Airway epithelial Fas ligand expression: potential role in modulating bronchial inflammation

Gochuico, Bernadette R.; Miranda, Kathleen; Hessel, Edith M.; Bie, J. J. De; Oosterhout, Antoon J. M. van; Cruikshank, William W.; Fine, Alan

doi:10.1152/ajplung.1998.274.3.l444

Cited by 42 publications

(39 citation statements)

References 24 publications

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“…The resistance of non-Clara bronchial epithelial cells to FasL activation was particularly striking because bronchial epithelial cells strongly express Fas receptor. 10,11,[77][78][79] The refractoriness of airway epithelial cells to Fas-induced apoptosis has been reported previously 62 and has been ascribed to the expression of prosurvival proteins such as the caspase inhibitors c-IAP1 and c-IAP-2.…”

Section: Discussionmentioning

confidence: 82%

Fas-Ligand-Induced Apoptosis of Respiratory Epithelial Cells Causes Disruption of Postcanalicular Alveolar Development

Paepe

Gundavarapu

Tantravahi

et al. 2008

The American Journal of Pathology

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Premature infants are at risk for bronchopulmonary dysplasia, a complex condition characterized by impaired alveolar development and increased alveolar epithelial apoptosis. The functional involvement of pulmonary apoptosis in bronchopulmonary dysplasiaassociated alveolar disruption remains undetermined. The aims of this study were to generate conditional lung-specific Fas-ligand (FasL) transgenic mice and to determine the effects of FasL-induced respiratory epithelial apoptosis on alveolar remodeling in postcanalicular lungs. Transgenic (TetOp) 7 -FasL responder mice, generated by pronuclear microinjection, were bred with Clara cell secretory protein (CCSP)-rtTA activator mice. Doxycycline (Dox) was administered from embryonal day 14 to postnatal day 7, and lungs were studied between embryonal day 19 and postnatal day 21. Dox administration induced marked respiratory epithelium-specific FasL mRNA and protein up-regulation in double-transgenic CCSP-rtTA

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Section: Discussionmentioning

confidence: 82%

Fas-Ligand-Induced Apoptosis of Respiratory Epithelial Cells Causes Disruption of Postcanalicular Alveolar Development

Paepe

Gundavarapu

Tantravahi

et al. 2008

The American Journal of Pathology

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“…[19][20][21][22]32 The gld mutant mice, which express a dysfunctional FasL protein, develop prominent infiltration of inflammatory cells in the airway. 33 Asthmatic individuals show an increase in the number of eosinophils, a decrease in the expression of FasL, and a decrease in the number of apoptotic cells in the airway but not that of healthy persons. 23,34 Moreover, the number of apoptotic eosinophils is reduced within the airway of asthmatic individuals compared with patients with other eosinophilic disorders of the lung, such as chronic bronchitis.…”

Section: Discussionmentioning

confidence: 98%

“…24 During allergic airway inflammation induced by OVA in mice, FasL mRNA and protein is markedly reduced in the airway epithelium. 33 These studies suggest that inflammatory cell apoptosis, especially eosinophils apoptosis is clinically relevant in asthma, and apoptosis may represent a mechanism that promotes the resolution of inflammation in asthma. It will be interesting to study whether the induction of apoptosis is beneficial in asthma.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus expressing Fas ligand gene decreases airway hyper-responsiveness and eosinophilia in a murine model of asthma

Chuang¹,

Cl²,

et al. 2004

Gene Ther

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Allergic asthma is characterized by airway hyper-responsiveness (AHR) and cellular infiltration of the airway with predominantly eosinophils and Th2 cells. The normal resolution of inflammation in the lung occurs through the regulated removal of unneeded cells by Fas-Fas ligandmediated apoptosis. Fas ligand (FasL) is a member of the tumor necrosis factor family, and when bound to Fas, it induces apoptosis of the cells. To examine the effect of the FasL gene on airway inflammation and immune effector cells in allergic asthma, recombinant adenovirus expressing murine FasL (Ad-FasL) was delivered intratracheally into ovalbumin (OVA)-immunized mice. We found that a single administration of Ad-FasL in OVA-immunized mice significantly alleviated AHR and eosinophilia by inducing the apoptosis of eosinophils and/or reducing eosinophil attractant factors, such as IL-5 and eotaxin levels. The number of infiltrated lymphocytes and Th2 cytokines, including IL-5 and IL-13, decreased in OVA-immunized mice by administration of Ad-FasL. KC and TNF-a production also decreased in AdFasL-treated OVA-immunized mice. These findings indicated that the administration of Ad-FasL to OVA-sensitized mice significantly suppressed pulmonary allergic responses. Although more studies are needed, these results suggested that Ad-FasL might be applied as an alternative therapy for allergic asthma.

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“…This finding obviously raises the question of the relevant source(s) of FasL. Constitutive cell-surface FasL expression has been detected in a variety of airway epithelial cells including Clara cells (50,51). Soluble FasL has also been detected in the bronchoalveolar lavage fluid of patients with a variety of interstitial lung diseases including IPF (52,53).…”

Section: Discussionmentioning

confidence: 99%

Increased Cell Surface Fas Expression Is Necessary and Sufficient To Sensitize Lung Fibroblasts to Fas Ligation-Induced Apoptosis: Implications for Fibroblast Accumulation in Idiopathic Pulmonary Fibrosis

Wynes

Edelman

Kostyk

et al. 2011

The Journal of Immunology

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Idiopathic pulmonary fibrosis (IPF) is associated with the accumulation of collagen-secreting fibroblasts and myofibroblasts in the lung parenchyma. Many mechanisms contribute to their accumulation, including resistance to apoptosis. In previous work, we showed that exposure to the proinflammatory cytokines TNF-α and IFN-γ reverses the resistance of lung fibroblasts to apoptosis. In this study, we investigate the underlying mechanisms. Based on an interrogation of the transcriptomes of unstimulated and TNF-α– and IFN-γ–stimulated primary lung fibroblasts and the lung fibroblast cell line MRC5, we show that among Fas-signaling pathway molecules, Fas expression was increased ∼6-fold in an NF-κB– and p38mapk-dependent fashion. Prevention of the increase in Fas expression using Fas small interfering RNAs blocked the ability of TNF-α and IFN-γ to sensitize fibroblasts to Fas ligation-induced apoptosis, whereas enforced adenovirus-mediated Fas overexpression was sufficient to overcome basal resistance to Fas-induced apoptosis. Examination of lung tissues from IPF patients revealed low to absent staining of Fas in fibroblastic cells of fibroblast foci. Collectively, these findings suggest that increased expression of Fas is necessary and sufficient to overcome the resistance of lung fibroblasts to Fas-induced apoptosis. Our findings also suggest that approaches aimed at increasing Fas expression by lung fibroblasts and myofibroblasts may be therapeutically relevant in IPF.

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Airway epithelial Fas ligand expression: potential role in modulating bronchial inflammation

Cited by 42 publications

References 24 publications

Fas-Ligand-Induced Apoptosis of Respiratory Epithelial Cells Causes Disruption of Postcanalicular Alveolar Development

Fas-Ligand-Induced Apoptosis of Respiratory Epithelial Cells Causes Disruption of Postcanalicular Alveolar Development

Adenovirus expressing Fas ligand gene decreases airway hyper-responsiveness and eosinophilia in a murine model of asthma

Increased Cell Surface Fas Expression Is Necessary and Sufficient To Sensitize Lung Fibroblasts to Fas Ligation-Induced Apoptosis: Implications for Fibroblast Accumulation in Idiopathic Pulmonary Fibrosis

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