Asthmatic Bronchial Epithelium Is More Susceptible to Oxidant-Induced Apoptosis

Bucchieri, Fabio; Puddicombe, Sarah M.; Lordan, James; Richter, Audrey; Buchanan, Diane; Wilson, Susan J.; Ward, James E.; Zummo, Giovanni; Howarth, Peter H.; Djukanović, Ratko; Holgate, Stephen T.; Davies, Donna E.

doi:10.1165/ajrcmb.27.2.4699

Cited by 225 publications

(196 citation statements)

References 37 publications

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“…It is possible that preferential activation of a non-preferred progenitor cell population within the chronically injured airway may contribute to functional alterations within the epithelium that may be transient or persistent. This notion is supported by the recent findings of Bucchieri and colleagues, 46 who demonstrated that functional differences between bronchial epithelia from asthmatic and normal subjects are maintained in culture, indicating irreversible alterations in lineage specification. The ability to introduce lineage tags within selective progenitor cell populations in vivo provides tools to unambiguously define the contribution that differential progenitor cell utilization makes toward altered epithelial cell function in airway disease.…”

Section: Discussionsupporting

confidence: 60%

Basal Cells Are a Multipotent Progenitor Capable of Renewing the Bronchial Epithelium

Hong

Reynolds

Watkins

et al. 2004

The American Journal of Pathology

479

390

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Commitment of the pulmonary epithelium to bronchial and bronchiolar airway lineages occurs during the transition from pseudoglandular to cannalicular phases of lung development, suggesting that regional differences exist with respect to the identity of stem and progenitor cells that contribute to epithelial maintenance in adulthood. We previously defined a critical role for Clara cell secretory protein-expressing (CE) cells in renewal of bronchiolar airway epithelium following injury. Even though CE cells are also the principal progenitor for maintenance of the bronchial airway epithelium, CE cell injury is resolved through a mechanism involving recruitment of a second progenitor cell population that we now identify as a GSI-B 4 reactive, cytokeratin-14-expressing basal cell. These cells exhibit multipotent differentiation capacity as assessed by analysis of cellular phenotype within clones of LacZ-tagged cells. Clones were derived from K14-expressing cells tagged in a cell-type-specific fashion by ligand-regulable Cre recombinase-mediated genomic rearrangement of the ROSA26 recombination substrate allele. We conclude that basal cells represent an alternative multipotent progenitor cell population of bronchial airways and that progenitor cell selection is dictated by the type of airway injury. Conducting airways of the lung are lined by a highly specialized epithelium whose composition and function varies along the proximal to distal axis. Despite a growing appreciation of mechanisms contributing to branching morphogenesis and lineage specification in the developing lung it is still unclear how a complex epithelium such as that present in the conducting airway is established and maintained through adulthood. Studies in the developing rat lung indicate that lineage restriction occurs during the transition from the pseudoglandular to cannalicular phases of lung development. At this time cells of the proximal airway lose the ability to respond to mesenchymally derived signals capable of inducing distal airway differentiation.

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Section: Discussionsupporting

confidence: 60%

Basal Cells Are a Multipotent Progenitor Capable of Renewing the Bronchial Epithelium

Hong

Reynolds

Watkins

et al. 2004

The American Journal of Pathology

479

390

View full text Add to dashboard Cite

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“…Previous studies have suggested epithelial cell apoptosis in the airways through observation of TUNEL-positive cells 8 and caspase-3 and PARP immunostaining in biopsies of asthmatic individuals. 10 However, Druilhe and colleagues 9 noted a failure to detect differences in the number of TUNEL-positive bronchial epithelial cells between control and asthmatic airway endobronchial biopsies, perhaps because of detachment and loss of many of the apoptotic epithelial cells into the lumen during the process of biopsy. Others have indicated that the loss of epithelium in asthmatic biopsies may be an artifact of sampling.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9][10][11] However, not all reports have confirmed increased TUNEL positivity in airways. 9 Furthermore, if airway epithelial cells are undergoing increased cell death, it is unclear whether this is because of an inherent cell defect or a response to the asthmatic airway environment.…”

mentioning

confidence: 99%

Superoxide Dismutase Inactivation in Pathophysiology of Asthmatic Airway Remodeling and Reactivity

Comhair

Ghosh

et al. 2005

The American Journal of Pathology

175

149

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Airway hyperresponsiveness and remodeling are defining features of asthma. We hypothesized that impaired superoxide dismutase (SOD) antioxidant defense is a primary event in the pathophysiology of hyperresponsiveness and remodeling that induces apoptosis and shedding of airway epithelial cells. Mechanisms leading to apoptosis were studied in vivo and in vitro. Asthmatic lungs had increased apoptotic epithelial cells compared to controls as determined by terminal dUTP nick-end labeling-positive cells. Apoptosis was confirmed by the finding that caspase-9 and -3 and poly (ADP-ribose) polymerase were cleaved. On the basis that SOD inactivation triggers cell death and low SOD levels occur in asthma, we tested whether SOD inactivation plays a role in airway epithelial cell death. SOD inhibition increased cell death and cleavage/activation of caspases in bronchial epithelial cells in vitro. Asthma is commonly diagnosed using physiological measures, but alterations in airway structure are the defining features of asthma. Damage to airway epithelium, eosinophil infiltration, smooth muscle hyperplasia, thickening and aberrant collagen, and protein composition of the basement membrane are well established elements of the asthmatic airway. 1,2 The injury to the bronchial epithelium in asthma is marked by loss of columnar epithelial cells. Extensive loss of cells and denuded basement membrane with few basal cells remaining on the airway surface are noted in severe asthma, but shedding of airway epithelium is present even in clinically mild asthma. 2,3 Physical loss of epithelial lining cells is considered one proximate cause of the airway hyperresponsiveness to inhaled mediators, and has been speculated to contribute to asthmatic airway remodeling, in particular abnormal collagen synthesis. Evidence from organ culture systems supports the concept of an epithelial-mesenchymal unit in which loss of epithelium leads to mucosal myofibroblast and fibroblast proliferation, and collagen deposition. 2,4 -6 Thus, if the epithelial injury and loss could be understood and prevented in asthma, the clinical symptoms of airway hyperresponsiveness and long-term progressive sequelae in the airways, which contribute to fixed airflow limitation, might be prevented.Several reports have proposed that loss of epithelial cells is because of apoptosis based on immunostaining for the proteins that regulate apoptosis, or by detection of DNA strand breaks by immunostaining with the terminal dUTP nick-end labeling (TUNEL) assay. 7-11 However, not all reports have confirmed increased TUNEL positivity in airways. 9 Furthermore, if airway epithelial cells are undergoing increased cell death, it is unclear whether this is because of an inherent cell defect or a response to the asthmatic airway environment. Although nonspecific events related to increased levels of reactive oxygen and

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“…Studies with bronchial biopsies suggest that, in asthma, the airway epithelium is D.S. Faffe www.bjournal.com.br more susceptible to injury than the normal epithelium (49,50). Indeed, epidermal growth factor receptor (EGFR) and the epithelium isoform of CD44 expression, markers of epithelial injury in vivo, increase in asthma in proportion to disease severity, and throughout the epithelium, suggesting a widespread damage.…”

Section: Epithelial-mesenchymal Unitmentioning

confidence: 99%

“…Also, epithelial expression of the neutrophil chemoattractants IL-8 and MIP-1α is increased in severe asthma and correlates with increased EGFR expression. Thus, the effect of different components of the inhaled environment, such as oxidants, on a susceptible epithelium can trigger epithelium activation and damage in asthma (49). Furthermore, in chronic asthma the airway epithelium seems to be impaired in its ability to reconstitute itself after injury, entering into a chronic wound response, with increased secretion of profibrogenic growth factors, such as fibroblast growth factor (FGF)-2.…”

Section: Epithelial-mesenchymal Unitmentioning

confidence: 99%

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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Asthmatic Bronchial Epithelium Is More Susceptible to Oxidant-Induced Apoptosis

Cited by 225 publications

References 37 publications

Basal Cells Are a Multipotent Progenitor Capable of Renewing the Bronchial Epithelium

Basal Cells Are a Multipotent Progenitor Capable of Renewing the Bronchial Epithelium

Superoxide Dismutase Inactivation in Pathophysiology of Asthmatic Airway Remodeling and Reactivity

Asthma: where is it going?

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