Protective effect of purinergic agonist ATPγS against acute lung injury
Protective effect of purinergic agonist ATPγS against acute lung injury
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DOI：
10.1152/ajplung.00283.2007
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发表时间：
2008-02-01
影响因子：
4.9
通讯作者：
Verin, Alexander D.
中科院分区：
文献类型：
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作者：
Kolosova, Irina A.;Mirzapoiazova, Tamara;Verin, Alexander D.
急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是急性呼吸衰竭的主要原因，发病率和死亡率很高。尽管 ALI/ARDS 发病机制尚不明确，但肺内皮在调节肺液平衡和肺水肿形成方面发挥着重要作用。因此，内皮靶向治疗可能对 ALI/ARDS 产生有益作用。最近，嘌呤能激动剂和拮抗剂用于治疗心血管和肺部疾病的治疗潜力受到关注。细胞外嘌呤（腺苷、ADP 和 ATP）和嘧啶（UDP 和 UTP）是重要的信号分子，通过细胞表面 P2Y 受体介导多种生物效应。我们之前描述了 ATP 通过复杂的细胞信号传导诱导内皮细胞 (EC) 屏障增强，并假设内皮嘌呤受体激活以发挥抗炎屏障保护作用。为了检验这一假设，我们使用了气管内施用内毒素/脂多糖（LPS）诱导的 ALI 小鼠模型和培养的肺 EC。非水解的 ATP 类似物 ATP gamma S（最终血液浓度为 50-100 μM）可减弱炎症反应，减少支气管肺泡灌洗液中细胞（48%，P < 0.01）和蛋白质（57%，P < 0.01）的积累，并减少中性粒细胞浸润和伊文思蓝白蛋白染料外渗到肺组织中。在细胞培养模型中，ATP gamma S 抑制 LPS 诱导的连接通透性。这些发现表明，嘌呤能受体刺激通过保护内皮细胞-细胞连接的完整性，发挥针对 ALI 的保护作用。
Acute lung injury (ALI) and acute respiratory distress syndrome ( ARDS) are major causes of acute respiratory failure associated with high morbidity and mortality. Although ALI/ARDS pathogenesis is only partly understood, pulmonary endothelium plays a major role by regulating lung fluid balance and pulmonary edema formation. Consequently, endothelium-targeted therapies may have beneficial effects in ALI/ARDS. Recently, attention has been given to the therapeutic potential of purinergic agonists and antagonists for the treatment of cardiovascular and pulmonary diseases. Extracellular purines ( adenosine, ADP, and ATP) and pyrimidines (UDP and UTP) are important signaling molecules that mediate diverse biological effects via cell-surface P2Y receptors. We previously described ATP-induced endothelial cell (EC) barrier enhancement via a complex cell signaling and hypothesized endothelial purinoreceptors activation to exert anti-inflammatory barrier-protective effects. To test this hypothesis, we used a murine model of ALI induced by intratracheal administration of endotoxin/lipopolysaccharide (LPS) and cultured pulmonary EC. The nonhydrolyzed ATP analog ATP gamma S (50-100 mu M final blood concentration) attenuated inflammatory response with decreased accumulation of cells (48%, P < 0.01) and proteins (57%, P < 0.01) in bronchoalveolar lavage and reduced neutrophil infiltration and extravasation of Evans blue albumin dye into lung tissue. In cell culture model, ATP gamma S inhibited junctional permeability induced by LPS. These findings suggest that purinergic receptor stimulation exerts a protective role against ALI by preserving integrity of endothelial cell-cell junctions.