Epidermal Growth Factor Receptor Inhibitor Ag1478 Inhibits Mucus Hypersecretion in Airway Epithelium

Takezawa, Kumiko; Ogawa, Takao; Shimizu, Shino; Shimizu, Takeshi

doi:10.2500/ajra.2016.30.4263

Cited by 28 publications

(20 citation statements)

References 29 publications

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“…We show, in murine models where Tyrphostin AG825 was administered either at the time of inflammatory stimulus or once inflammation was established, an impact on cell number, proinflammatory cytokine production and neutrophil apoptosis, further validating the use of ErbB inhibitors to reduce inflammation. The benefit of EGFR inhibitors in reducing inflammation in ventilator-induced and OVA/LPS-induced lung injury rodent models is shown by others, further supporting the targetting of this pathway in inflammatory disease settings (Bierman et al, 2008; Shimizu et al, 2018; Takezawa et al, 2016).…”

Section: Discussionmentioning

confidence: 61%

Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation

Rahman

Henry

Herman

et al. 2019

eLife

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Neutrophilic inflammation with prolonged neutrophil survival is common to many inflammatory conditions, including chronic obstructive pulmonary disease (COPD). There are few specific therapies that reverse neutrophilic inflammation, but uncovering mechanisms regulating neutrophil survival is likely to identify novel therapeutic targets. Screening of 367 kinase inhibitors in human neutrophils and a zebrafish tail fin injury model identified ErbBs as common targets of compounds that accelerated inflammation resolution. The ErbB inhibitors gefitinib, CP-724714, erbstatin and tyrphostin AG825 significantly accelerated apoptosis of human neutrophils, including neutrophils from people with COPD. Neutrophil apoptosis was also increased in Tyrphostin AG825 treated-zebrafish in vivo. Tyrphostin AG825 decreased peritoneal inflammation in zymosan-treated mice, and increased lung neutrophil apoptosis and macrophage efferocytosis in a murine acute lung injury model. Tyrphostin AG825 and knockdown of egfra and erbb2 by CRISPR/Cas9 reduced inflammation in zebrafish. Our work shows that inhibitors of ErbB kinases have therapeutic potential in neutrophilic inflammatory disease.

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Section: Discussionmentioning

confidence: 61%

Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation

Rahman

Henry

Herman

et al. 2019

eLife

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“…MUC5AC is expressed in increased quantities in CRS . Several investigators have utilized in vitro models of CRS to identify the stimulants causing MUC5AC overexpression . Most recently, Jiao et al studied the effects of Th1, Th2, and Th17 cytokines on MUC5AC expression and mucociliary function.…”

Section: Introductionmentioning

confidence: 99%

Models for the study of nasal and sinus physiology in health and disease: A review of the literature

Al-Sayed

Agu

Massoud

2017

Laryngoscope Investig Oto

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ObjectiveChronic sinusitis is a very common yet poorly understood medical condition with significant morbidity. Hence, it remains an entity that is difficult to treat with unsatisfactory outcomes of current management options. This necessitates research into the etiology and pathophysiology of the condition to enhance our knowledge and the therapeutic options. Unfortunately, this kind of research is not always feasible on human subjects due to practical and ethical limitations. Therefore, an alternative model that simulates the disease had to be found in order to overcome these limitations. These models could either be in vivo or in vitro. The aim of our review is to summarize the research findings and key discoveries of both in vivo and in vitro models of chronic sinusitis that have enhanced our understanding of the condition today and have paved the way for the future research of tomorrow. Data Sources: PubMed literature review.MethodsA review of the literature was conducted to identify the main successful in vivo and in vitro models for chronic sinusitis.ResultsCreating a successful model for chronic sinusitis is no easy task. Over the years, both in vivo animal models and in vitro tissue culture models were proposed, with each model having its accolades and pitfalls, with the ideal model remaining elusive to this day. However, advancing three‐dimensional cell culturing techniques seems to be a promising new way to find a more accurate model.ConclusionNone of the current models is perfect for a thorough study of chronic sinusitis. However, three‐dimensional cell cultures have the potential to bridge the gap between in vivo and in vitro studies.Level of EvidenceNA

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“…Experimental studies with EGFR reduces mucus secretion. An EGFR inhibitor AG1478 [N-(3-chlorophenyl)-6,7-dimethoxy-4-quinazolinamine] is effective at inhibiting MUC5AC secretion induced by LPS, TNF-a, or cigarette smoke from human airway epithelial cells in vitro and in cigarette smoke-induced MUC5AC secretion in rats in vivo (Hegab et al, 2007;Takezawa et al, 2016). However, a potent and selective EGFR inhibitor BIBW 2948 given by inhalation for 4 weeks in patients with COPD failed to show any reduction in epithelial mucus, despite evidence for target engagement measured by EGFR internalization (Woodruff et al, 2010).…”

Section: B Receptor Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Barnes

2016

Pharmacol Rev

102

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Epidermal Growth Factor Receptor Inhibitor Ag1478 Inhibits Mucus Hypersecretion in Airway Epithelium

Abstract: These results indicated that EGFR transactivation plays an important role in mucin and IL-8 secretion from airway epithelial cells. Intranasal instillation of an EGFR tyrosine kinase inhibitor may be a new therapeutic approach for the treatment of upper airway inflammation.

Cited by 28 publications

References 29 publications

Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation

Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation

Models for the study of nasal and sinus physiology in health and disease: A review of the literature

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

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