Konrad Franziska M, Zwergel Constantin, Ngamsri Kristian-Christos, Reutershan Jörg
Department of Anesthesiology and Intensive Care Medicine, University Hospital of Tübingen, Tübingen, Germany.
Department of Anesthesiology and Intensive Care Medicine, Hospital of Bayreuth, Bayreuth, Germany.
Front Immunol. 2017 Dec 20;8:1874. doi: 10.3389/fimmu.2017.01874. eCollection 2017.
Acute pulmonary inflammation is still a frightening complication in intensive care units. In our previous study, we determined that heme oxygenase (HO)-1 had anti-inflammatory effects in pulmonary inflammation. Recent literature has emphasized a link between HO-1 and the nucleotide adenosine. Since adenosine A- and A-receptors play a pivotal role in pulmonary inflammation, we investigated their link to the enzyme HO-1. In a murine model of pulmonary inflammation, the activation of HO-1 by hemin significantly decreased polymorphonuclear leukocyte (PMN) migration into the lung. This anti-inflammatory reduction of PMN migration was abolished in A- and A-knockout mice. Administration of hemin significantly reduced chemokine levels in the BAL of wild-type animals but had no effects in A and A mice. Microvascular permeability was significantly attenuated in HO-1-stimulated wild-type mice, but not in A and A mice. The activity of HO-1 rose after LPS inhalation in wild-type animals and, surprisingly, also in A and A mice after the additional administration of hemin. Immunofluorescence images of animals revealed alveolar macrophages to be the major source of HO-1 activity in both knockout strains-in contrast to wild-type animals, where HO-1 was also significantly augmented in the lung tissue. studies on PMN migration further confirmed our findings. In conclusion, we linked the anti-inflammatory effects of HO-1 to functional A/A-receptor signaling under conditions of pulmonary inflammation. Our findings may explain why targeting HO-1 in acute pulmonary inflammation has failed to prove effective in some patients, since septic patients have altered adenosine receptor expression.
急性肺部炎症仍是重症监护病房中令人恐惧的并发症。在我们之前的研究中，我们确定血红素加氧酶（HO）-1在肺部炎症中具有抗炎作用。最近的文献强调了HO-1与核苷酸腺苷之间的联系。由于腺苷A和A受体在肺部炎症中起关键作用，我们研究了它们与HO-1酶的联系。在肺部炎症的小鼠模型中，血红素激活HO-1可显著减少多形核白细胞（PMN）向肺部的迁移。在A和A基因敲除小鼠中，这种PMN迁移的抗炎性减少被消除。给予血红素可显著降低野生型动物支气管肺泡灌洗液中的趋化因子水平，但对A和A小鼠没有影响。在HO-1刺激的野生型小鼠中，微血管通透性显著降低，但在A和A小鼠中没有降低。野生型动物吸入脂多糖后HO-1的活性升高，令人惊讶的是，在额外给予血红素后，A和A小鼠的HO-1活性也升高。动物的免疫荧光图像显示，与野生型动物相比，在两种基因敲除品系中，肺泡巨噬细胞是HO-1活性的主要来源，在野生型动物中，肺组织中的HO-1也显著增加。对PMN迁移的研究进一步证实了我们的发现。总之，我们将HO-1的抗炎作用与肺部炎症条件下功能性A/A受体信号传导联系起来。我们的发现可能解释了为什么在急性肺部炎症中靶向HO-1在一些患者中未能证明有效，因为脓毒症患者的腺苷受体表达发生了改变。
