Integrin-Mediated Transforming Growth Factor-β Activation Regulates Homeostasis of the Pulmonary Epithelial-Mesenchymal Trophic Unit

Araya, Jun; Cambier, Stephanie; Morris, Alanna; Finkbeiner, Walter E.; Nishimura, Stephen L.

doi:10.2353/ajpath.2006.060049

Cited by 76 publications

(81 citation statements)

References 48 publications

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“…Antibodies to involucrin and keratin 6 stained the superficial and suprabasal cells of the squamous metaplastic epithelium ( Figure 3R). A pattern of immunoreactivity similar to that seen in SM of the airways in COPD was seen in the squamous mucosa of the cervix, and in the epidermis at the edge of healing wounds (Supplemental Data and Supplemental (10). Indeed, we found that α v β 8 integrin expression ( Figure 4, A and B) and α v β 8 integrin-mediated TGF-β activation ( Figure 4C) in human airway fibroblasts was increased by treatment either with recombinant IL-1β (data not shown) or by coculture with squamous metaplastic (P3) epithelial cells.…”

Section: Sm In the Small Airways Of Copd Patients Involucrin Is A Comentioning

confidence: 73%

“…Neutralizing anti-β8 and β8 siRNA blocked only approximately 50% of the total TGF-β activation as determined using a TGF-β neutralizing antibody that inhibits the function of all 3 TGF-β isoforms ( Figure 5C). Thus, the incomplete inhibition of TGF-β activation could be due to activation of TGF-β2 by an α v β 8 -independent mechanism, since α v β 8 is only involved in the activation of TGF-β1 and -β3 (10,20). Alternatively, the incomplete inhibition may be due to the relatively poor efficacy of the β8-neutralizing antibody and the incomplete silencing achieved with β8 siRNA ( Figure 5A).…”

Section: Sm In the Small Airways Of Copd Patients Involucrin Is A Comentioning

confidence: 99%

“…thelial cells express α v β 8 but do not efficiently support α v β 8 -mediated activation of TGF-β, which correlates with low expression of MT1-MMP (10). When fetal tracheal epithelial cells are stimulated with phorbol esters, MT1-MMP activity increases coincident with increasing α v β 8 -mediated activation of TGF-β (10).…”

Section: Figurementioning

confidence: 99%

“…Immunoprecipitations and SDS-PAGE were performed as previously described (10,63). Western blotting of conditioned medium of coculture system was performed as described with minor modification (10).…”

Section: Figurementioning

confidence: 99%

“…Thus, SM developing in response to pathologic stimuli may alter normal homeostatic autocrine and paracrine interactions between the epithelium and the surrounding fibroblast sheath. Recently, we provided evidence for a homeostatic role for integrin-mediated TGF-β activation in a human model of the epithelial-mesenchymal trophic unit (10). In this model, fibroblastic integrin α v β 8 -mediated TGF-β activation was found to regulate the fibrogenic phenotype as well as synthesis and secretion of HGF, which influences the proliferation of adjacent airway epithelial cells (10).…”

Section: Introductionmentioning

confidence: 98%

See 4 more Smart Citations

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

Araya¹,

Cambier²,

Markovics³

et al. 2007

J. Clin. Invest.

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232

228

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Squamous metaplasia (SM) is common in smokers and is associated with airway obstruction in chronic obstructive pulmonary disease (COPD). A major mechanism of airway obstruction in COPD is thickening of the small airway walls. We asked whether SM actively contributes to airway wall thickening through alteration of epithelial-mesenchymal interactions in COPD. Using immunohistochemical staining, airway morphometry, and fibroblast culture of lung samples from COPD patients; genome-wide analysis of an in vitro model of SM; and in vitro modeling of human airway epithelial-mesenchymal interactions, we provide evidence that SM, through the increased secretion of IL-1β, induces a fibrotic response in adjacent airway fibroblasts. We identify a pivotal role for integrin-mediated TGF-β activation in amplifying SM and driving IL-1β-dependent profibrotic mesenchymal responses. Finally, we show that SM correlates with increased severity of COPD and that fibroblast expression of the integrin α v β 8 , which is the major mediator of airway fibroblast TGF-β activation, correlated with disease severity and small airway wall thickening in COPD. Our findings have identified TGF-β as a potential therapeutic target for COPD.

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Section: Sm In the Small Airways Of Copd Patients Involucrin Is A Comentioning

confidence: 73%

Section: Sm In the Small Airways Of Copd Patients Involucrin Is A Comentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 3 more Smart Citations

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

Araya¹,

Cambier²,

Markovics³

et al. 2007

J. Clin. Invest.

Self Cite

232

228

View full text Add to dashboard Cite

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ITGB4is essential for containing HDM-induced airway inflammation and airway hyperresponsiveness

Liu

Lin

Zou

et al. 2018

Journal of Leukocyte Biology

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Airway epithelial cells play a significant role in the pathogenesis of asthma. Although the structural and functional defects of airway epithelial cells have been postulated to increase asthma susceptibility and exacerbate asthma severity, the mechanism and implication of these defects remain uncertain. Integrin β4 (ITGB4) is a structural adhesion molecule that is downregulated in the airway epithelium of asthma patients. In this study, we demonstrated that ITGB4 deficiency leads to severe allergy-induced airway inflammation and airway hyper-responsiveness (AHR) in mice. After house dust mite (HDM) challenge, epithelial cell-specific ITGB4-deleted mice showed increased lymphocyte, eosinophil, and neutrophil infiltration into lung compared with that of the wild-type mice. ITGB4 deficiency also resulted in increased expression of the Th2 cytokine IL-4, IL-13, and the Th17 cytokine IL-17A in the lung tissue and in the T cells after HDM challenge. The aggravated inflammation in ITGB4 defect mice was partly caused by enhanced disrupted epithelial barrier integrity after HDM stress, which induced the increased thymic stromal lymphopoietin secretion from airway epithelial cells. This study therefore demonstrates that ITGB4 plays a pivotal role in containing allergen-mediated lung inflammation and airway hyper-responsiveness in allergic asthma.

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Primary airway epithelial cell culture and asthma in children-lessons learnt and yet to come

et al. 2015

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Until recently the airway epithelial cell (AEC) was considered a simple barrier that prevented entry of inhaled matter into the lung parenchyma. The AEC is now recognized as having an important role in the inflammatory response of the respiratory system to inhaled exposures, and abnormalities of these responses are thought to be important to asthma pathogenesis. This review first explores how the challenges of studying nasal and bronchial AECs in children have been addressed and then summarizes the results of studies of primary AEC function in children with and without asthma. There is good evidence that nasal AECs may be a suitable surrogate for the study of certain aspects of bronchial AEC function, although bronchial AECs remain the gold standard for asthma research. There are consistent differences between children with and without asthma for nasal and bronchial AEC mediator release following exposure to a range of pro-inflammatory stimulants including interleukins (IL)-1β, IL-4, and IL-13. However, there are inconsistencies between studies, e.g., release of IL-6, an important pro-inflammatory cytokine, is not increased in children with asthma relative to controls in all studies. Future work should expand current understanding of the "upstream" signalling pathways in AEC, study AEC from children before the onset of asthma symptoms and in vitro models should be developed that replicate the in vivo status more completely, e.g., co-culture with dendritic cells. AECs are difficult to obtain from children and collaboration between centers is expected to yield meaningful advances in asthma understanding and ultimately help deliver novel therapies.

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Integrin-Mediated Transforming Growth Factor-β Activation Regulates Homeostasis of the Pulmonary Epithelial-Mesenchymal Trophic Unit

Cited by 76 publications

References 48 publications

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

ITGB4is essential for containing HDM-induced airway inflammation and airway hyperresponsiveness

Primary airway epithelial cell culture and asthma in children-lessons learnt and yet to come

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