Department of Rheumatology Immunology & Allergy, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, People's Republic of China.
Department of Pathology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, People's Republic of China.
Respir Res. 2023 Feb 14;24(1):50. doi: 10.1186/s12931-023-02360-2.
Intrauterine growth restriction (IUGR) is strongly correlated with an increased risk of asthma later in life. Farm dust protects mice from developing house dust mite-induced asthma, and loss of ubiquitin modifying enzyme A20 in lung epithelium would abolish this protective effect. However, the mechanisms of A20 in the development of asthma following IUGR remains unknown.
An IUGR rat model induced by maternal nutrient restriction was used for investigating the role of A20 in the response characteristics of IUGR rats to ovalbumin (OVA) challenge. The ubiquitination of proteins and N6-methyladenosine (m6A) modifications were used to further assess the potential mechanism of A20.
IUGR can reduce the expression of A20 protein in lung tissue of newborn rats and continue until 10 weeks after birth. OVA challenging can increase the expression of A20 protein in lung tissue of IUGR rats, but its level was still significantly lower than the control OVA group. The differentially ubiquitinated proteins in lung tissues were also observed in IUGR and normal newborn rats. Furthermore, this ubiquitination phenomenon continued from the newborn to adulthood. In the detected RNA methylations, m6A abundance of the motif GGACA was the highest. The higher abundances of m6A modification of A20 mRNA from IUGR were negatively correlated with the trend of A20 protein levels.
These findings indicate A20 as a key regulator during the development of asthma following IUGR, providing further insight into the prevention of asthma induced by environmental factors.
宫内生长受限（IUGR）与日后发生哮喘的风险增加密切相关。农田灰尘可保护小鼠免受屋尘螨诱导的哮喘，而肺上皮细胞中泛素修饰酶 A20 的缺失则会消除这种保护作用。然而，A20 在 IUGR 后发展为哮喘的机制尚不清楚。
采用母体营养限制诱导的 IUGR 大鼠模型，研究 A20 在 IUGR 大鼠对卵清蛋白（OVA）挑战反应特征中的作用。采用泛素化和 N6-甲基腺苷（m6A）修饰来进一步评估 A20 的潜在机制。
IUGR 可降低新生大鼠肺组织中 A20 蛋白的表达，并持续至出生后 10 周。OVA 挑战可增加 IUGR 大鼠肺组织中 A20 蛋白的表达，但水平仍明显低于对照 OVA 组。在 IUGR 和正常新生大鼠的肺组织中也观察到差异泛素化蛋白。此外，这种泛素化现象从新生儿持续到成年。在所检测的 RNA 甲基化中，GGACA 基序的 m6A 丰度最高。IUGR 中 A20 mRNA 的 m6A 修饰丰度越高，与 A20 蛋白水平的趋势呈负相关。
这些发现表明 A20 是 IUGR 后哮喘发展的关键调节因子，为预防环境因素引起的哮喘提供了进一步的见解。
