Department of Immunology, Allergology and Immunotoxicology, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany.
Clin Exp Allergy. 2011 Apr;41(4):592-601. doi: 10.1111/j.1365-2222.2010.03636.x. Epub 2010 Nov 9.
Bronchial asthma is characterized by airway inflammation and reversible obstruction. Since the gold standard of therapy, a combination of anti-inflammatory corticosteroids and bronchodilatory β(2) agonists, has recently been discussed to be related to an increased mortality, there is a need for novel therapeutic pathways.
A new experimental concept that encompasses the vasoactive intestinal peptide/pituitary adenylate cyclase activating peptide (PACAP) family of receptors by demonstrating the anti-inflammatory effects of the PACAP receptor 1 (PAC1R) in a murine model of allergic asthma is described.
PAC1R expression was investigated in lung tissue and isolated dendritic cells (DCs) via real-time PCR. Ovalbumin (OVA)-induced asthma models were used in PAC1R-deficient mice and BALB/c mice treated with PAC1R agonist maxadilan (MAX). Bronchoalveolar lavages have been performed and investigated at the cellular and cytokine levels. Fluorescence staining of a frozen lung section has been performed to detect eosinophil granulocytes in lung tissue. Plasma IgE levels have been quantified via the ELISA technique. Lung function was determined using head-out body plethysmography or whole-body plethysmography.
Increased PAC1R mRNA expression in lung tissue was present under inflammatory conditions. PAC1R expression was detected on DCs. In OVA-induced asthma models, which were applied to PAC1R-deficient mice (PAC1R(-/-)) and to BALB/c mice treated with the specific PAC1R agonist MAX, PAC1R deficiency resulted in inflammatory effects, while agonistic stimulation resulted in anti-inflammatory effects. No effects on lung function were detected both in the gene-depletion and in the pharmacologic studies. In summary, here, we demonstrate that anti-inflammatory effects can be achieved via PAC1R.
PAC1R agonists may represent a promising target for an anti-inflammatory therapy in airway diseases such as bronchial asthma.
支气管哮喘的特征是气道炎症和可逆转的阻塞。由于抗炎皮质类固醇和支气管扩张β（2）激动剂的联合治疗最近被认为与死亡率增加有关，因此需要新的治疗途径。
描述了一种新的实验概念，该概念通过在过敏性哮喘的小鼠模型中证明血管活性肠肽/垂体腺苷酸环化酶激活肽（PACAP）家族受体的 PACAP 受体 1（PAC1R）的抗炎作用，涵盖了该受体家族。
通过实时 PCR 研究肺组织和分离的树突状细胞（DC）中的 PAC1R 表达。在 PAC1R 缺陷型小鼠和用 PAC1R 激动剂 maxadilan（MAX）处理的 BALB/c 小鼠中进行卵清蛋白（OVA）诱导的哮喘模型。进行支气管肺泡灌洗，并在细胞和细胞因子水平上进行研究。通过荧光染色冷冻肺切片检测肺组织中的嗜酸性粒细胞粒细胞。通过 ELISA 技术定量测定血浆 IgE 水平。使用头出式体描仪或全身体描仪测定肺功能。
在炎症条件下，肺组织中 PAC1R mRNA 表达增加。在 DC 上检测到 PAC1R 表达。在应用于 PAC1R 缺陷型小鼠（PAC1R（-/-））和用特异性 PAC1R 激动剂 MAX 处理的 BALB/c 小鼠的 OVA 诱导的哮喘模型中，PAC1R 缺乏导致炎症作用，而激动剂刺激导致抗炎作用。在基因耗竭和药理学研究中均未检测到对肺功能的影响。总之，在这里，我们证明 PAC1R 可以实现抗炎作用。
PAC1R 激动剂可能成为支气管哮喘等气道疾病抗炎治疗的有前途的靶点。
