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.

CONCLUSION:

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: Bao-Ping Tian, Li-Xia Xia, Zheng-Qiang Bao, Hao Zhang, Zhi-Wei Xu, Yuan-Yuan Mao, Chao Cao, Luan-Qing Che, Jin-Kai Liu, Wen Li, Zhi-Hua Chen, Songmin Ying, Hua-Hao Shen
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 140 Issue 2 Pg. 418-430 (Aug 2017) ISSN: 1097-6825 [Electronic] United States
• PMID: 28043871 (Publication Type: Journal Article)
• Copyright: Copyright © 2017. Published by Elsevier Inc.

Chemical References

• ABT-737
• Adrenal Cortex Hormones
• Allergens
• Alum Compounds
• Anti-Inflammatory Agents
• Biphenyl Compounds
• Bridged Bicyclo Compounds, Heterocyclic
• Nitrophenols
• Piperazines
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• aluminum sulfate
• Dexamethasone
• Ovalbumin
• Freund's Adjuvant
• venetoclax

Topics

• Adrenal Cortex Hormones (pharmacology, therapeutic use)
• Allergens (immunology)
• Alum Compounds
• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Asthma (drug therapy, immunology, metabolism)
• Biphenyl Compounds (pharmacology, therapeutic use)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology, therapeutic use)
• Bronchoalveolar Lavage Fluid (cytology)
• Dexamethasone (pharmacology, therapeutic use)
• Drug Resistance (drug effects)
• Eosinophils (drug effects, immunology)
• Freund's Adjuvant (immunology)
• Humans
• Lung (drug effects, metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Neutrophils (drug effects, immunology)
• Nitrophenols (pharmacology, therapeutic use)
• Ovalbumin (immunology)
• Piperazines (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics, metabolism)
• Sulfonamides (pharmacology, therapeutic use)