The potential use of tyrosine kinase inhibitors in severe asthma

Guntur, Vamsi P.; Reinero, Carol R.

doi:10.1097/aci.0b013e32834ecb4f

Cited by 38 publications

(32 citation statements)

References 78 publications

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“…Asthma is characterized by chronic airway inflammation, variable airflow obstruction, and increased sensitivity of the airways to inhaled constrictor agents, referred to as airway hyperresponsiveness (AHR). Severe asthmatics often do not respond adequately to corticosteroid therapy (2,3), highlighting the need for novel therapeutic approaches. The development of AHR in human asthma involves the complex interplay between the immune system, the airway epithelium, and the mesenchymal cells involved in airway remodeling.…”

Section: Introductionmentioning

confidence: 99%

“…The importance of tyrosine phosphorylation pathways in asthma is becoming increasingly appreciated (2,10). Tyrosine phos phorylation signaling pathways are regulated not only by protein tyrosine kinases (PTKs), but also by protein tyrosine phos phatases (PTPs), which are less well understood.…”

Section: Introductionmentioning

confidence: 99%

“…Both receptor tyrosine kinases and nonreceptor tyrosine kinases play critical roles in a variety of cell types in asthma, and several tyrosine kinase inhibitors have demonstrated efficacy in animal models of asthma (2,10). SFKs, composed of 9 different nonreceptor tyrosine kinases, play critical proximal roles in many signaling pathways implicated in asthma pathogenesis, including those of antigen receptors, growth factor receptors, G protein-coupled receptors (GPCRs), and integrins (16).…”

Section: Introductionmentioning

confidence: 99%

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The phosphatase CD148 promotes airway hyperresponsiveness through SRC family kinases

Katsumoto¹,

Kudo²,

Chen³

et al. 2013

J. Clin. Invest.

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Increased airway smooth muscle (ASM) contractility and the development of airway hyperresponsiveness (AHR) are cardinal features of asthma, but the signaling pathways that promote these changes are poorly understood. Tyrosine phosphorylation is tightly regulated by the opposing actions of protein tyrosine kinases and phosphatases, but little is known about whether tyrosine phosphatases influence AHR. Here, we demonstrate that genetic inactivation of receptor-like protein tyrosine phosphatase J (Ptprj), which encodes CD148, protected mice from the development of increased AHR in two different asthma models. Surprisingly, CD148 deficiency minimally affected the inflammatory response to allergen, but significantly altered baseline pulmonary resistance. Mice specifically lacking CD148 in smooth muscle had decreased AHR, and the frequency of calcium oscillations in CD148-deficient ASM was substantially attenuated, suggesting that signaling pathway alterations may underlie ASM contractility. Biochemical analysis of CD148-deficient ASM revealed hyperphosphorylation of the C-terminal inhibitory tyrosine of SRC family kinases (SFKs), implicating CD148 as a critical positive regulator of SFK signaling in ASM. The effect of CD148 deficiency on ASM contractility could be mimicked by treatment of both mouse trachea and human bronchi with specific SFK inhibitors. Our studies identify CD148 and the SFKs it regulates in ASM as potential targets for the treatment of AHR.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The phosphatase CD148 promotes airway hyperresponsiveness through SRC family kinases

Katsumoto¹,

Kudo²,

Chen³

et al. 2013

J. Clin. Invest.

View full text Add to dashboard Cite

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“…Inhibitors of protein kinases involved in cellular signalling of pro-inflammatory cytokines implicated in the pathogenesis of asthma may have a role in the treatment of severe asthma [61][62][63][64][65] . Several p38 mitogen-activated protein kinase (MAPK) inhibitors restore corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) and alveolar macrophages from patients with severe asthma 63,66 .…”

Section: Protein Kinase Inhibitorsmentioning

confidence: 99%

New and developing non-adrenoreceptor small molecule drugs for the treatment of asthma

Thomson

2017

Expert Opinion on Pharmacotherapy

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IntroductionInhaled corticosteroids (ICS) alone or in combination with an inhaled long-acting beta2-agonist (LABA) are the preferred long-term treatment for adults and adolescents with symptomatic asthma. Additional drugs include leukotriene-receptor antagonists, slow-release theophylline and the long-acting muscarinic antagonist (LAMA) tiotropium (approved in 2015). There is a need for more effective therapies, as many patients continue to have poorly controlled asthma. Areas coveredNew and developing long-acting non-adrenoreceptor synthetic drugs for the treatment of symptomatic chronic asthma despite treatment with an ICS alone or combined with a LABA.Data was reviewed from studies published up until November 2016. Expert opinionTiotropium improves lung function and has a modest effect in reducing exacerbations when

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“…Novel analogues of macrolides have been developed that have greater anti-inflammatory effects than current macrolides, such as solithromycin (CEM-101) [115,116] or that lack anti-bacterial properties but retain anti-inflammatory activity, such as the non-antibiotic azithromycin derivative CSY0073 [120]. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Protein kinase inhibitors Inhibition of protein kinase, such as p38MAPK, narrow spectrum kinase and tyrosine kinase, that are involved in cellular signaling of pro-inflammatory cytokines, may have a role in the treatment of severe asthma associated with corticosteroid insensitivity [121][122][123]. Several p38MAPK inhibitors restore corticosteroid sensitivity in PBMCs from patients with severe asthma [121,124] and COPD [125].…”

Section: Macrolidesmentioning

confidence: 99%

Addressing corticosteroid insensitivity in adults with asthma

Thomson

2016

Expert Review of Respiratory Medicine

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Corticosteroids are the most effective treatment for asthma, but the therapeutic response varies markedly between individuals, with up to one third of patients showing evidence of insensitivity to corticosteroids. This article summarizes information on genetic, environmental and asthma-related factors as well as demographic and pharmacokinetic variables associated with corticosteroid insensitivity in asthma. Molecular mechanisms proposed to explain corticosteroid insensitivity are reviewed including alterations in glucocorticoid receptor subtype, binding and nuclear translocation, increased proinflammatory transcription factors and defective histone acetylation. Current therapies and future interventions that may restore corticosteroid sensitivity in asthma are discussed, including small molecule drugs and biological agents. In the future, biomarkers may be used in the clinic to predict corticosteroid sensitivity in patients with poorly controlled asthma. Word count: 120 wordsKey words: Adherence; asthma; biological agents; biomarkers; cigarette smoking; corticosteroids; corticosteroid insensitivity; corticosteroid resistance; small molecule drugs. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 IntroductionAsthma is a chronic inflammatory disease of the airways that affects 300 million people worldwide. Both national and international guidelines recommend daily inhaled corticosteroid as the preferred controller treatment for adults and adolescents with asthma who have poor symptom control or who at risk of exacerbations [201, 202]. Inhaled corticosteroid use in asthma reduces symptoms, improves quality of life and increases lung function as well as decreases the rate of exacerbations [201, 202]. The majority of the therapeutic benefits of inhaled corticosteroids are achieved at low to medium doses [1], although higher doses are often required in patients with more severe asthma [2] [202]. Short courses of oral corticosteroids are administered to treat severe exacerbations and daily oral corticosteroids are used in the lowest dose providing adequate control to treat patients with severe asthma when symptoms are uncontrolled despite maximal therapy [201, 202].Guideline recommendations for inhaled and oral corticosteroid use in asthma are based on average therapeutic responses from clinical trial populations that may not be representative of 'real-life' patients [3]. Numerous studies in adults and children with asthma have noted a considerable patient-to-patient variability in improvements in lung function and airway hyperreactivity with inhaled and oral corticosteroid treatment in patients with apparently similar levels of disease severity [4][5][6] (Figure 1). The findings from these studies suggest that corticosteroid insensitivity may be present in approximately one third of patients with asthma.Inhaled corticosteroids exhib...

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The potential use of tyrosine kinase inhibitors in severe asthma

Abstract: Asthma and even severe asthma does not consist of a single phenotype. Targeting key inflammatory and remodeling pathways engaged across subphenotypes with tyrosine kinase inhibitors appears to hold promise.

Cited by 38 publications

References 78 publications

The phosphatase CD148 promotes airway hyperresponsiveness through SRC family kinases

The phosphatase CD148 promotes airway hyperresponsiveness through SRC family kinases

New and developing non-adrenoreceptor small molecule drugs for the treatment of asthma

Addressing corticosteroid insensitivity in adults with asthma

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