Regulation of ozone-induced lung inflammation by the epidermal growth factor receptor in mice

Feng, Feifei; Jin, Yuefei; Liu, Duan; Yan, Zhen; Wang, Shouying; Li, Fangfang; Liu, Yingying; Samet, James M.; Wu, Weidong

doi:10.1002/tox.22202

Cited by 22 publications

(11 citation statements)

References 36 publications

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“…Pulmonary edema is mainly responsible for fatal HFMD [3,4], which could be defined as an extra-vascular increasing fluid in the lungs [27]. L m , EG-VEGF and NA are known as the indicators of pulmonary edema [28][29][30]. In our study, we found increased lung mass, L m , EG-VEGF and NA in lung lysates, mucus production and erythrocytefilled fluid in the alveolar spaces of mice lungs after infection.…”

Section: Discussionsupporting

confidence: 58%

Mast cells contribute to Enterovirus 71 infection-induced pulmonary edema in neonatal mice

Jin

Zhang

Wang

et al. 2018

Laboratory Investigation

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Enterovirus (EV) 71 infection has been widely acknowledged as the leading cause of severe hand, foot and mouth disease (HFMD), which may rapidly lead to fatal pulmonary edema. In this study, we established a mouse model for EV71 infection exhibiting high incidence of severe symptoms with pulmonary edema. Mast cells (MCs) accumulation, activation and allergic inflammation were found in the brains, lungs and skeletal muscle of mice after EV71 infection, especially in the lungs of mice. Levels of histamine, platelet-activating factor (PAF), interleukin (IL)-4, IL-5, IL-13, tumor necrosis factor-α (TNF-α), nitric oxide (NO), endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and noradrenaline (NA) were increased in EV71-infected lungs. In addition, EV71 infection reduced the number of pulmonary T cells, dendritic cells (DCs) and monocytes, and increased the number of lung eosinophils, Tregs and MCs. MCs number and tryptase expression in target organs or tissues posed a trend towards an increase from control to severe mice. There were positive correlations between MCs number in the brains (r = 0.701, P = 0.003), lungs (r = 0.802, P < 0.0001), skeletal muscles (r = 0.737, P = 0.001) and mean clinical score. Thus, our results suggested that MCs contributed to the pulmonary edema during EV71 infection.

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Section: Discussionsupporting

confidence: 58%

Mast cells contribute to Enterovirus 71 infection-induced pulmonary edema in neonatal mice

Jin

Zhang

Wang

et al. 2018

Laboratory Investigation

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“…Furthermore, IL-10 overexpression protects mice from the detrimental inflammatory, NF-κB-mediated effects of ozone (30). The EGFR kinase inhibitor PD153035, given prophylactically, prevents ozone-induced EGFR (Y1068) phosphorylation in the lung sections and significantly attenuates lung inflammation (31). The effects of therapeutic administration on inflammation and lung function should be measured.…”

Section: Mechanisms Implicated In Ozone Actions On the Airway Epitheliummentioning

confidence: 99%

Transcriptional Effects of Ozone and Impact on Airway Inflammation

2019

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Epidemiological and challenge studies in healthy subjects and in individuals with asthma highlight the health impact of environmental ozone even at levels considered safe. Acute ozone exposure in man results in sputum neutrophilia in 30% of subjects particularly young children, females, and those with ongoing cardiopulmonary disease. This may be associated with systemic inflammation although not in all cases. Chronic exposure amplifies these effects and can result in the formation of asthma-like symptoms and immunopathology. Asthmatic patients who respond to ozone (responders) induce a greater number of genes in bronchoalveolar (BAL) macrophages than healthy responders with up-regulation of inflammatory and immune pathways under the control of cytokines and chemokines and the enhanced expression of remodeling and repair programmes including those associated with protease imbalances and cell-cell adhesion. These pathways are under the control of several key transcription regulatory factors including nuclear factor (NF)-κB, anti-oxidant factors such as nuclear factor (erythroid-derived 2)-like 2 NRF2, the p38 mitogen activated protein kinase (MAPK), and priming of the immune system by up-regulating toll-like receptor (TLR) expression. Murine and cellular models of acute and chronic ozone exposure recapitulate the inflammatory effects seen in humans and enable the elucidation of key transcriptional pathways. These studies emphasize the importance of distinct transcriptional networks in driving the detrimental effects of ozone. Studies indicate the critical role of mediators including IL-1, IL-17, and IL-33 in driving ozone effects on airway inflammation, remodeling and hyperresponsiveness. Transcription analysis and proof of mechanisms studies will enable the development of drugs to ameliorate the effects of ozone exposure in susceptible individuals.

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“…EGFR becomes activated by receptor overexpression (mainly in cancer) as well as ligand-dependent and ligand-independent mechanisms in response to a variety of stimuli [ 66 ]. It has been widely appreciated that EGFR-dependent signaling plays an important role in the pathogenesis of inflammation through regulation of pro-inflammatory genes [ 67 , 68 ]. The cytoplasmic Src (c-Src) kinase is known to trans-activate EGFR.…”

Section: Ev71 Infection Activates Epidermal Growth Factor Receptomentioning

confidence: 99%

Antiviral and Inflammatory Cellular Signaling Associated with Enterovirus 71 Infection

Jin

Zhang

2018

Viruses

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Enterovirus 71 (EV71) infection has become a major threat to global public health, especially in infants and young children. Epidemiological studies have indicated that EV71 infection is responsible for severe and even fatal cases of hand, foot, and mouth disease (HFMD). Accumulated evidence indicates that EV71 infection triggers a plethora of interactive signaling pathways, resulting in host immune evasion and inflammatory response. This review mainly covers the effects of EV71 infection on major antiviral and inflammatory cellular signal pathways. EV71 can activate cellular signaling networks including multiple cell surface and intracellular receptors, intracellular kinases, calcium flux, and transcription factors that regulate antiviral innate immunity and inflammatory response. Cellular signaling plays a critical role in the regulation of host innate immune and inflammatory pathogenesis. Elucidation of antiviral and inflammatory cellular signaling pathways initiated by EV71 will not only help uncover the potential mechanisms of EV71 infection-induced pathogenesis, but will also provide clues for the design of therapeutic strategies against EV71 infection.

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Regulation of ozone-induced lung inflammation by the epidermal growth factor receptor in mice

Cited by 22 publications

References 36 publications

Mast cells contribute to Enterovirus 71 infection-induced pulmonary edema in neonatal mice

Mast cells contribute to Enterovirus 71 infection-induced pulmonary edema in neonatal mice

Transcriptional Effects of Ozone and Impact on Airway Inflammation

Antiviral and Inflammatory Cellular Signaling Associated with Enterovirus 71 Infection

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