在过敏性气道炎症小鼠模型中，垂体腺苷酸环化酶激活肽受体1介导了抗炎效应
2010/12/31
摘要
背景：支气管哮喘表现为气道炎症和可逆性气道阻塞。联合抗炎的皮质类固醇和支气管扩张剂（b2受体激动剂）已经成为哮喘治疗的金标准。但近期研究显示，该治疗与死亡率增加相关。因此，有必要选择新的治疗途径。
目的：近期，有关针对血管活性肠肽/垂体腺苷酸环化酶激活肽受体(PACAP)家族的动物实验显示，PACAP受体1（PAC1R）在鼠类过敏性哮喘模型中具有抗炎作用。
方法：采用实时PCR，检测肺组织和分离的树突状细胞（DCs）中PAC1R 的表达。在PAC1R缺陷小鼠和采用PAC1R激动剂（maxadilan [MAX]）治疗的BALB/c小鼠中，采用卵清蛋白（OVA）建立哮喘模型。收集支气管肺泡灌洗液，在细胞水平和细胞因子水平对其进行研究。对冰冻肺组织切片进行荧光染色，检测肺组织嗜酸粒细胞。血浆IgE水平通过ELISA检测。采用头体体积描记法或全身体积描记法检测肺功能。
结果：在炎症环境下，肺组织中的PAC1R mRNA表达显著增加。DCs也存在PAC1R 表达。在OVA诱导的哮喘小鼠中，PAC1R缺陷导致炎症反应，而BALB/c小鼠给予PAC1R激动剂刺激后发现具有抗炎作用。两组小鼠均未见到对肺功能产生影响。总之，我们的结果显示，PAC1R在体内具有一定的抗炎作用。
结论：PAC1R激动剂可能有希望成为治疗气道疾病（支气管哮喘）新型抗炎药物。
（陈欣 审校）
Clin Exp Allergy. 2010 Nov 9. doi: 10.1111/j.1365-2222.2010.03636.x. [Epub ahead of print]
Pituitary adenylate cyclase-activating peptide receptor 1 mediates anti-inflammatory effects in allergic airway inflammation in mice.
Lauenstein HD, Quarcoo D, Plappert L, Schleh C, Nassimi M, Pilzner C, Rochlitzer S, Brabet P, Welte T, Hoymann HG, Krug N, Müller M, Lerner EA, Braun A, Groneberg DA.
Department of Immunology, Allergology and Immunotoxicology, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany Clinic for Pneumology, Hannover Medical School, Hannover, Germany Institute of Occupational Medicine, Charité-Universitätsmedizin Berlin, Free University Berlin and Humboldt University, Berlin, Germany Institut des Neurosciences de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, MA, USA.
Abstract
Background 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. Objective 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. Methods 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. Results 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. Conclusion PAC1R agonists may represent a promising target for an anti-inflammatory therapy in airway diseases such as bronchial asthma.
Clin Exp Allergy. 2010 Nov 9. doi: 10.1111/j.1365-2222.2010.03636.x. [Epub ahead of print]
背景：支气管哮喘表现为气道炎症和可逆性气道阻塞。联合抗炎的皮质类固醇和支气管扩张剂（b2受体激动剂）已经成为哮喘治疗的金标准。但近期研究显示，该治疗与死亡率增加相关。因此，有必要选择新的治疗途径。
目的：近期，有关针对血管活性肠肽/垂体腺苷酸环化酶激活肽受体(PACAP)家族的动物实验显示，PACAP受体1（PAC1R）在鼠类过敏性哮喘模型中具有抗炎作用。
方法：采用实时PCR，检测肺组织和分离的树突状细胞（DCs）中PAC1R 的表达。在PAC1R缺陷小鼠和采用PAC1R激动剂（maxadilan [MAX]）治疗的BALB/c小鼠中，采用卵清蛋白（OVA）建立哮喘模型。收集支气管肺泡灌洗液，在细胞水平和细胞因子水平对其进行研究。对冰冻肺组织切片进行荧光染色，检测肺组织嗜酸粒细胞。血浆IgE水平通过ELISA检测。采用头体体积描记法或全身体积描记法检测肺功能。
结果：在炎症环境下，肺组织中的PAC1R mRNA表达显著增加。DCs也存在PAC1R 表达。在OVA诱导的哮喘小鼠中，PAC1R缺陷导致炎症反应，而BALB/c小鼠给予PAC1R激动剂刺激后发现具有抗炎作用。两组小鼠均未见到对肺功能产生影响。总之，我们的结果显示，PAC1R在体内具有一定的抗炎作用。
结论：PAC1R激动剂可能有希望成为治疗气道疾病（支气管哮喘）新型抗炎药物。
（陈欣 审校）
Clin Exp Allergy. 2010 Nov 9. doi: 10.1111/j.1365-2222.2010.03636.x. [Epub ahead of print]
Pituitary adenylate cyclase-activating peptide receptor 1 mediates anti-inflammatory effects in allergic airway inflammation in mice.
Lauenstein HD, Quarcoo D, Plappert L, Schleh C, Nassimi M, Pilzner C, Rochlitzer S, Brabet P, Welte T, Hoymann HG, Krug N, Müller M, Lerner EA, Braun A, Groneberg DA.
Department of Immunology, Allergology and Immunotoxicology, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany Clinic for Pneumology, Hannover Medical School, Hannover, Germany Institute of Occupational Medicine, Charité-Universitätsmedizin Berlin, Free University Berlin and Humboldt University, Berlin, Germany Institut des Neurosciences de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, MA, USA.
Abstract
Background 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. Objective 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. Methods 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. Results 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. Conclusion PAC1R agonists may represent a promising target for an anti-inflammatory therapy in airway diseases such as bronchial asthma.
Clin Exp Allergy. 2010 Nov 9. doi: 10.1111/j.1365-2222.2010.03636.x. [Epub ahead of print]
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