An endogenous amniotic fluid-derived 10-amino acid peptide improves lung development and hyperoxia injury.

Background: Bronchopulmonary dysplasia (BPD) is a chronic lung disease that occurs in preterm infants and lacks effective treatment. We aim to reveal the relationship between amniotic fluid (AF) peptides and lung development by analyzing the differences in the composition of AF peptides at different gestational periods, thus providing a new means of prevention and treatment for BPD. Methods: Based on the stages of lung development, we collected AF by amniocentesis in two different gestational periods, using the 25th week of pregnancy as the cut-off. We conducted a peptide omics analysis of these AF samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Additionally, we verified the regulatory effects of hyperoxia and the peptide COL5A2 on BPD-related cells [(mouse lung epithelial (MLE-12) cells] by 5-Ethynyl-2'-deoxyuridine (EdU) staining, JC-1 staining, flow cytometry, and reactive oxygen species (ROS) assay. Results: There were 131 differentially expressed peptides, including 85 up-regulated and 46 down-regulated [fold change (FC) ≥1.2 or ≤1/1.2, P<0.05], in the ≥25 weeks' gestation group compared to the <25 weeks' gestation group. Further bioinformatics analysis revealed that the precursor proteins of the differentially expressed peptides between these two groups were involved in the regulation of the developmental process, anatomical structure development, and other biological processes, suggesting that these differential peptides may play a key role in lung development. We found peptide COL5A2 with the sequence GPPGEPGPPG and verified the regulatory effects of COL5A2 on the proliferation, apoptosis, cell viability, and ROS levels of MLE-12 cells by cell assays. Conclusions: In this study, peptidomic studies using AF from different gestational periods revealed that peptides in AF may be involved in lung development. They could be used in the future to assist in the postnatal development of preterm infants and provide new therapeutic prospects for BPD.

Airway exposure to perfluorooctanoate exacerbates airway hyperresponsiveness and downregulates glucocorticoid receptor expression in asthmatic mice.

BACKGROUND: Multiple environmental risk factors play a vital role in the pathogenesis of asthma, which contribute to the phenotypic expression of asthma. Perfluorooctanoate (PFOA) is the most common and abundant perfluorocarbon (PFC) in humans, and it has been detected in water and the atmosphere worldwide. Glucocorticoid receptor (GR) is considered to exert a protective effect on asthma and is associated with the sensitivity to glucocorticoids. Dermal or oral exposure to PFOA has been shown to contribute various effects on airway inflammation in individuals with ovalbumin (OVA)-induced asthma. Notably, airway exposure has a critical contribution to the pathogenesis of asthma. However, the effect of airway exposure to PFOA on airway hyperresponsiveness (AHR) in patients with asthma is not currently understood. METHODS: BALB/c mice were administered OVA to induce asthma. PFOA was then administered intratracheally to OVA-induced mice for seven days. Then we assessed the effect of airway exposure to PFOA on AHR and the regulation of the GR expression in asthmatic mice. RESULTS: The results showed aggravated AHR and T helper type 2 (Th2) airway inflammation in asthmatic mice. Furthermore, these mice show a substantial decrease in the expression of the GR mRNA and protein. CONCLUSIONS: These data strongly suggest that acute airway exposure to PFOA leads to Th2-related AHR and decreases GR expression, which may increase the difficulty in the treatment of asthma.

Inhibiting the Notch signaling pathway suppresses Th17-associated airway hyperresponsiveness in obese asthmatic mice.

Notch signaling is crucial for the regulation of asthma and obesity. The interleukin (IL)-17-expressing CD4+ T cell (Th17 cell) response and airway hyperresponsiveness (AHR) are critical features of both asthma and obesity. We previously demonstrated that inhibiting the Notch signaling pathway alleviates the Th17 response in a mouse model of asthma. However, obese asthmatic individuals show increased Th17 responses and AHR, with the underlying mechanism not currently understood. We aimed to assess the function of Notch signaling in obese mice with asthma and to determine the impact of a γ-secretase inhibitor (GSI), which inhibits the Notch signaling pathway, on the regulation of the Th17 response and AHR. C57BL/6 mice were administered ovalbumin (OVA) to induce asthma, while a high-fat diet (HFD) was used to induce mouse diet-induced obesity (DIO). GSI was then administered intranasally for 7 days in DIO-OVA-induced mice. The results showed increased Notch1 and hes family bHLH transcription factor 1 (Hes1) mRNA levels and Notch receptor intracellular domain (NICD) protein levels in obese asthmatic mice. Furthermore, these mice showed an increased proportion of Th17 cells, serum IL-17A, IL-6, and IL-1ß levels, mucin 5AC (MUC5AC) mRNA level, retinoic acid-related orphan receptor-γt (RORγt) mRNA and protein levels, and increased AHR severity. Interestingly, GSI treatment resulted in reduced Notch1 and Hes1 mRNA and NICD protein levels in DIO-OVA-induced mice, with a decreased Th17 cell proportion and IL-17A quantity and alleviated AHR. These data strongly indicate that the Notch pathway is critical in obese asthmatic mice. In addition, inhibiting the Notch pathway ameliorates AHR and the Th17 response in obese mice with asthma.