Epithelial stress and structural remodelling in childhood asthma

Fedorov, I.A.; Wilson, Susan J.; Davies, Donna E.; Holgate, Stephen T.

doi:10.1136/thx.2004.030262

Cited by 183 publications

(157 citation statements)

References 38 publications

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“…Many patients with severe asthma show persistent airway dysfunction despite inflammatory control (5) and anti-inflammatory therapy does not improve airway remodeling. In fact, airway remodeling has been detected in children with short-term underlying airway inflammation (6,7). Taken together, these observations suggested the hypothesis of a role for activation or reactivation of the epithelial-mesenchymal unit, involving mechanisms similar to those observed during normal lung morphogenesis.…”

Section: Introductionsupporting

confidence: 52%

“…However, structural changes poorly improve with anti-inflammatory therapy. Furthermore, subepithelial fibrosis, a marker for remodeling, is actually also a very early marker for the asthmatic phenotype in young children, whereas it does not correlate with duration of the disease or necessarily with the severity of inflammation (6,7). Taken together, these observations suggest that some features of asthma physiology may be related to mechanisms other than chronic inflammation.…”

Section: Epithelial-mesenchymal Unitmentioning

confidence: 61%

“…The presence of remodeling features in bronchial biopsy specimens from young children in the absence of eosinophilic infiltrates suggests an early role for epithelialmesenchymal trophic interactions, secondary to epithelial injury and stress (6,7). Actually, remodeling can be defined as structural changes during growth or in response to injury or inflammation.…”

Section: Epithelial-mesenchymal Unitmentioning

confidence: 99%

“…Although studies on both asthmatic adults and children have reported dissociation between airway inflammation and the degree of airway responsiveness (5)(6)(7)37,38) Fibroblasts and myofibroblasts Involved in airway remodeling Connective tissue components, such as collagen and proteoglycans PGD2 = prostaglandin D2; MBP = major basic protein; ECP = eosinophilic cationic protein; EPO = eosinophil peroxidase; IL = interleukin; TNF-α = tumor necrosis factor-α; GM-CSF = granulocyte-macrophage colony-stimulating factor; G-CSF = granulocyte colony-stimulating factor; MIP-1α: macrophage inflammatory protein-1 α; TARC = thymus and activation-regulated chemokine; VEGF = vascular endothelial growth factor (33,34,36,42). Figure 1.…”

Section: Airway Inflammationmentioning

confidence: 99%

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Asthma: where is it going?

Faffe¹

2008

Braz J Med Biol Res

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Asthma is characterized by reversible airway obstruction, airway hyperresponsiveness, and airway inflammation. Although our understanding of its pathophysiological mechanisms continues to evolve, the relative contributions of airway hyperresponsiveness and inflammation are still debated. The first mechanism identified as important for asthma was bronchial hyperresponsiveness. In a second step, asthma was recognized also as an inflammatory disease, with chronic inflammation inducing structural changes or remodeling. However, persistence of airway dysfunction despite inflammatory control is observed in chronic severe asthma of both adults and children. More recently, a potential role for epithelial-mesenchymal communication or transition is emerging, with epithelial injury often resulting in a self-sustaining phenotype of wound repair modulation by activation/ reactivation of the epithelial-mesenchymal trophic unit, suggesting that chronic asthma can be more than an inflammatory disease. It is noteworthy that the gene-environmental interactions critical for the development of a full asthma phenotype involve processes similar to those occurring in branching morphogenesis. In addition, a central role for airway smooth muscle in the pathogenesis of the disease has been explored, highlighting its secretory function as well as different intrinsic properties compared to normal subjects. These new concepts can potentially shed light on the mechanisms underlying some asthma phenotypes and improve our understanding of the disease in terms of the therapeutic strategies to be applied. How we understand asthma and its mechanisms along time will be the focus of this overview.

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Section: Introductionsupporting

confidence: 52%

Section: Epithelial-mesenchymal Unitmentioning

confidence: 61%

Section: Epithelial-mesenchymal Unitmentioning

confidence: 99%

Section: Airway Inflammationmentioning

confidence: 99%

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Asthma: where is it going?

Faffe¹

2008

Braz J Med Biol Res

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“…Pretreatment with gefitinib inhibits the activation of EGFR and Akt, reduces the release of Th2 cytokines from airway epithelium, and decreases the recruitment of eosinophils into airway epithelium. In fact, EGFR expression is increased in bronchial epithelium in adult and childhood asthma and there is an increasing number of studies using EGFR to regulate airway inflammation in asthma (Amishima et al, 1998;Polosa et al, 2002;Fedorov et al, 2005). However, it is not well known the mechanisms that EGFR tyrosine kinase inhibitor inhibits allergic airway inflammation.…”

Section: Discussionmentioning

confidence: 99%

Potential use of an anticancer drug gefinitib, an EGFR inhibitor, on allergic airway inflammation

Hur

Lee²,

Lee³

et al. 2007

Exp Mol Med

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The EGFR plays an essential role in goblet cell hyperplasia and mucus hypersecretion. EGFR has an intrinsic tyrosine kinase activity that, when activated, induces the production of MUC5AC through the signaling kinase cascade in the airway epithelium. We have investigated the effects of an EGFR tyrosine kinase inhibitor, gefitinib, on ovalbumin (OVA)-induced, allergic inflammation in airway epithelia of mice. OVA-sensitized mice were pretreated with gefitinib at two different doses (12.5 and 50 mg/kg) and then challenged with OVA. The OVA challenge increased the total cell count and eosinophil count in bronchoalveolar lavage fluid (BALF), as well as the concentrations of T-helper2 (Th2) cytokines, such as IL-4 and IL-13, overall eosinophil recruitment in the lung tissue and airway hyperresponsiveness (AHR). Pretreatment with gefitinib reduced the inflammatory cell counts and released cytokine concentrations (IL-4 and IL-13) in BALF, as well as eosinophil recruitment in the lungs and AHR, in a dose-dependent manner. This was associated with decreased EGFR and Akt phosphorylation. We showed that gefitnib inhibits EGFR and phosphoinositol 3'-kinase (PI3K)/Akt activation which were activated in OVA sensitized mice. These findings suggest that inhibitors of the EGFR cascade may have a role in the treatment of asthma.

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