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Interferon-gamma and pulmonary macrophages contribute to the mechanisms underlying prolonged airway hyperresponsiveness.

机译：γ-干扰素和肺巨噬细胞有助于延长气道高反应性。

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BACKGROUND: 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. OBJECTIVE: Using improved methods of assessing AHR in a mouse model of allergic airway disease, to investigate the basis of the development of prolonged AHR. METHOD: 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. RESULTS: 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. CONCLUSION: 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.
机译：背景：哮喘患者的气道高反应性（AHR）包括可变成分，该成分在过敏原激发后仍然持续存在。这可能与炎症细胞募集分离，暗示驻留的肺细胞在调节反应中起作用。目的：使用改良的评估过敏性气道疾病小鼠模型中AHR的方法，研究延长AHR发展的基础。方法：对BALB / c小鼠进行全身致敏，然后用雾化的卵清蛋白（OVA）攻击。在最后一次OVA攻击后的基线，第1天，第1、2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，通过单克隆抗体的阻断或清除来评估IFN-γ以及CCR3（+）和CD4（+）细胞在延长的AHR发生中的作用。通过选择性化学消耗这些细胞来评估肺巨噬细胞的作用。结果：最后一次OVA攻击后1天，气道反应性增加至基线以上，并持续1周。相比之下，在1天时，组织特异性反应仅比基线显着增加。 IFN-γ的中和或肺巨噬细胞的耗竭抑制了延长的AHR的发展，但CD4（+）T细胞或CCR3（+）嗜酸性粒细胞的耗竭却没有抑制作用。结论：γ-干扰素与肺巨噬细胞之间的相互作用促进了气道高反应性的延长。相反，T细胞和嗜酸性粒细胞无助于AHR的延长。这些发现强调了先天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目标的潜在相关性。

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