Immunocytochemical evidence for extra-cellular initiation of elastase-induced bronchial secretory cell metaplasia in hamsters

Christensen, Thomas G.; Alonso, PA

doi:10.1183/09031936.96.09030535

Cited by 9 publications

(5 citation statements)

References 48 publications

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“…Our laboratory and others have reported that proteolytic activity is required for NE-induced gene expression (12,37). In studies with airway epithelial cells, NE has been immunolocalized to the extracellular space (38). Therefore, we predict that the primary event in NEregulated gene expression is NE interaction with the epithelial cell membrane.…”

Section: Discussionmentioning

confidence: 80%

Neutrophil Elastase Induces MUC5AC Gene Expression in Airway Epithelium via a Pathway Involving Reactive Oxygen Species

Fischer

Voynow²

2002

Am J Respir Cell Mol Biol

196

119

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Neutrophil-predominant airway inflammation and mucus obstruction of the airways are major pathologic features of chronic airway diseases, including cystic fibrosis and chronic bronchitis. Neutrophils release elastase, a serine protease that impairs mucociliary clearance and stimulates goblet cell metaplasia and mucin production. We previously reported that neutrophil elastase increases expression of a major respiratory mucin gene, MUC5AC, by enhancing mRNA stability. However, the molecular mechanisms of elastase-regulated MUC5AC expression are not known. We hypothesized that reactive oxygen species, generated by elastase treatment, mediate MUC5AC gene expression. To test this hypothesis, A549, a respiratory epithelial cell line, was treated with elastase in the presence or absence of the oxygen radical scavenger, dimethylthiourea, or the iron chelator, desferrioxamine. MUC5AC mRNA levels were assessed by Northern analysis. Both antioxidants significantly inhibited elastase-induced MUC5AC gene expression. Dimethylthiourea also inhibited the neutrophil elastase (NE)-induced increase in MUC5AC expression in normal human bronchial epithelial cells. To determine whether elastase treatment generated reactive oxygen species, A549 and normal human bronchial epithelial cells were loaded with dichlorodihydrofluorescein, a fluorescent indicator of oxidative stress. NE treatment increased cellular fluorescence in both cell types, indicating generation of intracellular reactive oxygen species. We conclude that NE treatment increases MUC5AC gene expression by an oxidant-dependent mechanism.

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Section: Discussionmentioning

confidence: 80%

Neutrophil Elastase Induces MUC5AC Gene Expression in Airway Epithelium via a Pathway Involving Reactive Oxygen Species

Fischer

Voynow²

2002

Am J Respir Cell Mol Biol

196

119

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“…7), suggesting a direct effect of tiotropium on NE-induced mucin production in airway epithelial cells. NE has been found to act on the epithelial cell surface [20] and activate signalling via multiple pathways, including generation of reactive oxygen species [21,22], activation of toll-like receptor 4 [23] and activation of the epidermal growth factor receptor (EGFR) [11]. Transforming growth factor-a, cleaved by NE, and reactive oxygen species, produced by NE, have been shown to activate EGFR and induce MUC5AC production in NCI-H292 cells in vitro [11].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of neutrophil elastase-induced goblet cell metaplasia by tiotropium in mice

Arai¹,

Kondo²,

Izumo³

et al. 2009

Eur Respir J

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Airway occlusion by mucus in chronic obstructive disease (COPD) is associated with a poor prognosis. We hypothesised that tiotropium has the ability to inhibit neutrophil elastase (NE)-induced goblet cell metaplasia in mice and mucin production in vitro.On days 1, 4, and 7, tiotropium or vehicle was administered to C57BL/6 mice by inhalation and they were allowed to intranasally aspirate human NE. Bronchoalveolar lavage fluid (BALF) and lung sections were analysed on days 8, 11 and 14. The effect of late administration of tiotropium on the goblet cell metaplasia by NE aspiration was also assessed. NE-induced MUC5AC production by NCI-H292 cells was measured with ELISA.Repeated NE aspiration induced marked goblet cell metaplasia. The grading of goblet cell metaplasia, neutrophil count and eosinophil count in BALF, keratinocyte-derived chemokine level and leukotriene B 4 level in BALF, and M 3 receptor expression by immunohistochemistry, were lower in the tiotropium group than in the vehicle group. Late administration of tiotropium inhibited the established goblet cell metaplasia. Tiotropium inhibited NE-induced MUC5AC production.Tiotropium inhibited NE-induced goblet cell metaplasia and mucin production, probably mediated by suppression of inflammation and a direct action on epithelial cells. This result suggests that tiotropium may be useful for the treatment of mucus overproduction in COPD.

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“…The mechanism of PKC activation by HNE is currently unknown. Because HNE is a large molecule (molecular mass Х 29.5 kDa), and because a study showed solely extracellular staining of HNE after prolonged incubation of HNE with airway epithelium (41), it is speculated that HNE exerts its function on cell membrane surface. Further studies to identify a possible HNE receptor or other cell surface molecules are needed to understand fully the actions of HNE.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil Elastase Induces MUC5AC Mucin Production in Human Airway Epithelial Cells via a Cascade Involving Protein Kinase C, Reactive Oxygen Species, and TNF-α-Converting Enzyme

Shao

Nadel

2005

The Journal of Immunology

211

165

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Mucus hypersecretion is a prominent manifestation in patients with chronic inflammatory airway diseases and contributes to their morbidity and mortality by plugging airways and causing recurrent infections. Human neutrophil elastase (HNE) exists in high concentrations (1–20 μM) in airway secretions of these patients and induces overproduction of MUC5AC mucin, a major component of airway mucus. Previous studies showed that HNE induces MUC5AC mucin production involving reactive oxygen species (ROS) generation and TGF-α-dependent epidermal growth factor receptor (EGFR) activation in human airway epithelial cells. However, the molecular mechanisms involved in these responses are not defined. TNF-α-converting enzyme (TACE) cleaves pro-TGF-α into soluble TGF-α and can be activated by ROS. We hypothesize that HNE activates TACE via ROS generation, resulting in cleavage of pro-TGF-α, EGFR activation, and MUC5AC mucin expression in airway epithelial cells. Here we show that in human airway epithelial cells HNE increases TGF-α release, EGFR phosphorylation, and MUC5AC mucin expression, effects that were attenuated by TACE inhibitor TAPI-1 and by specific knockdown of TACE expression with small interfering RNA, implicating TACE in HNE-induced responses. These responses to HNE were also reduced by pretreatment with ROS scavengers, implicating ROS. Furthermore, we show that HNE causes protein kinase C (PKC) activation and translocation from cytosol to plasma membrane; blockade of this effect by PKC inhibitors reduced HNE-induced ROS generation and other responses, implicating PKC. We conclude that HNE induces MUC5AC mucin expression via a cascade involving PKC-ROS-TACE in human airway epithelial cells.

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Immunocytochemical evidence for extra-cellular initiation of elastase-induced bronchial secretory cell metaplasia in hamsters

Cited by 9 publications

References 48 publications

Neutrophil Elastase Induces MUC5AC Gene Expression in Airway Epithelium via a Pathway Involving Reactive Oxygen Species

Neutrophil Elastase Induces MUC5AC Gene Expression in Airway Epithelium via a Pathway Involving Reactive Oxygen Species

Inhibition of neutrophil elastase-induced goblet cell metaplasia by tiotropium in mice

Neutrophil Elastase Induces MUC5AC Mucin Production in Human Airway Epithelial Cells via a Cascade Involving Protein Kinase C, Reactive Oxygen Species, and TNF-α-Converting Enzyme

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