Therapeutic anti-inflammatory effects of myeloid cell adenosine receptor A2a stimulation in lipopolysaccharide-induced lung injury
Therapeutic anti-inflammatory effects of myeloid cell adenosine receptor A2a stimulation in lipopolysaccharide-induced lung injury
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DOI：
10.4049/jimmunol.179.2.1254
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发表时间：
2007-07-15
影响因子：
4.4
通讯作者：
Ley, Klaus
中科院分区：
文献类型：
--
作者：
Reutershan, Jorg;Cagnina, Rebecca E.;Ley, Klaus
为了确定腺苷受体A2 a在LPS诱导的肺损伤小鼠模型中的作用，通过流式细胞术测定多形核白细胞（PMN）向肺的不同隔室的迁移，通过伊文思蓝外渗评估微血管通透性，并通过ELISA测定趋化细胞因子向肺泡气隙的释放。在野生型和A2 a基因缺陷型小鼠（A2 a（-1-））中进行测量。为了区分A2 a对造血和非造血细胞的作用，我们通过在野生型和A2 a（-1-）小鼠之间转移骨髓（BM）来创建嵌合小鼠，并使用在骨髓细胞上选择性缺乏A2 a表达的小鼠（A2 a（flox/flox）x LysM-cre）。使用特异性A2 a受体激动剂（ATL 202）来评估其在体内减少肺损伤的潜力。在野生型小鼠中，用ATL 202治疗性处理减少了LPS诱导的PMN募集和细胞因子的释放。治疗前，但不是治疗后，也减少了伊文思蓝外渗。在BM衍生细胞上缺乏A2 a的BM嵌合小鼠中，PMN向肺泡腔的迁移增加了约50%。这些发现在A2 a（flox/flox）x LysM-cre小鼠中得到证实。ATL 202仅在A2 a存在于BM衍生细胞上时有效。A2 a激动剂可有效抑制炎性肺组织损伤。
To determine the role of the adenosine receptor A2a in a murine model of LPS-induced lung injury, migration of polymorphonuclear leukocytes (PMNs) into the difirerent compartments of the lung was determined by flow cytometry, microvascular permeability was assessed by the extravasation of Evans blue, and the release of chernotactic cytokines into the alveolar airspace was determined by ELISA. Measurements were performed in wild-type and A2a gene-deficient mice (A2a(-1-)). To differentiate the role of A2a on hemopoietic and nonhemopoietic cells, we created chimeric mice by transfer of bone marrow (BM) between wild-type and A2a(-1-) mice and used mice that lacked A2a expression selectively on myeloid cells (A2a(flox/flox) x LysM-cre). A specific A2a receptor agonist (ATL202) was used to evaluate its potential to reduce lung injury in vivo. In wild-type mice, therapeutic treatment with ATL202 reduced LPS-induced PMN recruitment, and release of cytokines. Pretreatment, but not posttreatment, also reduced Evans blue extravasation. In the BM chimeric mice lacking A2a on BM-derived cells, PMN migration into the alveolar space was increased by similar to 50%. These findings were confirmed in A2a(flox/flox) x LysM-cre mice. ATL202 was only effective when A2a was present on BM-derived cells. A2a agonists may be effective at curbing inflammatory lung tissue damage.