Centre for Asthma and Respiratory Disease, School of Biomedical Sciences, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW 2300, Australia.
Clin Exp Allergy. 2010 Jan;40(1):163-73. doi: 10.1111/j.1365-2222.2009.03393.x. Epub 2009 Nov 6.
Airway hyperresponsiveness (AHR) in asthmatics includes a variable component that persists following an allergen challenge. This may be dissociated from inflammatory cell recruitment, implying a role for resident pulmonary cells in regulating the response.
Using improved methods of assessing AHR in a mouse model of allergic airway disease, to investigate the basis of the development of prolonged AHR.
BALB/c mice were systemically sensitized and then challenged with aerosolized ovalbumin (OVA). Airway and tissue responsiveness were measured at baseline and at 1 day, and 1, 2 and 3 weeks after the last OVA challenge. Inflammatory cell numbers in BALF and levels of mRNA for eotaxin-1 and -2, IFN-gamma, IL-5 and -13 in the lung were measured at each time-point. In further experiments, the roles of IFN-gamma and of CCR3(+) and CD4(+) cells in the development of prolonged AHR were assessed by blockade or depletion with monoclonal antibodies. The role of pulmonary macrophages was assessed by selective chemical depletion of these cells.
Airway responsiveness was increased above baseline at 1 day after the last OVA challenge, and this was sustained for 1 week. In contrast, tissue-specific responsiveness was only significantly increased above baseline at 1 day. Development of prolonged AHR was inhibited by neutralization of IFN-gamma or by depletion of pulmonary macrophages, but not by depletion of either CD4(+) T cells or CCR3(+) eosinophils.
An interaction between IFN-gamma and pulmonary macrophages contributed to the prolongation of airway hyperresponsiveness. In contrast, T cells and eosinophils did not contribute to prolongation of AHR. These findings emphasize the importance of the innate host response in the development of manifestations of asthma, as well as its potential relevance as a target for therapeutic intervention.
哮喘患者的气道高反应性（AHR）包括一个随变的成分，这种成分在变应原刺激后持续存在。这种变应原刺激后气道高反应性可能与炎症细胞募集相分离，这暗示了肺固有细胞在调节反应中的作用。
使用改良的方法评估过敏性气道疾病小鼠模型中的 AHR，以研究持续 AHR 发展的基础。
BALB/c 小鼠经全身致敏，然后用雾化卵清蛋白（OVA）进行攻击。在基线和最后一次 OVA 攻击后 1 天、1 周、2 周和 3 周测量气道和组织反应性。在每个时间点测量 BALF 中的炎症细胞数量以及肺中 eotaxin-1 和 -2、IFN-γ、IL-5 和 -13 的 mRNA 水平。在进一步的实验中，通过单克隆抗体阻断或耗竭来评估 IFN-γ以及 CCR3(+)和 CD4(+)细胞在持续 AHR 发展中的作用。通过选择性化学耗竭这些细胞来评估肺巨噬细胞的作用。
最后一次 OVA 攻击后 1 天，气道反应性高于基线，且持续 1 周。相比之下，组织特异性反应性仅在第 1 天显著高于基线。IFN-γ中和或肺巨噬细胞耗竭抑制了持续 AHR 的发展，但 CD4(+)T 细胞或 CCR3(+)嗜酸性粒细胞耗竭则没有抑制。
IFN-γ与肺巨噬细胞之间的相互作用导致气道高反应性的延长。相反，T 细胞和嗜酸性粒细胞对 AHR 的延长没有贡献。这些发现强调了固有宿主反应在哮喘表现发展中的重要性，以及其作为治疗干预靶点的潜在相关性。
