Dept. of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Guggenheim 1334, 200 First St. S.W., Rochester, MN 55905, USA.
Am J Physiol Lung Cell Mol Physiol. 2012 Jan 15;302(2):L185-92. doi: 10.1152/ajplung.00274.2010. Epub 2011 Oct 14.
The neurotransmitter dopamine and its dopamine receptor D2 (D2DR) agonists are known to inhibit vascular permeability factor/vascular endothelial growth factor (VEGF)-mediated angiogenesis and vascular permeability. Lung injury is a clinical syndrome associated with increased microvascular permeability. However, the effects of dopamine on pulmonary edema, a phenomenon critical to the pathophysiology of both acute and chronic lung injuries, have yet to be established. Therefore, we sought to determine the potential therapeutic effects of dopamine in a murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Compared with sham-treated controls, pretreatment with dopamine (50 mg/kg body wt) ameliorated LPS-mediated edema formation and lowered myeloperoxidase activity, a measure of neutrophil infiltration. Moreover, dopamine significantly increased survival rates of LPS-treated mice, from 0-75%. Mechanistically, we found that dopamine acts through the VEGF-VEGFR2 axis to reduce pulmonary edema, as dopamine pretreatment in LPS-treated mice resulted in decreased serum VEGF, VEGFR2 phosphorylation, and endothelial nitric oxide synthase phosphorylation. We used D2DR knockout mice to confirm that dopamine acts through D2DR to block vascular permeability in our lung injury model. As expected, a D2DR agonist failed to reduce pulmonary edema in D2DR(-/-) mice. Taken together, our results suggest that dopamine acts through D2DR to inhibit pulmonary edema-associated vascular permeability, which is mediated through VEGF-VEGFR2 signaling and conveys protective effects in an ALI model.
神经递质多巴胺及其多巴胺受体 D2（D2DR）激动剂已知可抑制血管通透性因子/血管内皮生长因子（VEGF）介导的血管生成和血管通透性。肺损伤是一种与微血管通透性增加相关的临床综合征。然而，多巴胺对肺水肿（急性和慢性肺损伤病理生理学的关键现象）的影响尚未确定。因此，我们试图确定多巴胺在脂多糖（LPS）诱导的急性肺损伤（ALI）小鼠模型中的潜在治疗作用。与假处理对照相比，多巴胺（50mg/kg 体重）预处理可改善 LPS 介导的水肿形成，并降低髓过氧化物酶活性（中性粒细胞浸润的衡量标准）。此外，多巴胺还显著提高了 LPS 处理小鼠的存活率，从 0%到 75%。从机制上讲，我们发现多巴胺通过 VEGF-VEGFR2 轴发挥作用，减少肺水肿，因为多巴胺预处理可降低 LPS 处理小鼠的血清 VEGF、VEGFR2 磷酸化和内皮型一氧化氮合酶磷酸化。我们使用 D2DR 敲除小鼠来确认多巴胺通过 D2DR 来阻止我们的肺损伤模型中的血管通透性。正如预期的那样，D2DR 激动剂未能减少 D2DR(-/-)小鼠的肺水肿。总之，我们的研究结果表明，多巴胺通过 D2DR 抑制与肺水肿相关的血管通透性，这是通过 VEGF-VEGFR2 信号传导介导的，并在 ALI 模型中提供保护作用。
