Abstract：
Exaggeration of type 2 immune responses promotes lung inflammation and altered lung development; however, eosinophils, despite expansion in the postnatal lung, have not been specifically assessed in the context of neonatal lung disease. Furthermore, early life factors including prematurity and respiratory infection predispose infants to chronic obstructive pulmonary disease later in life. To assess eosinophils in the developing lung and how they may contribute to chronic lung disease, we generated mice harboring eosinophil-specific deletion of the negative regulatory enzyme SH2 domain-containing inositol 5\' phosphatase-1. This increased the activity and number of pulmonary eosinophils in the developing lung, which was associated with impaired lung development, expansion of activated alveolar macrophages (AMφ), multinucleated giant cell formation, enlargement of airspaces, and fibrosis. Despite regression of eosinophils following completion of lung development, AMφ-dominated inflammation persisted, alongside lung damage. Bone marrow chimera studies showed that SH2 domain-containing inositol 5\' phosphatase-1-deficient eosinophils were not sufficient to drive inflammatory lung disease in adult steady-state mice but once inflammation and damage were present, it could not be resolved. Depletion of eosinophils during alveolarization alleviated pulmonary inflammation and lung pathology, demonstrating an eosinophil-intrinsic effect. These results show that the presence of activated eosinophils during alveolarization aggravates AMφs and promotes sustained inflammation and long-lasting lung pathology.
摘要：
2型免疫反应的夸大促进肺部炎症和改变肺部发育;然而，嗜酸性粒细胞,尽管出生后肺部扩张，尚未在新生儿肺部疾病的背景下进行具体评估。此外，包括早产和呼吸道感染在内的早期因素使婴儿在以后的生活中易患慢性阻塞性肺疾病。为了评估正在发育的肺部中的嗜酸性粒细胞以及它们如何导致慢性肺部疾病，我们产生了具有嗜酸性粒细胞特异性负调节酶SHIP-1缺失的小鼠。这增加了正在发育的肺中的肺嗜酸性粒细胞的活性和数量，这与肺发育受损有关，活化肺泡巨噬细胞（AMφ）的扩增，多核巨细胞形成，扩大空域,和纤维化。尽管肺发育完成后嗜酸性粒细胞消退，以AMφ为主的炎症持续存在，伴随着肺损伤。骨髓嵌合体研究表明，SHIP-1缺乏的嗜酸性粒细胞不足以驱动成年稳态小鼠的炎症性肺病，但一旦出现炎症和损伤，它无法解决。肺泡化过程中嗜酸性粒细胞的消耗减轻了肺部炎症和肺部病理，显示嗜酸性粒细胞的内在作用。这些结果表明，肺泡化过程中激活的嗜酸性粒细胞的存在会加重AMφs，并促进持续的炎症和持久的肺部病理。
