Xu Lingqi, Ma Shurong, Qu Minhan, Li Na, Sun Xu, Wang Tingting, Chen Lulu, Zhu Jie, Ding Yifang, Gong Yuan, Hu Fangjie, Dong Zhenzhen, Zhang Rui, Wang Jiang Huai, Wang Jian, Zhou Huiting
Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China.
Department of Surgery, Children's Hospital of Soochow University, Suzhou, China.
Cell Death Discov. 2024 Jul 31;10(1):345. doi: 10.1038/s41420-024-02114-z.
Necrotizing enterocolitis (NEC) involves intestinal epithelial damage and inflammatory response and is associated with high morbidity and mortality in infants. To improve therapeutic prospects, elucidating underlying molecular mechanisms of intestinal epithelial damage during NEC is of the essence. Poly (ADP-ribose) polymerase 1 (PARP1)-dependent parthanatos is a programmed inflammatory cell death. In the present study, the presence of parthanatos-associated proteins PARP1 and poly (ADP-ribose) (PAR), along with high expression of DNA damage-associated biomarkers, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and phosphorylation of histone H2AX (γH2AX), were discovered in the intestinal tissues of NEC infants. Additionally, the upregulated expression of PARP1 and PAR in NEC intestinal tissues correlated distinctly with clinical indices indicative of NEC incidence and severity. Furthermore, we demonstrated that inhibiting the expression of parthanatos-associated proteins, by either pharmacological blockage using 3-aminobenzamide (3-AB), an inhibitor of PARP1, or genetic knockout using Parp1-deficient mice, resulted in substantial improvements in both histopathological severity scores associated with intestinal injury and inflammatory reactions. Moreover, in an in vitro NEC model, reactive oxygen species (ROS)-induced DNA damage promoted the formation of PAR and nuclear translocation of apoptosis-inducing factor (AIF), thus activating PARP1-dependent parthanatos in Caco-2 cells and human intestinal organoids. Our work verifies a previously unexplored role for parthanatos in intestinal epithelial damage during NEC and suggests that inhibition of parthanatos may serve as a potential therapeutic strategy for intervention of NEC.
坏死性小肠结肠炎（NEC）涉及肠道上皮损伤和炎症反应，且与婴儿的高发病率和死亡率相关。为改善治疗前景，阐明NEC期间肠道上皮损伤的潜在分子机制至关重要。聚（ADP-核糖）聚合酶1（PARP1）依赖性细胞焦亡是一种程序性炎症细胞死亡。在本研究中，在NEC婴儿的肠道组织中发现了与细胞焦亡相关的蛋白质PARP1和聚（ADP-核糖）（PAR），以及DNA损伤相关生物标志物8-羟基-2'-脱氧鸟苷（8-OHdG）和组蛋白H2AX磷酸化（γH2AX）的高表达。此外，NEC肠道组织中PARP1和PAR的表达上调与指示NEC发病率和严重程度的临床指标明显相关。此外，我们证明，通过使用PARP1抑制剂3-氨基苯甲酰胺（3-AB）进行药理学阻断或使用Parp1基因敲除小鼠进行基因敲除来抑制与细胞焦亡相关的蛋白质的表达，可使与肠道损伤和炎症反应相关的组织病理学严重程度评分得到显著改善。此外，在体外NEC模型中，活性氧（ROS）诱导的DNA损伤促进了PAR的形成和凋亡诱导因子（AIF）的核转位，从而激活了Caco-2细胞和人肠道类器官中PARP1依赖性细胞焦亡。我们的工作证实了细胞焦亡在NEC期间肠道上皮损伤中以前未被探索的作用，并表明抑制细胞焦亡可能作为干预NEC的潜在治疗策略。
