EGFR Tyrosine Kinase Inhibition Worsens Acute Lung Injury in Mice with Repairing Airway Epithelium

Harada, Chikako; Kawaguchi, Tomonobu; Ogata-Suetsugu, Saiko; Yamada, Masakazu; Hamada, Naoki; Maeyama, Takashige; Souzaki, Ryota; Tajiri, Tatsuro; Taguchi, Tomoaki; Kuwano, Kazuyoshi; Nakanishi, Yoichi

doi:10.1164/rccm.201002-0188oc

Cited by 61 publications

(73 citation statements)

References 30 publications

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“…The importance of EGFR activation in naphthalene-induced lung injury was recently explored using the EGFR tyrosine kinase inhibitor gefitinib (24). The results suggested that EGFR inhibition prolongs lung injuries associated with increased neutrophil sequestration, especially at earlier stages of epithelial regeneration (24,29).…”

Section: Discussionmentioning

confidence: 99%

“…The results suggested that EGFR inhibition prolongs lung injuries associated with increased neutrophil sequestration, especially at earlier stages of epithelial regeneration (24,29). Although neutrophil infiltration is commonly associated with acute lung injury, neutrophils are also capable of promoting epithelial repair mechanisms (55).…”

Section: Discussionmentioning

confidence: 99%

“…With respect to the potential mechanisms by which DUOX1 activation promotes epithelial cell migration, previous studies with airway epithelial cells indicated a critical role for DUOX1 in the oxidant-dependent activation of EGFR signaling (12,14), and the activations of EGFR and its ligands comprise critical events in epithelial repair pathways (40,41), and contribute to epithelial regeneration after naphthalene injury (24,29). Moreover, the H 2 O 2 -dependent activation of EGFR has also been demonstrated to involve an initial activation of the nonreceptor tyrosine kinase Src (42,43), which is known to play critical roles in epithelial motility and migration (32,33).…”

Section: Duox1 Mediates Epithelial Repair By the Activation Of Src-egmentioning

confidence: 99%

“…Our results show that DUOX1 promotes epithelial wound responses in in vitro studies with primary murine tracheal epithelial (MTE) cells and promotes epithelial regeneration in an in vivo murine model of naphthalene-induced epithelial injury, in part through the activation of EGFR and signal transducer and activator of transcription-3 (STAT3) signaling as critical events in promoting epithelial cell migration (21)(22)(23) and effective epithelial regeneration after injury (24,25).…”

mentioning

confidence: 92%

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Dual Oxidase–1 Is Required for Airway Epithelial Cell Migration and Bronchiolar Reepithelialization after Injury

Gorissen

Hristova

Habibovic

et al. 2013

Am J Respir Cell Mol Biol

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The respiratory epithelium plays a critical role in innate defenses against airborne pathogens and pollutants, and alterations in epithelial homeostasis and repair mechanisms are thought to contribute to chronic lung diseases associated with airway remodeling. Previous studies implicated the nicotinamide adenine dinucleotide phosphate-reduced oxidase dual oxidase-1 (DUOX1) in redox signaling pathways involved in in vitro epithelial wound responses to infection and injury. However, the importance of epithelial DUOX1 in in vivo epithelial repair pathways has not been established. Using small interfering (si)RNA silencing of DUOX1 expression, we show the critical importance of DUOX1 in wound responses in murine tracheal epithelial (MTE) cells in vitro, as well as its contribution to epithelial regeneration in vivo in a murine model of epithelial injury induced by naphthalene, a selective toxicant of nonciliated respiratory epithelial cells (club cells [Clara]). Whereas naphthalene-induced club-cell injury is normally followed by epithelial regeneration after 7 and 14 days, such airway reepithelialization was significantly delayed after the silencing of airway DUOX1 by oropharyngeal administration of DUOX1-targeted siRNA. Wound closure in MTE cells was related to DUOX1-dependent activation of the epidermal growth factor receptor (EGFR) and the transcription factor signal transducer and activator of transcription-3 (STAT3), known mediators of epithelial cell migration and wound responses. Moreover, in vivo DUOX1 silencing significantly suppressed naphthalene-induced activation of STAT3 and EGFR during early stages of epithelial repair. In conclusion, these experiments demonstrate for the first time an important function for epithelial DUOX1 in lung epithelial regeneration in vivo, by promoting EGFR-STAT3 signaling and cell migration as critical events in initial repair.Keywords: airway injury; redox signaling; EGFR; STAT3; naphthalene The respiratory epithelium forms an interface between the airways and the external environment, and represents the first line of defense against inhaled pollutants, microorganisms, and allergens. Critical in the proper functioning of the airway epithelium is the maintenance of a carefully regulated physical epithelial barrier that minimizes microbial invasion and allows for optimal surface hydration and mucociliary clearance in the upper airways, and for efficient gas exchange in the alveolar regions.Epithelial cells must therefore be capable of evoking rapid responses to injurious stimuli to minimize the loss of epithelial integrity, and disorderly epithelial repair mechanisms are thought to contribute to structural and functional alterations as important features of chronic respiratory diseases such as asthma, emphysema, pulmonary fibrosis, and lung cancer (1, 2). Epithelial defense mechanisms in response to infectious or injurious challenges rely on the presence of a wide range of pattern recognition receptors at the epithelial surface that rapidly detect and respond to a variety of ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Duox1 Mediates Epithelial Repair By the Activation Of Src-egmentioning

confidence: 99%

mentioning

confidence: 92%

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Dual Oxidase–1 Is Required for Airway Epithelial Cell Migration and Bronchiolar Reepithelialization after Injury

Gorissen

Hristova

Habibovic

et al. 2013

Am J Respir Cell Mol Biol

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“…All of them are mitogens in type II pneumocytes, and act synergistically to mediate their maturation and increase surfactant synthesis [8]. EGF had benefi cial eff ects in an animal model of ALI [39], and inhibition of EGF receptor had a detrimental eff ect during airway epithelium repair [40]. KGF has been linked to upregulation of anti-infl am matory cytokines and modulation of epithelial cell migration [41].…”

Section: Therapeutic Strategies Aimed At Lung Repairmentioning

confidence: 99%

Repair after Acute Lung Injury: Molecular Mechanisms and Therapeutic Opportunities

González-López¹,

Albaiceta²

2012

Annual Update in Intensive Care and Emergency Medicine 2012

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TWEAK transactivation of the epidermal growth factor receptor mediates renal inflammation

Rayego‐Mateos

Morgado‐Pascual

Sanz

et al. 2013

The Journal of Pathology

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TWEAK, a member of the TNF superfamily, binds to the Fn14 receptor, eliciting biological responses. EGFR signalling is involved in experimental renal injury. Our aim was to investigate the relationship between TWEAK and EGFR in the kidney. Systemic TWEAK administration into C57BL/6 mice increased renal EGFR phosphorylation, mainly in tubular epithelial cells. In vitro, in these cells TWEAK phosphorylated EGFR via Fn14 binding, ADAM17 activation and subsequent release of the EGFR ligands HB-EGF and TGFα. In vivo the EGFR kinase inhibitor Erlotinib inhibited TWEAK-induced renal EGFR activation and downstream signalling, including ERK activation, up-regulation of proinflammatory factors and inflammatory cell infiltration. Moreover, the ADAM17 inhibitor WTACE-2 also prevented those TWEAK-induced renal effects. In vitro TWEAK induction of proinflammatory factors was prevented by EGFR, ERK or ADAM17 inhibition. In contrast, EGFR transactivation did not modify TWEAK-mediated NF-κB activation. Our data suggest that TWEAK transactivates EGFR in the kidney, leading to modulation of downstream effects, including ERK activation and inflammation, and suggest that inhibition of EGFR signalling could be a novel therapeutic tool for renal inflammation.

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EGFR Tyrosine Kinase Inhibition Worsens Acute Lung Injury in Mice with Repairing Airway Epithelium

Abstract: EGFR inhibition in repairing airway epithelial cells modulated significant expression of genes involved in the airway microenvironment, prolonged inflammation, and potentiated acute lung injury.

Cited by 61 publications

References 30 publications

Dual Oxidase–1 Is Required for Airway Epithelial Cell Migration and Bronchiolar Reepithelialization after Injury

Dual Oxidase–1 Is Required for Airway Epithelial Cell Migration and Bronchiolar Reepithelialization after Injury

Repair after Acute Lung Injury: Molecular Mechanisms and Therapeutic Opportunities

TWEAK transactivation of the epidermal growth factor receptor mediates renal inflammation

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