Activation of the Epidermal Growth Factor Receptor by Respiratory Syncytial Virus Results in Increased Inflammation and Delayed Apoptosis

Monick, Martha M.; Cameron, Kelli; Staber, Janice M.; Powers, Linda S.; Yarovinsky, Timur O.; Koland, John G.; Hunninghake, Gary W.

doi:10.1074/jbc.m408745200

Cited by 90 publications

(94 citation statements)

References 53 publications

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“…These results therefore define an EGFR signaling pathway that protects against ciliated cell apoptosis via selective PI3K signaling to downstream factors that prohibit mitochondrial dysfunction and consequent programmed cell death. As discussed below, the findings stand in some contrast to reports of EGFR and other receptor signals to ERK1/2 that prevent cell death under other circumstances (38,50,51).…”

Section: Persistent Activation Of Egfr On Ciliated Epithelial Cells contrasting

confidence: 54%

Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals

Tyner

Kim

Ide

et al. 2006

Journal of Clinical Investigation

238

243

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Epithelial hyperplasia and metaplasia are common features of inflammatory and neoplastic disease, but the basis for the altered epithelial phenotype is often uncertain. Here we show that long-term ciliated cell hyperplasia coincides with mucous (goblet) cell metaplasia after respiratory viral clearance in mouse airways. This chronic switch in epithelial behavior exhibits genetic susceptibility and depends on persistent activation of EGFR signaling to PI3K that prevents apoptosis of ciliated cells and on IL-13 signaling that promotes transdifferentiation of ciliated to goblet cells. Thus, EGFR blockade (using an irreversible EGFR kinase inhibitor designated EKB-569) prevents virus-induced increases in ciliated and goblet cells whereas IL-13 blockade (using s-IL-13Rα2-Fc) exacerbates ciliated cell hyperplasia but still inhibits goblet cell metaplasia. The distinct effects of EGFR and IL-13 inhibitors after viral reprogramming suggest that these combined therapeutic strategies may also correct epithelial architecture in the setting of airway inflammatory disorders characterized by a similar pattern of chronic EGFR activation, IL-13 expression, and ciliated-to-goblet cell metaplasia. IntroductionEpithelial cell hyperplasia and metaplasia are common consequences of inflammation and may be associated with protective as well as pathogenic outcomes. In the lung, airway epithelial remodeling can be life threatening, since mucous cell metaplasia is the foundation for hypersecretion that can obstruct the airway lumen. Despite the critical nature of this process, little is known about how mucous cell metaplasia develops in the setting of acute or chronic inflammatory disease. Particularly, little is known about the mechanism for what is likely the most common cause of mucous cell metaplasia in the lung, i.e., respiratory viral infection, since previous work has focused on bacterial, allergic, and carcinogenic stimuli. Perhaps because of the paucity of mechanistic information, no effective and specific pharmacologic treatment is currently available to treat epithelial cell metaplasia in general or mucous cell metaplasia in particular.In this context, recent work on mucous cell metaplasia has often focused on signaling pathways initiated by activation of the IL-13 receptor (IL-13R) and EGFR (also designated ErbB1 and HER1). The experimental role of IL-13R was established when a decoy receptor for IL-13 (soluble IL-13Rα2-Fc) was found to inhibit allergen-induced mucous (goblet) cell formation in mice (1, 2). These reports have been followed by evidence that IL-13 can directly drive mucin gene expression in airway epithelial cells cultured under physiologic conditions and in vivo (3-6). Moreover, IL-13 is often overexpressed in the setting of mucous cell metaplasia in asthma

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Section: Persistent Activation Of Egfr On Ciliated Epithelial Cells contrasting

confidence: 54%

Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals

Tyner

Kim

Ide

et al. 2006

Journal of Clinical Investigation

238

243

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“…It preferentially infects airway epithelium and is responsible for significant pathology in infants, young children, asthmatics, and immunocompromised adults (1)(2)(3)(4). Virtually all children become infected with RSV by the age of 2 years.…”

Section: R Espiratory Syncytial Virus (Rsv)mentioning

confidence: 99%

“…A549 cells were used because they most closely mimic RSV observations in primary human airway cells (3,4,36). Cells were maintained in 75-cm 2 tissue culture flasks (Corning) in minimal essential medium (Invitrogen Life Technologies) with 10% FCS and gentamicin.…”

Section: Epithelial Cell Culture and Viral Infectionmentioning

confidence: 99%

“…The resulting cDNA (2 l; from either mouse lungs or a human cell line) was then mixed with 48 l of PCR master mix consisting of iQ SYBR Green Supermix (Bio-Rad), 15 pmol of forward primer, and 15 pmol of reverse primer in a 0.2-ml PCR tube (Bio-Rad). PCR amplification was then performed in an iCycler iQ Fluorescence Thermocycler (Bio-Rad) (3,4,36). Chemokine gene expression was normalized to the housekeeping gene, hypoxanthine-guanine phosphoribosyltransferase (HPRT), with approximately equal amplification efficiency.…”

Section: Real-time Rt-pcr (Qrt-pcr)mentioning

confidence: 99%

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Respiratory Syncytial Virus Synergizes with Th2 Cytokines to Induce Optimal Levels of TARC/CCL17

Monick

Powers

Hassan

et al. 2007

The Journal of Immunology

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Respiratory syncytial virus (RSV) is a ubiquitous virus that preferentially infects airway epithelial cells, causing asthma exacerbations and severe disease in immunocompromised hosts. Acute RSV infection induces inflammation in the lung. Thymus- and activation-regulated chemokine (TARC) recruits Th2 cells to sites of inflammation. We found that acute RSV infection of BALB/c mice increased TARC production in the lung. Immunization of BALB/c mice with individual RSV proteins can lead to the development of Th1- or Th2-biased T cell responses in the lung after RSV infection. We primed animals with a recombinant vaccinia virus expressing either the RSV fusion (F) protein or the RSV attachment (G) protein, inducing Th1- and Th2-biased pulmonary memory T cell responses, respectively. After RSV infection, TARC production significantly increased in the vaccinia virus G-primed animals only. These data suggest a positive feedback loop for TARC production between RSV infection and Th2 cytokines. RSV-infected lung epithelial cells cultured with IL-4 or IL-13 demonstrated a marked increase in the production of TARC. The synergistic effect of RSV and IL-4/IL-13 on TARC production reflected differential induction of NFκB and STAT6 by the two stimuli (both are in the TARC promoter). These findings demonstrate that RSV induces a chemokine TARC that has the potential to recruit Th2 cells to the lung.

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“…Subsequent studies showed that a wide variety of stimuli cause mucin production via EGFR activation, effects that are inhibited selectively by EGFR tyrosine kinase inhibitors. These stimuli include mechanical irritants (12), allergens (11), interleukin-13 (13), oxidative stress and neutrophils (14), eosinophil products (15), neutrophil elastase (16,17), other neutrophil products (13), cigarette smoke and its components (18,19), Pseudomonas aeruginosa bacteria (20), bacterial lipopolysaccharide (21), respiratory syncytial virus infection (22), as well as inflammatory mediators such as phorbol 12-myristate 13-acetate (PMA) (21,23). Studies also show that EGFR activation in the nose causes mucin production (24,25).…”

mentioning

confidence: 99%

Role of the Airway Epithelium in Defense Against Inhaled Invaders

Nadel

2005

COPD: Journal of Chronic Obstructive Pulmonary Disease

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Activation of the Epidermal Growth Factor Receptor by Respiratory Syncytial Virus Results in Increased Inflammation and Delayed Apoptosis

Cited by 90 publications

References 53 publications

Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals

Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals

Respiratory Syncytial Virus Synergizes with Th2 Cytokines to Induce Optimal Levels of TARC/CCL17

Role of the Airway Epithelium in Defense Against Inhaled Invaders

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