The Role of Osthole on TGF-β-Induced Lung Epithelium Apoptosis Injury and Epithelial-Mesenchymal Transition-Mediated Airway Remodeling in Pediatric Asthma

Abstract

Osthole, a coumarin compound derived from Fructus Cnidii, exerts anti-inflammatory effects in an asthma model. But the effect of osthole on epithelial injury and epithelial-mesenchymal transition (EMT) in asthma remains unclear. 16HBE cells were incubated with TGF-β1 with or without osthole in vitro. Ovalbumin (OVA)-induced asthmatic mouse model was established in vivo. Cell counting kit-8 was carried out to evaluate the viability of 16HBE cells. The impact of osthole on TGF-β1-evoked cell apoptosis and EMT process was measured by flow cytometry based on Annexin V-FITC/PI staining, transwell assay, immunofluorescence, and Western blot. The regulatory role of osthole in TGF-β1/Smad and p38, ERK1/2, and JNK MAPK signaling was detected via Western blot. Osthole treatment significantly suppressed TGF-β1-induced 16HBE cell apoptosis, verified by a reduced percentage of apoptotic cells, decreased expression of proapoptotic proteins (cleaved-caspase3 and Bax), and enhanced antiapoptotic factor (Bcl-2) expression. In addition, the promotive impact of TGF-β1 on the migration of 16HBE cells was reversed by osthole, accompanied by elevated E-cadherin expression and reduced Snail and N-cadherin expression. The activation of the Smad2/3 and MAPKs pathway evoked by TGF-β1 was inhibited by osthole in 16HBE cells. We also found that osthole mitigated airway epithelium injury and subepithelial fibrosis in OVA-challenged asthmatic mice in vivo. Osthole could mitigate TGF-β1-induced epithelial cell injury and EMT process by suppressing the activation of MAPK and Smad2/3 pathways separately. Our present study showed a new insight into understanding the underlying mechanism of osthole injury on epithelium injury and subepithelial fibrosis in airway remodeling. Asthma, epithelial injury, epithelial-mesenchymal transition, and airway remodeling are the effects of osthole on airway remodeling.

Osthole regulates N6‐methyladenosine‐modified TGM2 to inhibit the progression of rheumatoid arthritis and associated interstitial lung disease

“… 53 Moreover, systemic inflammation was associated with an increased risk of developing RA‐ILD, 42 and attenuating general inflammation and disease activity could improve lung function in RA‐ILD patients. 54 Therefore, OS might alleviate RA‐ILD by mitigating the aggregation of CD11b + macrophages in lungs of CIA models and downregulating systemic inflammation, further suggesting OS as a drug candidate, 55 , 56 , 57 which might be beneficial to the treatment of RA‐ILD.…”

Repair and regeneration of the alveolar epithelium in lung injury

“…49 Transforming growth factor β1 (TGF-β1) induces alveolar epithelial cells apoptosis and enhances Fas cell surface death receptor (Fas)-mediated epithelial cell apoptosis. 50,51 However, prolonged exposure to TGF-β1 could result in an obvious inhibition of the Fas/ Fas ligand (FasL)-induced apoptosis. 52…”

“…Neutrophils promote apoptosis of alveolar basal epithelial cells by secreting S100 Calcium‐Binding Protein A8/A9 (S100A8/A9), participating in the occurrence and development of pneumonia 49 . Transforming growth factor β1 (TGF‐β1) induces alveolar epithelial cells apoptosis and enhances Fas cell surface death receptor (Fas)‐mediated epithelial cell apoptosis 50,51 . However, prolonged exposure to TGF‐β1 could result in an obvious inhibition of the Fas/Fas ligand (FasL)‐induced apoptosis 52 …”

Programmed Cell Death in Asthma: Apoptosis, Autophagy, Pyroptosis, Ferroptosis, and Necroptosis

“…62 Bao Ping Tian et al synthesized a nano preparation of ABT-199, Nf-ABT-199, which can explicitly deliver ABT-199 to the mitochondria of airway inflammatory cells, has been confirmed in asthmatic mice that it can specifically and effectively induce eosinophil apoptosis, and considerably reducing airway inflammation. 63 Some studies discovered that traditional Chinese medicine ingredients, such as Ephedrae Herba-Armeniacae Semen Amarum, 64 Osthole, 65 and Apigenin, 66 were advantageous to asthma by inhibiting airway epithelial cells from apoptosis. Combined Extracts of Epimedii Folium and Ligustri Lucidi Fructus were determined to induce apoptosis in lung tissue and relieve airway remodeling in asthmatic rats.…”