Bcl-2 inhibitors reduce steroid-insensitive airway inflammation

Tian, Bo; Xia, Lixia; Bao, Zhengqiang; Zhang, Hao; Xu, Zhiwei; Mao, Yuanyuan; Cao, Chao; Che, Luanqing; Liu, Jin-kai; Li, Wen; Chen, Zhihua; Ying, Songmin; Shen, Huahao

doi:10.1016/j.jaci.2016.11.027

Cited by 64 publications

(55 citation statements)

References 45 publications

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“…Similar results were obtained in previous studies using different BCL‐2 inhibitors in various inflammatory conditions characterized by the uncontrolled proliferation of lymphocytes; BCL‐2 inhibitors were efficacious in reducing accumulated lymphocytes in murine models of autoimmune diseases , arthritis and lupus , and suppressed allogeneic T and B cell responses after skin transplantation in vitro and in vivo . A recent report assessing the effects of BCL‐2 inhibitors in steroid‐insensitive airway inflammation showed that BCL‐2 inhibitors ameliorate corticosteroid‐resistant airway inflammation . Increased BCL‐2 was found to be responsible for the persistence of granulocytes in bronchoalveolar lavage fluid after allergic challenge.…”

Section: Discussionsupporting

confidence: 83%

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BCL-2 levels do not predict azathioprine treatment response in inflammatory bowel disease, but inhibition induces lymphocyte apoptosis and ameliorates colitis in mice

Weder

Mozaffari

Biedermann

et al. 2018

Clinical and Experimental Immunology

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In inflammatory bowel disease (IBD), inflammation is sustained by an exaggerated response of lymphocytes. This results from enhanced expression of anti-apoptotic B cell lymphoma (BCL-2) and BCL-XL associated with a diminished turnover. Azathioprine (AZA) directly targets BCL-2 family-mediated apoptosis. We investigated whether the BCL-2 family expression pattern could be used to predict treatment response to AZA and determined whether BCL-2 inhibitor A-1211212 effectively diminishes lymphocytes and ameliorates inflammation in a model of colitis. BCL-2 family expression pattern was determined by next-generation sequencing (NGS). BCL-2 inhibitor was administered orally to Il10-/- mice. Haematological analyses were performed with an ADVIA 2120 and changes in immune cells were investigated using quantitative polymerase chain reaction (qPCR) and fluorescence activated cell sorter (FACS). We determined similar expression levels of BCL-2 family members in patients with remission and patients refractory to treatment, showing that BCL-2 family expression can not predict AZA treatment response. Expression was not correlated with the modified Truelove and Witts activity index (MTWAI). BCL-2 inhibitor initiated cell death in T cells from patients refractory to AZA and reduced lymphocyte count in Il10-/- mice. FACS revealed diminished CD8 T cells upon BCL-2 inhibitor in Il10-/- mice without influencing platelets. Tnf, Il1β, IfnƔ and Mcp-1 were decreased upon BCL-2 inhibitor. A-1211212 positively altered the colonic mucosa and ameliorated inflammation in mice. Pro-apoptotic BCL-2 inhibitor A-1211212 diminishes lymphocytes and ameliorates colitis in Il10-/- mice without inducing thrombocytopenia. BCL-2 inhibition could be a new therapy option for patients refractory to AZA.

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Section: Discussionsupporting

confidence: 83%

“…Increased BCL‐2 was found to be responsible for the persistence of granulocytes in bronchoalveolar lavage fluid after allergic challenge. Notably, BCL‐2 inhibitors were more efficient than steroids in inducing granulocyte apoptosis in cells from patients with severe asthma .…”

Section: Discussionmentioning

confidence: 99%

BCL-2 levels do not predict azathioprine treatment response in inflammatory bowel disease, but inhibition induces lymphocyte apoptosis and ameliorates colitis in mice

Weder

Mozaffari

Biedermann

et al. 2018

Clinical and Experimental Immunology

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“…The removal of these granulocytes would contribute to the resolution of airway inflammation in asthma. Tian et al discovered that promoted apoptosis of inflammatory cells, such as eosinophils and neutrophils would be essential for the clearance of allergen-induced airway inflammation, especially for corticosteroid-insensitive neutrophilic airway inflammation [74]. However, noneosinophilic asthma shows an enhancement of blood neutrophil chemotaxis and survival [69].…”

Section: Asthmatic Neutrophilsmentioning

confidence: 99%

Advanced Role of Neutrophils in Common Respiratory Diseases

Liu

Pang

Wang

et al. 2017

Journal of Immunology Research

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Respiratory diseases, always being a threat towards the health of people all over the world, are most tightly associated with immune system. Neutrophils serve as an important component of immune defense barrier linking innate and adaptive immunity. They participate in the clearance of exogenous pathogens and endogenous cell debris and play an essential role in the pathogenesis of many respiratory diseases. However, the pathological mechanism of neutrophils remains complex and obscure. The traditional roles of neutrophils in severe asthma, chronic obstructive pulmonary diseases (COPD), pneumonia, lung cancer, pulmonary fibrosis, bronchitis, and bronchiolitis had already been reviewed. With the development of scientific research, the involvement of neutrophils in respiratory diseases is being brought to light with emerging data on neutrophil subsets, trafficking, and cell death mechanism (e.g., NETosis, apoptosis) in diseases. We reviewed all these recent studies here to provide you with the latest advances about the role of neutrophils in respiratory diseases.

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“…The BCL-2 inhibitor ABT-199, in clinical trials for leukemia [59], was also shown to reduce the level of airway eosinophils and Th2 cells in a mouse model of asthma [60]. Huang et.…”

Section: Discussionmentioning

confidence: 99%

Comparative Efficacy of Glucocorticoid Receptor Agonists on Th2 Cell Function and Attenuation by Progesterone

Luchak

Solomon

Kanagalingam

et al. 2019

Preprint

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Background: Corticosteroids (CS) suppress cytokine production and induce apoptosis of inflammatory cells. Prednisone and dexamethasone are oral CS prescribed for treating asthma exacerbations. While prednisone is more commonly prescribed, dexamethasone is long acting and a more potent glucocorticoid receptor (GR) agonist. It can be administered as a one or two dose regime, unlike the five to seven days required for prednisone, a feature that increases compliance. We compared the relative ability of these two oral CS to suppress type 2 inflammation. Since progesterone has affinity for the GR and women are more likely to relapse following an asthma exacerbation, we assessed its influence on CS action. Results: Dexamethasone suppressed the level of IL-5 and IL-13 mRNA within Th2 cells with 10-fold less than prednisolone (the active form of prednisone). Dexamethasone induced a higher proportion of apoptotic and dying cells than prednisolone, at all concentrations examined. Addition of progesterone reduced their capacity to drive cell death, though dexamethasone maintained significantly more killing activity. Progesterone blunted dexamethasone-induction of FKBP5 mRNA, indicating the mechanism of action was by interference of the GC:GR complex. Conclusions: Dexamethasone is both more potent and effective than prednisolone in suppressing type 2 cytokine levels and mediating apoptosis. Progesterone attenuated these anti-inflammatory effects, indicating its potential influence on corticosteroid responses in vivo . Collectively, our data suggest that when oral corticosteroid is required, dexamethasone may be better able to control type 2 inflammation, eliminate Th2 cells and ultimately lead to improved long-term outcomes. Further research in asthmatics is needed

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Bcl-2 inhibitors reduce steroid-insensitive airway inflammation

Cited by 64 publications

References 45 publications

BCL-2 levels do not predict azathioprine treatment response in inflammatory bowel disease, but inhibition induces lymphocyte apoptosis and ameliorates colitis in mice

BCL-2 levels do not predict azathioprine treatment response in inflammatory bowel disease, but inhibition induces lymphocyte apoptosis and ameliorates colitis in mice

Advanced Role of Neutrophils in Common Respiratory Diseases

Comparative Efficacy of Glucocorticoid Receptor Agonists on Th2 Cell Function and Attenuation by Progesterone

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