Immunophenotyping of Acute Inflammatory Exacerbations of Lung Injury Driven by Mutant Surfactant Protein-C: A Role for Inflammatory Eosinophils.
Immunophenotyping of Acute Inflammatory Exacerbations of Lung Injury Driven by Mutant Surfactant Protein-C: A Role for Inflammatory Eosinophils.
复制标题
DOI：
10.3389/fphar.2022.875887
复制
发表时间：
2022
影响因子：
5.6
通讯作者：
Venosa, Alessandro
中科院分区：
文献类型：
--
作者：
Nguyen, Jacklyn;Armstrong, Brittnie S.;Cowman, Sophie;Tomer, Yaniv;Veerabhadraiah, Shivakumar R.;Beers, Michael F.;Venosa, Alessandro
关键词：
急性炎症加重（AIE）代表许多慢性肺部疾病（包括COPD、哮喘和肺纤维化（PF））的免疫驱动恶化。一线治疗以广谱免疫调节为代表。在AIE期间动员的几种炎症群体中，嗜酸性粒细胞已被确定为活动性炎症恶化的有希望的指标。为了更好地研究AIE-PF期间的嗜酸性粒细胞-实质串扰，这项工作利用了由肺泡上皮2型细胞表面活性蛋白-C基因[SP-CI 73 T]中突变的诱导表达触发的炎症加重的临床相关模型。对照和SP-CI 73 T突变体在与嗜酸性粒细胞增多峰值（14天）协调的时间的无偏单细胞测序分析定义了嗜酸性粒细胞中升高的炎症活化、趋化性和存活信号传导（IL-6、IL-4/13、STAT 3、糖皮质激素受体、mTOR和MYC）。为了研究嗜酸性粒细胞在炎症恶化中的影响，将SP-CI 73 T系与嗜酸性粒细胞谱系缺陷小鼠（GATA 1 Δdbl）杂交以产生SP-CI 73 TGATA 1 KO系。时程分析（7-42天）证明SP-CI 73 TGATA 1 KO队列中肺组织学、存活率改善，炎症减少。光谱流式细胞术的组织凝集证实了嗜酸性粒细胞耗竭的GATA 1 KO小鼠和中性粒细胞和未成熟单核细胞募集的代偿性转变的情况下。嗜酸性粒细胞缺失导致单核细胞衍生的巨噬细胞累积进行性（损伤后14天），同时CD 3 + CD 4+淋巴细胞和B220+ B细胞丰度下降。组织化学分析显示SP-CI 73 TGATA 1 KO小鼠的非典型炎症细胞活化，Arg-1+和iNOS+细胞数量减少，但支气管肺泡灌洗液细胞和组织中tgfb 1 mRNA表达增加。地塞米松治疗（每天lmg/kg，i. p.）用于研究皮质类固醇在由突变体SP-CI 73 T诱导的高度嗜酸性粒细胞性加重中的功效。地塞米松在第14天时成功降低了总嗜酸性粒细胞（CD 11b +SigF+ CD 11 c −）计数，并与结构损伤和血管周围浸润证据减少有关。总之，这些结果说明了嗜酸性粒细胞在肺纤维化之前的炎性事件中的有害作用，并证明了皮质类固醇治疗在由突变体SP-CI 73 T诱导的高度嗜酸性粒细胞加重中的功效。
Acute inflammatory exacerbations (AIEs) represent immune-driven deteriorations of many chronic lung conditions, including COPD, asthma, and pulmonary fibrosis (PF). The first line of therapy is represented by broad-spectrum immunomodulation. Among the several inflammatory populations mobilizing during AIEs, eosinophils have been identified as promising indicators of an active inflammatory exacerbation. To better study the eosinophil-parenchymal crosstalk during AIE-PF, this work leverages a clinically relevant model of inflammatory exacerbations triggered by inducible expression of a mutation in the alveolar epithelial type 2 cell Surfactant Protein-C gene [SP-CI73T]. Unbiased single-cell sequencing analysis of controls and SP-CI73T mutants at a time coordinated with peak eosinophilia (14 days) defined heightened inflammatory activation, chemotaxis, and survival signaling (IL-6, IL-4/13, STAT3, Glucocorticoid Receptor, mTOR, and MYC) in eosinophils. To study the impact of eosinophils in inflammatory exacerbations, the SP-CI73T line was crossed with eosinophil lineage deficient mice (GATA1Δdbl) to produce the SP-CI73TGATA1KO line. Time course analysis (7–42 days) demonstrated improved lung histology, survival, and reduced inflammation in SP-CI73TGATA1KO cohorts. Spectral flow cytometry of tissue digests confirmed eosinophil depletion in GATA1KO mice and the absence of a compensatory shift in neutrophils and immature monocyte recruitment. Eosinophil deletion resulted in progressive monocyte-derived macrophage accumulation (14 days post-injury), combined with declines in CD3+CD4+ lymphocyte and B220+ B cell abundance. Histochemical analysis revealed atypical inflammatory cell activation in SP-CI73TGATA1KO mice, with reduced numbers of Arg-1+ and iNOS+ cells, but increases in tgfb1 mRNA expression in bronchoalveolar lavage cells and tissue. Dexamethasone treatment (1 mg/kg daily, i.p.) was utilized to investigate corticosteroid efficacy in highly eosinophilic exacerbations induced by mutant SP-CI73T. Dexamethasone successfully reduced total and eosinophil (CD11b+SigF+CD11c−) counts at 14 days and was linked to reduced evidence of structural damage and perivascular infiltrate. Together, these results illustrate the deleterious role of eosinophils in inflammatory events preceding lung fibrosis and demonstrate the efficacy of corticosteroid treatment in highly eosinophilic exacerbations induced by mutant SP-CI73T.
登录
查看更多内容
影响因子：
8
作者：
Habiel DM;Espindola MS;Kitson C;Azzara AV;Coelho AL;Stripp B;Hogaboam CM
通讯作者：
Hogaboam CM
影响因子：
5.5
作者：
Beamer, Celine A.;Migliaccio, Christopher T.;Holian, Andrij
通讯作者：
Holian, Andrij
DOI：
10.1152/ajplung.00217.2014
发表时间：
2015-01-01
影响因子：
4.9
作者：
Hawkins, Arie;Guttentag, Susan H.;Beers, Michael F.
通讯作者：
Beers, Michael F.
DOI：
10.1165/rcmb.2020-0387oc
发表时间：
2021-06-01
影响因子：
6.4
作者：
Ali, Mohamed F.;Egan, Ashley M.;Carmona, Eva M.
通讯作者：
Carmona, Eva M.
影响因子：
5.8
作者：
Behr J;Richeldi L
通讯作者：
Richeldi L