title: Bcl-2 inhibitors reduce steroid-insensitive airway inflammation.
abstract: BACKGROUND
  Asthmatic inflammation is dominated by accumulation of either eosinophils, neutrophils, or both in the airways. Disposal of these inflammatory cells is the key to disease control. Eosinophilic airway inflammation is responsive to corticosteroid treatment, whereas neutrophilic inflammation is resistant and increases the burden of global health care. Corticosteroid-resistant neutrophilic asthma remains mechanistically poorly understood and requires novel effective therapeutic strategies.
  
  
  OBJECTIVE
  We sought to explore the underlying mechanisms of airway inflammation persistence, as well as corticosteroid resistance, and to investigate a new strategy of effective treatment against corticosteroid-insensitive neutrophilic asthma.
  
  
  METHODS
  Mouse models of either eosinophil-dominated or neutrophil-dominated airway inflammation were used in this study to test corticosteroid sensitivity in vivo and in vitro. We also used vav-Bcl-2 transgenic mice to confirm the importance of granulocytes apoptosis in the clearance of airway inflammation. Finally, the Bcl-2 inhibitors ABT-737 or ABT-199 were tested for their therapeutic effects against eosinophilic or neutrophilic airway inflammation and airway hyperresponsiveness.
  
  
  RESULTS
  Overexpression of Bcl-2 protein was found to be responsible for persistence of granulocytes in bronchoalveolar lavage fluid after allergic challenge. This was important because allergen-induced airway inflammation aggravated and persisted in vav-Bcl-2 transgenic mice, in which nucleated hematopoietic cells were overexpressed with Bcl-2 and resistant to apoptosis. The Bcl-2 inhibitors ABT-737 or ABT-199 play efficient roles in alleviation of either eosinophilic or corticosteroid-resistant neutrophilic airway inflammation by inducing apoptosis of immune cells, such as eosinophils, neutrophils, TH2 cells, TH17 cells, and dendritic cells. Moreover, these inhibitors were found to be more efficient than steroids to induce granulocyte apoptosis ex vivo from patients with severe asthma.
  
  
  CONCLUSIONS
  Apoptosis of inflammatory cells is essential for clearance of allergen-induced airway inflammation. The Bcl-2 inhibitors ABT-737 or ABT-199 might be promising drugs for the treatment of airway inflammation, especially for corticosteroid-insensitive neutrophilic airway inflammation.
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China.
authors.forename: Bao-Ping
authors.initials: BP
authors.lastname: Tian
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China.
authors.forename: Li-Xia
authors.initials: LX
authors.lastname: Xia
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Zheng-Qiang
authors.initials: ZQ
authors.lastname: Bao
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China; Department of Critical Care Medicine, Ningbo Medical Center, Lihuili Hospital, Ningbo University, Ningbo, China.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Xu
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Mao
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Cao
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China.
authors.forename: Luan-Qing
authors.initials: LQ
authors.lastname: Che
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China.
authors.forename: Jin-Kai
authors.initials: JK
authors.lastname: Liu
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Chen
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: yings@zju.edu.cn.
authors.forename: Songmin
authors.initials: S
authors.lastname: Ying
authors.affiliation: Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, China; State Key Laboratory of Respiratory Diseases, Guangzhou, China. Electronic address: huahaoshen@163.com.
authors.forename: Hua-Hao
authors.initials: HH
authors.lastname: Shen
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology / Q000627:therapeutic use; D000485:Allergens / Q000276:immunology; D000534:Alum Compounds; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D004351:Drug Resistance / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D005620:Freund's Adjuvant / Q000276:immunology; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D009596:Nitrophenols / Q000494:pharmacology / Q000627:therapeutic use*; D010047:Ovalbumin / Q000276:immunology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C501332:ABT-737; D000305:Adrenal Cortex Hormones; D000485:Allergens; D000534:Alum Compounds; D000893:Anti-Inflammatory Agents; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C041524:aluminum sulfate; D003907:Dexamethasone; D010047:Ovalbumin; D005620:Freund's Adjuvant; C579720:venetoclax
keywords: Airway inflammation; Bcl-2; apoptosis; eosinophil; neutrophil; steroid insensitive