GSDMD deficiency ameliorates hyperoxia-induced BPD and ROP in neonatal mice.
GSDMD deficiency ameliorates hyperoxia-induced BPD and ROP in neonatal mice.
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DOI：
10.1038/s41598-022-27201-y
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发表时间：
2023-01-04
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
支气管肺发育不良（BPD）和早产儿视网膜病变（ROP）是影响接受氧疗的极早产儿的最常见疾病。许多临床研究表明 BPD 与晚期 ROP 相关。然而，高氧、BPD 和 ROP 之间的机制联系仍有待探索。 Gasdermin D (GSDMD) 是炎症小体诱导的细胞焦亡和炎症的关键执行者。抑制 GSDMD 已被证明可以减轻新生小鼠高氧诱导的 BPD 和脑损伤。本研究的目的是进一步明确 GSDMD 在小鼠模型高氧诱导的 BPD 和 ROP 发病机制中的机制作用。在这里，我们表明，全局 GSDMD 敲除 (GSDMD-KO) 通过减少巨噬细胞浸润、改善肺泡化和血管发育以及减少细胞死亡来预防高氧诱导的 BPD。此外，GSDMD 缺乏可通过减少血管闭塞和新生血管形成、改善多个视网膜组织层变薄以及减少小胶质细胞活化来预防高氧诱导的 ROP。对肺和视网膜的 RNA 测序分析表明，在两种模型中，相似的基因，包括来自炎症、细胞死亡、组织重塑以及组织和血管发育信号通路的基因，都是由高氧诱导的，并受到 GSDMD-KO 的影响。这些数据强调了 GSDMD 在 BPD 和 ROP 发病机制中的重要性，并表明针对 GSDMD 可能有利于预防和治疗早产儿 BPD 和 ROP。
Bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) are among the most common morbidities affecting extremely premature infants who receive oxygen therapy. Many clinical studies indicate that BPD is associated with advanced ROP. However, the mechanistic link between hyperoxia, BPD, and ROP remains to be explored. Gasdermin D (GSDMD) is a key executor of inflammasome-induced pyroptosis and inflammation. Inhibition of GSDMD has been shown to attenuate hyperoxia-induced BPD and brain injury in neonatal mice. The objective of this study was to further define the mechanistic roles of GSDMD in the pathogenesis of hyperoxia-induced BPD and ROP in mouse models. Here we show that global GSDMD knockout (GSDMD-KO) protects against hyperoxia-induced BPD by reducing macrophage infiltration, improving alveolarization and vascular development, and decreasing cell death. In addition, GSDMD deficiency prevented hyperoxia-induced ROP by reducing vasoobliteration and neovascularization, improving thinning of multiple retinal tissue layers, and decreasing microglial activation. RNA sequencing analyses of lungs and retinas showed that similar genes, including those from inflammatory, cell death, tissue remodeling, and tissue and vascular developmental signaling pathways, were induced by hyperoxia and impacted by GSDMD-KO in both models. These data highlight the importance of GSDMD in the pathogenesis of BPD and ROP and suggest that targeting GSDMD may be beneficial in preventing and treating BPD and ROP in premature infants.
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影响因子：
9.3
作者：
Galvani G;Mottolese N;Gennaccaro L;Loi M;Medici G;Tassinari M;Fuchs C;Ciani E;Trazzi S
通讯作者：
Trazzi S
影响因子：
37.8
作者：
Huang X;Dai Z;Cai L;Sun K;Cho J;Albertine KH;Malik AB;Schraufnagel DE;Zhao YY
通讯作者：
Zhao YY
影响因子：
16.6
作者：
Kariotis S;Jammeh E;Swietlik EM;Pickworth JA;Rhodes CJ;Otero P;Wharton J;Iremonger J;Dunning MJ;Pandya D;Mascarenhas TS;Errington N;Thompson AAR;Romanoski CE;Rischard F;Garcia JGN;Yuan JX;An TS;Desai AA;Coghlan G;Lordan J;Corris PA;Howard LS;Condliffe R;Kiely DG;Church C;Pepke-Zaba J;Toshner M;Wort S;Gräf S;Morrell NW;Wilkins MR;Lawrie A;Wang D;UK National PAH Cohort Study Consortium
通讯作者：
UK National PAH Cohort Study Consortium
影响因子：
8
作者：
Klinger, Gil;Levy, Itzhak;Reichman, Brian
通讯作者：
Reichman, Brian
影响因子：
6
作者：
Alrashdi, Saeed F.;Deliyanti, Devy;Wilkinson-Berka, Jennifer L.
通讯作者：
Wilkinson-Berka, Jennifer L.