Background: The airway epithelium serves as the first line of defense between the lung's internal environment and the external environment, functioning through physical barriers and mucus-ciliary clearance to protect against external allergens and other harmful substances. Airway epithelial damage is a common feature of asthma, and research has shown that apoptosis plays a significant role in airway injury and inflammation in asthma. Although Kechuan Decoction (KCD) has demonstrated clinical efficacy in treating pediatric asthma, its precise mechanism of action remains unclear.
Objective: To elucidate the therapeutic mechanism of KCD in mitigating apoptosis of airway epithelial cells (AECs) in a house dust mite (HDM)-induced asthma mouse model.
Methods: To evaluate the effects of KCD on asthma-associated airway inflammation and AECs apoptosis, an asthma model was established in C57BL/6 J mice using HDM. The major chemical constituents of KCD were analyzed using LC-MS. Subsequently, we utilized network pharmacology approaches to predict the potential targets and mechanisms of KCD in asthma. Additionally, we conducted lipidomics analysis of lung tissue and mitochondria in the lung was conducted using LC-MS. Finally, the mechanisms underlying the effects of KCD on AECs apoptosis in asthmatic mice were investigated through Western blotting, qPCR, and Transmission electron microscopy (TEM) examination techniques.
Results: The efficacy of KCD has been shown to improve lung function, reduce airway inflammation, and prevent apoptosis of AECs in a HDM-induced asthma model. Through the use of UPLC-LTQ-Orbitrap-MS, we identified 24 potential active components of KCD. Network pharmacology analysis revealed that KCD shares 102 core targets with asthma. GO enrichment analysis, in conjunction with a literature review, indicated that the targets of KCD treatment for AECs apoptosis primarily focus on the mitochondrial membrane. Furthermore, lipidomics analysis of lung tissue and mitochondria in the lungs of mice with HDM-induced asthma revealed disruptions in lipid metabolism, with a decrease in phosphatidylcholine (PC) content in asthmatic mice, which was effectively restored by KCD treatment. KCD reinstates the expression of START domain-containing protein 7 (StarD7) and START domain-containing protein 10 (StarD10) in lung tissue, leading to increase in PC within the mitochondrial membrane. This regulation indirectly influences mitochondrial fusion and fission proteins, promoting mitochondrial membrane stability and reducing cytochrome c (Cyt c) release into the cytoplasm. Ultimately, this process helps mitigate mitochondria-mediated apoptosis of AECs.
Conclusion: KCD can restore the content of PC in the mitochondria of AECs by regulating StarD7 and StarD10. It also restores proteins associated with mitochondrial fusion and fission, stabilizing mitochondrial structure, effectively reducing the release of Cyt c into the cytoplasm, and ultimately inhibiting mitochondria-mediated apoptosis of AECs induced by HDM in asthmatic mice.
Keywords: Apoptosis; Asthma; Kechuan decoction; Lipidomics; Network pharmacology; Phospholipid transfer protein.
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