Abstract
Angiogenesis is a key characteristic of asthma airway remodeling. By releasing cationic granule proteins, such as major basic protein (MBP), activated eosinophils play a prominent role in asthma, but the underlying mechanisms are still not fully understood. In this study, we demonstrated that fibroblast growth factor-binding protein 1 (FGFBP1) was dramatically upregulated in airway epithelial cell lines treated by poly-L-arginine (PLA), a mimic of MBP. Elevated FGFBP1 expression was also detected in asthma clinical samples, as well as in ovalbumin (OVA)-induced chronic asthma mouse models. PLA enhanced FGFBP1 expression through activation of the mechanistic target of rapamycin complex 1-signal transducer and activator of transcription 3 (mTORC1-STAT3) signaling pathway. STAT3 transactivated FGFBP1 by directly binding to the promoter of the FGFBP1 gene. Furthermore, we identified that FGFBP1 secreted by PLA-treated airway epithelial cells served as a proangiogenesis factor. Lastly, we found the mTORC1-STAT3-FGFBP1 signaling pathway was activated in an OVA-induced chronic asthma model with airway remodeling features. Rapamycin treatment alleviated respiratory symptoms and reduced angiogenesis in asthmatic mice. Therefore, activation of the mTORC1-STAT3-FGFBP1 pathway in the airway epithelium contributes to the progress of angiogenesis and should be targeted for the treatment of asthma.
Highlights
Bronchial asthma is a chronic inflammatory airway disorder that adversely affects the quality of life in both children and adults [1]
The fibroblast growth factor-binding protein 1 (FGFBP1) antibody was from R&D Systems (Minneapolis, MN, USA; #196519) and Beijing Bo’aosen Biotechnology Co., Ltd (Beijing, China; #MAB1593). mechanistic target of rapamycin (mTOR) (#9964), regulatory-associated protein of mTOR (Raptor) (#2280), rapamycin-insensitive companion of mTOR (Rictor) (#2114), secondary activator of transcription 3 (STAT3) (#9139), phospho-STAT3 (Tyr705) (#9145), S6 ribosomal protein (#2217), phospho-S6 ribosomal protein (Ser235/236) (#4858), phospho-p70 S6 kinase (p-S6K) (Thr389) (#9205), TSC1 (#6935), TSC2 (#4308), p44/42 mitogen-activated protein kinase (MAPK) (ERK1/2) (#4695), phospho-p44/42 MAPK (ERK1/2) (#4370), p38 MAPK (#8690), phospho-p38 MAPK (#4511), c-Myc (#13987), and β-actin (#4970) antibodies were purchased from Cell Signaling Technology (CST, Danvers, MA, USA)
The results showed that messenger RNA expressions of these genes were increased by PLA treatment (Fig. 1B)
Summary
Bronchial asthma is a chronic inflammatory airway disorder that adversely affects the quality of life in both children and adults [1]. Asthma is characterized by variable airflow limitation and respiratory symptoms such as coughing, wheezing, and chest tightness, accompanied by eosinophilic airway inflammation and airway wall structural changes called airway remodeling [2, 3]. Airway remodeling is characterized by a persistently altered airway wall structure, including airway wall thickening, mucus hypersecretion, subepithelial fibrosis, angiogenesis, and increased smooth muscle mass [4]. Among the multiple postulated mechanisms, an abnormal increase of angiogenesis in the airway tissue and enhanced expression of proangiogenesis factors are critical contributors to airway structural remodeling [5]. Angiogenesis is a pathophysiological process of generating new capillaries, accompanied by increases in vessel density and size, induced by multiple cytokines and chemokines released by inflammatory and structural cells in bronchial asthma [5, 6]. The initiation mechanism of increased angiogenesis has not been extensively investigated and therapeutic antiangiogenesis interventions have received little attention
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