Alveolar Epithelial A2B Adenosine Receptors in Pulmonary Protection during Acute Lung Injury.
Alveolar Epithelial A2B Adenosine Receptors in Pulmonary Protection during Acute Lung Injury.
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DOI：
10.4049/jimmunol.1401957
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发表时间：
2015-08-15
期刊：
影响因子：
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通讯作者：
Eltzschig HK
中科院分区：
文献类型：
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作者：
Hoegl S;Brodsky KS;Blackburn MR;Karmouty-Quintana H;Zwissler B;Eltzschig HK
急性肺损伤(ALI)是一种急性炎症性肺部疾病，可导致危重患者的发病率和死亡率。然而，有许多情况下，ALI通过内源性途径自发缓解，有助于控制过度的肺部炎症。以前的研究表明，细胞外信号分子腺苷和通过A2B腺苷受体的信号事件在肺保护中起作用。在此背景下，我们假设A2B腺苷受体的组织特异性表达是先前描述的ALI减弱的原因。为了解决这一假设，我们将组织特异性Adora2b缺失的小鼠暴露于ALI，利用两次击打模型，在该模型中，气管内注射内毒素后进行损伤性机械通气。有趣的是，对髓系(Adora2bloxP/loxP LysM Cre+)、内皮细胞(Adora2bloxP/loxP VE-Cherin Cre+)或肺泡上皮细胞(Adora2bloxP/loxP SPC Cre+)缺失Adora2b的小鼠进行头对头比较发现，Adora2bloxP/loxP SPC Cre+小鼠疾病易感性有选择性地增加。对Adora2bloxP/loxP SPC Cre+小鼠的更详细分析证实，肺部炎症增加，肺泡液清除减弱。为了将A2B腺苷受体特异性激动剂直接输送到肺泡上皮细胞，我们随后进行了吸入海湾60-6583的研究。事实上，雾化海湾60-6583治疗与减轻肺水肿、改善组织学肺损伤和抑制肺部炎症有关。总之，这些发现提示肺泡上皮A2B腺苷受体信号转导有助于肺保护，并提示吸入性A2B腺苷受体激动剂在ALI治疗中的作用。
Acute lung injury (ALI) is an acute inflammatory lung disease that causes morbidity and mortality in critically ill patients. However, there are many instances where ALI resolves spontaneously through endogenous pathways that help to control excessive lung inflammation. Previous studies have implicated the extracellular signaling molecule adenosine and signaling events through the A2B adenosine receptor in lung protection. In this context, we hypothesized that tissue-specific expression of the A2B adenosine receptor is responsible for the previously described attenuation of ALI. To address this hypothesis, we exposed mice with tissue-specific deletion of Adora2b to ALI, utilizing a two-hit-model where intratracheal LPS treatment is followed by injurious mechanical ventilation. Interestingly, a head-to-head comparison of mice with deletion of Adora2b in the myeloid lineage (Adora2bloxP/loxP LysM Cre+), endothelial cells (Adora2bloxP/loxP VE-Cadherin Cre+) or alveolar epithelial cells (Adora2bloxP/loxP SPC Cre+) revealed a selective increase in disease susceptibility in Adora2bloxP/loxP SPC Cre+ mice. More detailed analysis of Adora2bloxP/loxP SPC Cre+ mice confirmed elevated lung inflammation and attenuated alveolar fluid clearance. To directly deliver an A2B adenosine receptor-specific agonist to alveolar-epithelial cells, we subsequently performed studies with inhaled BAY 60-6583. Indeed, aerosolized BAY 60-6583 treatment was associated with attenuated pulmonary edema, improved histologic lung injury and dampened lung inflammation. Together these findings suggest that alveolar epithelial A2B adenosine receptor signaling contributes to lung protection, and implicate inhaled A2B adenosine receptor agonists in ALI treatment.