Neutrophil Elastase Induces <i>MUC</i>5AC Gene Expression in Airway  Epithelium via a Pathway Involving Reactive Oxygen Species

Fischer, Bernard M.; Voynow, Judith A.

doi:10.1165/ajrcmb.26.4.4473

Cited by 196 publications

(129 citation statements)

References 37 publications

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“…It has been previously documented that ROS may alter the expression of certain genes by interfering with message stability (75)(76)(77)(78). Our present data provide evidence that the irondependent generation of ROS indeed coincided with a decrease in the stability of elastin mRNA (Figs.…”

Section: Discussionsupporting

confidence: 80%

Fluctuations of Intracellular Iron Modulate Elastin Production

Bunda

Kaviani

Hinek

2005

Journal of Biological Chemistry

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Production of insoluble elastin, the major component of elastic fibers, can be modulated by numerous intrinsic and exogenous factors. Because patients with hemolytic disorders characterized with fluctuations in iron concentration demonstrate defective elastic fibers, we speculated that iron might also modulate elastogenesis. In the present report we demonstrate that treatment of cultured human skin fibroblasts with low concentration of iron 2-20 M (ferric ammonium citrate) induced a significant increase in the synthesis of tropoelastin and deposition of insoluble elastin. Northern blot and realtime reverse transcription-PCR analysis revealed that treatment with 20 M iron led to an increase of ϳ3-fold in elastin mRNA levels. Because treatment with an intracellular iron chelator, desferrioxamine, caused a significant decrease in elastin mRNA level and consequent inhibition of elastin deposition, we conclude that iron facilitates elastin gene expression. Our experimental evidence also demonstrates the existence of an opposite effect, in which higher, but not cytotoxic concentrations of iron (100 -400 M) induced the production of intracellular reactive oxygen species that coincided with a significant decrease in elastin message stability and the disappearance of iron-dependent stimulatory effect on elastogenesis. This stimulatory elastogenic effect was reversed, however, in cultures simultaneously treated with high iron concentration (200 M) and the intracellular hydroxyl radical scavenger, dimethylthiourea. Thus, presented data, for the first time, demonstrate the existence of two opposite iron-dependent mechanisms that may affect the steady state of elastin message. We speculate that extreme fluctuations in intracellular iron levels result in impaired elastic fiber production as observed in hemolytic diseases.Mature elastic fibers and laminae provide extensibility and elastic recoil to vascular walls and ligaments and form a connective tissue framework of lungs, elastic cartilage, and skin (1, 2). They are complex structures made of polymeric (insoluble) elastin and 12-nm microfibrils that consist of several glycoproteins, e.g. fibrillins, fibulins, and microfibril-associated glycoproteins (3-6). Elastic fiber formation (elastogenesis) is a complex process involving several intracellular and extracellular events. Cells (fibroblasts, endothelial cells, chondroblasts, or vascular smooth muscle cells) must first synthesize and secrete numerous glycoproteins to form a microfibrillar scaffold upon which tropoelastin, the precursor peptides, are properly assembled and covalently cross-linked by lysyl oxidase into a resilient polymer, insoluble elastin (7-10). Production of elastin reaches its highest levels in the third trimester of the fetal life and steadily decreases during early postnatal development (11,12). In undisturbed tissues, elastic fibers may last over the entire human lifespan (13,14).The net deposition of elastin appears to be controlled on both the transcriptional level (tropoelastin mRNA message express...

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Section: Discussionsupporting

confidence: 80%

Fluctuations of Intracellular Iron Modulate Elastin Production

Bunda

Kaviani

Hinek

2005

Journal of Biological Chemistry

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“…NE stimulates translocation of PKCδ to the plasma membrane, resulting in activation of dual oxidase 1 (DUOX1 (Shao and Nadel, 2005a) and subsequent activation of TNFα-converting enzyme (TACE) to cleave and release the EGFR ligand, TGFα, permitting activation of EGFR and down-stream signaling via RAS-Raf-MEK1/2-ERK1/2 and either NF-κB (Song et al, 2005) or Sp1 (Perrais et al, 2002) activation. We and others have shown that NE also induces oxidant signaling in airway epithelial cells (Aoshiba et al, 2001, Fischer and Voynow, 2002 and these oxidants are required for increased MUC5AC expression. We have recently reported that NE upregulates a cytoplasmic oxidoreductase, NADPH quinone oxidoreductase 1 that is required for NE-induced lipid peroxidation and for NE-regulated MUC5AC mRNA expression .…”

Section: Neutrophil Elastase and Mucins Mucus Secretion And Mucocilmentioning

confidence: 69%

Proteases and cystic fibrosis

Voynow

Fischer

Zheng

2008

The International Journal of Biochemistry & Cell Biology

175

159

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Cystic fibrosis is the most common, inherited fatal disease in Caucasians. The major cause of morbidity and mortality is chronic lung disease due to infection and inflammation in the airways leading to bronchiectasis and respiratory failure. The signature pathologic features of CF lung disease including abnormal mucus obstructing airways, chronic infection with S. aureus, P. aeruginosa and other gram negative bacteria, and a robust neutrophil-dominant airway inflammation, are exacerbated by unopposed proteases present at high concentrations in the ASL. There is strong evidence that proteases, particularly neutrophil elastase, contribute to the pathology of CF by impairing mucociliary clearance, interfering with innate immune functions, and perpetuating neutrophilic inflammation. The mechanisms employed by proteases to impact airway function in CF will be reviewed.

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“…This effect was recently found to occur via a proteolytic activation of epidermal growth factor receptor signalling cascade involving TGF-a [28]. An additional mechanism involving reactive oxygen species has been put forward [29]. Since DBA/2 mice are sensitive to oxidants, have normal BALF EIC values and do not develop significant GCM, it can be assumed that the proteolytic pathway of MUC5AC activation is more relevant under the experimental conditions of the current study.…”

Section: Discussionmentioning

confidence: 81%

Different lung responses to cigarette smoke in two strains of mice sensitive to oxidants

Bartalesi¹

2005

Eur Respir J

152

113

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The development of cigarette smoke-induced pulmonary changes in C57 Bl/6J and DBA/2 mice was investigated. Both strains are sensitive to oxidants and C57Bl/6J mice are moderately deficient in serum alpha1-proteinase inhibitor.Following chronic exposure to cigarette smoke, patchy emphysema was present in mice of both strains, but developed faster in DBA/2 mice. A positive reaction for mouse neutrophil elastase was seen on the septa of both strains. Additionally, the DBA/2 mice developed a uniform parenchymal dilation that was preceded by the appearance of apoptotic cells in areas with a low signal for vascular endothelial growth factor-receptor 2. Fibrotic areas scattered throughout the parenchyma, coupled with a positive immunohistochemical reaction for transforming growth factor-b was seen only in DBA/2 mice.Both DBA/2 and C57Bl/6J strains showed epithelial cell injury and areas of deciliation in their airways. However, the appearance of goblet cell metaplasia was common in C57Bl/6J mice but rare in DBA/2 mice. A positive immunohistochemical reaction for interleukin (IL)-4, IL-13 and MUC5AC was seen only in the airways of C57Bl/6J mice.Strain characteristics (alpha1-proteinase inhibitor levels, sensitivity to oxidants, and constitutive levels of vascular endothelial growth factor-receptor 2) and phenotypical responses (apoptosis and cytokine distribution) may condition parenchymal and airway changes to cigarette smoke.

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

Cited by 196 publications

References 37 publications

Fluctuations of Intracellular Iron Modulate Elastin Production

Fluctuations of Intracellular Iron Modulate Elastin Production

Proteases and cystic fibrosis

Different lung responses to cigarette smoke in two strains of mice sensitive to oxidants

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