酶-2的表达，还可减轻肺组织的病理改变。用COX-2特异性抑制剂治疗呼吸道合胞病毒感染的棉花大鼠后，肺组织5-LOmRNA和AA-Mϕ的表达增强。总之，这些数据提示了一种新的治疗呼吸道合胞病毒的方法，即通过激活5-LO途径来促进AA-Mϕ的分化。
Resolution of severe RSV-induced bronchiolitis is mediated by alternatively activated macrophages (AA-Mϕ) that counteract cyclooxygenase (COX)-2-induced lung pathology. Herein, we report that RSV infection of 5-lipoxygenase (LO)−/− and 15-LO−/− macrophages or mice failed to elicit AA-Mϕ differentiation and concomitantly exhibited increased COX-2 expression. Further, RSV infection of 5-LO−/− mice resulted in enhanced lung pathology. Pharmacologic inhibition of 5-LO or 15-LO also blocked differentiation of RSV-induced AA-Mϕ in vitro and, conversely, treatment of 5-LO−/− macrophages with downstream products, lipoxin A4 (LXA4) and resolvin E1 (RvE1), but not leukotriene B4 (LTB4) or LTD4, partially restored expression of AA-Mϕ markers. Indomethacin blockade of COX activity in RSV-infected macrophages increased 5-LO, and 15-LO, as well as arginase-1 mRNA expression. Treatment of RSV-infected mice with indomethacin also resulted not only in enhanced lung arginase-1 mRNA expression and decreased COX-2, but also, decreased lung pathology in RSV-infected 5-LO−/− mice. Treatment of RSV-infected cotton rats with a COX-2-specific inhibitor resulted in enhanced lung 5-LO mRNA and AA-Mϕ marker expression. Together, these data suggest a novel therapeutic approach for RSV that promotes AA-Mϕ differentiation by activating the 5-LO pathway.
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DOI：
10.4161/hv.6.6.11562
发表时间：
2010-06
期刊：
Human vaccines
影响因子：
--
作者：
Blanco JC;Boukhvalova MS;Shirey KA;Prince GA;Vogel SN
通讯作者：
Vogel SN
影响因子：
6.4
作者：
Shay, DK;Holman, RC;Anderson, LJ
通讯作者：
Anderson, LJ
影响因子：
8
作者：
Null, D;Bimle, C;Top, FH
通讯作者：
Top, FH
影响因子：
4.4
作者：
Richardson, JY;Ottolini, MG;Blanco, JCG
通讯作者：
Blanco, JCG
DOI：
10.4049/jimmunol.181.6.4159
发表时间：
2008-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Shirey KA;Cole LE;Keegan AD;Vogel SN
通讯作者：
Vogel SN