DataSheet_1_Airway allergy causes alveolar macrophage death, profound alveolar disorganization and surfactant dysfunction.pdf

Respiratory disorders caused by allergy have been associated to bronchiolar inflammation leading to life-threatening airway narrowing. However, whether airway allergy causes alveolar dysfunction contributing to the pathology of allergic asthma remains unaddressed. To explore whether airway allergy causes alveolar dysfunction that might contribute to the pathology of allergic asthma, alveolar structural and functional alterations were analyzed during house dust mite (HDM)-induced airway allergy in mice, by flow cytometry, light and electron microscopy, monocyte transfer experiments, assessment of intra-alveolarly-located cells, analysis of alveolar macrophage regeneration in Cx3cr1cre:R26-yfp chimeras, analysis of surfactant-associated proteins, and study of lung surfactant biophysical properties by captive bubble surfactometry. Our results demonstrate that HDM-induced airway allergic reactions caused severe alveolar dysfunction, leading to alveolar macrophage death, pneumocyte hypertrophy and surfactant dysfunction. SP-B/C proteins were reduced in allergic lung surfactant, that displayed a reduced efficiency to form surface-active films, increasing the risk of atelectasis. Original alveolar macrophages were replaced by monocyte-derived alveolar macrophages, that persisted at least two months after the resolution of allergy. Monocyte to alveolar macrophage transition occurred through an intermediate stage of pre-alveolar macrophage and was paralleled with translocation into the alveolar space, Siglec-F upregulation, and downregulation of CX3CR1. These data support that the severe respiratory disorders caused by asthmatic reactions not only result from bronchiolar inflammation, but additionally from alveolar dysfunction compromising an efficient gas exchange.

过敏引起的呼吸系统疾病与细支气管炎症相关，进而导致生命威胁性的气道狭窄。然而，气道过敏是否会引起肺泡功能障碍，从而加剧过敏性哮喘的病理进程，这一问题尚未得到解决。为了探究气道过敏是否会引起肺泡功能障碍，进而可能对过敏性哮喘的病理产生影响，本研究通过流式细胞术、光学和电子显微镜、单核细胞转移实验、评估肺泡内定位细胞、Cx3cr1cre:R26-yfp嵌合体中肺泡巨噬细胞再生的分析、表面活性物质相关蛋白的分析，以及通过封闭气泡表面活性剂滴定法研究肺表面活性剂的生物物理性质，对小鼠在尘螨诱导的气道过敏过程中肺泡的结构和功能改变进行了分析。我们的研究结果表明，尘螨诱导的气道过敏性反应导致了严重的肺泡功能障碍，表现为肺泡巨噬细胞死亡、肺泡上皮细胞肥大和表面活性物质功能障碍。过敏性肺表面活性物质中的SP-B/C蛋白含量降低，表面活性剂形成表面活性膜的效率降低，增加了肺不张的风险。原位肺泡巨噬细胞被单核细胞来源的肺泡巨噬细胞所替代，这种替代至少持续到过敏反应的解决后两个月。单核细胞向肺泡巨噬细胞的转化过程通过前肺泡巨噬细胞的中间阶段，并与肺泡空间内的转移、Siglec-F的上调以及CX3CR1的下调相伴随。这些数据支持了严重的呼吸系统疾病不仅由支气管炎症引起，而且还由肺泡功能障碍引起，这种功能障碍损害了有效的气体交换。