Abstract
ABSTRACTInfants with intrauterine growth retardation (IUGR) have a high risk of developing bronchial asthma in childhood, but the underlying mechanisms remain unclear. This study aimed to disclose the role of vascular non-inflammatory molecule 1 (vannin-1, encoded by the Vnn1 gene) and its downstream signaling in IUGR asthmatic mice induced by ovalbumin. Significant histological alterations and an increase of vannin-1 expression were revealed in IUGR asthmatic mice, accompanied by elevated methylation of Vnn1 promoter regions. In IUGR asthmatic mice, we also found (i) a direct binding of HNF4α and PGC1α to Vnn1 promoter by ChIP assay; (ii) a direct interaction of HNF4α with PGC1α; (iii) upregulation of phospho-PI3K p85/p55 and phospho-AktSer473 and downregulation of phospho-PTENTyr366, and (iv) an increase in nuclear NFκB p65 and a decrease in cytosolic IκB-α. In primary cultured bronchial epithelial cells derived from the IUGR asthmatic mice, knockdown of Vnn1 prevented upregulation of phospho-AktSer473 and an increase of reactive oxygen species (ROS) and TGF-β production. Taken together, we demonstrate that elevated vannin-1 activates the PI3K/Akt/NFκB signaling pathway, leading to ROS and inflammation reactions responsible for asthma occurrence in IUGR individuals. We also disclose that interaction of PGC1α and HNF4α promotes methylation of Vnn1 promoter regions and then upregulates vannin-1 expression.
Highlights
In recent years, the survival rate of premature and low birth weight infants has increased year by year globally with the continuous development of perinatal medicine, assisted reproductive technology and rescue technology for infants
Asthma is induced in the nmIUG and the intrauterine growth retardation (IUGR) mice As previously described (Fu et al, 2006; Xing et al, 2019), the normal intrauterine growth and the IUGR pups were produced by feeding female mice with normal and low protein diets, respectively
Asthma was induced with OVA in 6-week-old IUGR and nmIUG mice, whereas the PBS inductions were used as the controls
Summary
The survival rate of premature and low birth weight infants has increased year by year globally with the continuous development of perinatal medicine, assisted reproductive technology and rescue technology for infants. With the increasing incidence of IUGR, the pathogenesis and physiological mechanism of bronchial asthma have been continuously recognized and updated. At present, it mainly focuses on inflammation, immune response changes and airway remodeling caused by abnormal subepithelial myofibroblasts and chronic inflammation. Many studies have shown that activation of the PI3K/Akt pathway plays an important role in the development of asthma by activating oxidative stress and inflammatory responses (Wagh et al, 2017; Yang et al, 2018). The molecular mechanism of bronchial asthma in IUGR children is not clear
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