Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-β on tropoelastin mRNA in lung fibroblasts

DiCamillo, Sandra J.; Yang, Shiyong; Toselli, Paul; Naggar, Estee F.; Rich, Celeste B.; Stone, Phillip J.; Nugent, Matthew A.; Panchenko, Mikhail P.

doi:10.1152/ajplung.00530.2005

Cited by 33 publications

(31 citation statements)

References 41 publications

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“…In particular, excessive damage and lack of repair of the lung extracellular matrix (ECM) appear to play a central role in the ultimate loss of pulmonary function. In this light, we have focused on how injury to the pulmonary ECM alters its ability to control the access and response of cells to growth factors (7,11,12,18,65). In the present study, we report an interesting connection between neutrophil elastase (NE) and vascular endothelial growth factor (VEGF) with implications for lung injury and repair.…”

mentioning

confidence: 88%

Neutrophil elastase cleaves VEGF to generate a VEGF fragment with altered activity

Kurtagic¹,

Jedrychowski²,

Nugent³

2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Excessive neutrophil elastase (NE) activity and altered vascular endothelial growth factor (VEGF) signaling have independently been implicated in the development and progression of pulmonary emphysema. In the present study, we investigated the potential link between NE and VEGF. We noted that VEGF(165) is a substrate for NE. Digestion of purified VEGF(165) with NE generated a partially degraded disulfide-linked fragment of VEGF. Mass spectrometric analysis revealed that NE likely cleaves VEGF(165) at both the NH(2) and COOH termini to produce VEGF fragment chains approximately 5 kDa reduced in size. NE treatment of VEGF-laden endothelial cell cultures and smooth muscle cells endogenously expressing VEGF generated VEGF fragments similar to those observed with purified VEGF(165). NE-generated VEGF fragment showed significantly reduced binding to VEGF receptor 2 and heparin yet retained the ability to bind to VEGF receptor 1. Interestingly, VEGF fragment showed altered signaling in pulmonary artery endothelial cells compared with intact VEGF(165). Specifically, treatment with VEGF fragment did not activate extracellular-regulated kinases 1 and 2 (ERK1/2), yet resulted in enhanced activation of protein kinase B (Akt). Treatment of monocyte/macrophage RAW 264.7 cells with VEGF fragment, on the other hand, led to both Akt and ERK1/2 activation, increased VEGFR1 expression, and stimulated chemotaxis. These findings suggest that the tissue response to NE-mediated injury might involve the generation of diffusible VEGF fragments that stimulate inflammatory cell recruitment and activation via VEGF receptor 1.

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mentioning

confidence: 88%

Neutrophil elastase cleaves VEGF to generate a VEGF fragment with altered activity

Kurtagic¹,

Jedrychowski²,

Nugent³

2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Importantly, fibroblasts in emphysema have reduced responsiveness to transcriptional regulation by TGF-b1 and myofibroblast differentiation (26). Neutrophil elastase, which is highly expressed in emphysema, releases epidermal growth factor from the cell surface and initiates epidermal growth factor receptor/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (EGFR/MEK/ERK) signaling to down-regulate elastin synthesis in rat lung fibroblasts (50,51); this is mediated at least in part by stabilization of the Smad corepressor (TG-interacting factor), which inhibits TGF-b signaling (52). In addition to reduced synthetic capacity, fibroblasts exposed to cigarette smoke may induce higher proteolytic activity in the extracellular milieu by production/release of proteases.…”

Section: Fibroblast Biologymentioning

confidence: 99%

Matrix Remodeling in Pulmonary Fibrosis and Emphysema

Kulkarni

O’Reilly

Antony

et al. 2016

Am J Respir Cell Mol Biol

108

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Pulmonary fibrosis and emphysema are chronic lung diseases characterized by a progressive decline in lung function, resulting in significant morbidity and mortality. A hallmark of these diseases is recurrent or persistent alveolar epithelial injury, typically caused by common environmental exposures such as cigarette smoke. We propose that critical determinants of the outcome of the injury-repair processes that result in fibrosis versus emphysema are mesenchymal cell fate and associated extracellular matrix dynamics. In this review, we explore the concept that regulation of mesenchymal cells under the influence of soluble factors, in particular transforming growth factor-b1, and the extracellular matrix determine the divergent tissue remodeling responses seen in pulmonary fibrosis and emphysema.

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“…8,9 The mechanism most studied is probably the decreased elastin gene transcription by bFGF in human vSMCs 10 and rat pulmonary fibroblasts. [11][12][13][14] EGF and bFGF were shown to decrease elastin gene transcription by activating extracellular signalregulated kinases 1/2 (ERK1/2), resulting in its translocation to the nucleus and subsequent induction of c-fos and fra1.…”

mentioning

confidence: 99%

Inhibition of ERK1/2 Phosphorylation: A New Strategy to Stimulate Elastogenesis in the Aorta

et al. 2014

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Abstract-Haploinsufficiency of elastin leads, in more than half of patients with Williams-Beuren syndrome, to development of supravalvular aortic stenosis and hypertension. Determining mechanisms implicated in elastin synthesis would be of interest to find new elastogenic molecules to treat such a pathology. Here, we analyzed the signaling pathway linking intracellular calcium concentration to elastin regulation to find new molecules able to increase elastin synthesis. Their elastogenic ability was then investigated, in vitro and in vivo, using inhibitors of the highlighted pathway. The Brown Norway rat strain was used here as an arterial elastin-deficient model. Our data indicated that A23187, a calcium ionophore, decreases elastin expression in cultured vascular smooth muscle cells, both transcriptionally and post-transcriptionally. Addition of A23187 induced transient activation of extracellular signal-regulated kinases 1/2, leading to an upregulation of activator protein-1 transcription factors, which correlated with the inhibition of elastin gene transcription. Pretreatment with U0126, an inhibitor of extracellular signal-regulated kinases 1/2 phosphorylation, abolished the inhibition of elastin gene transcription by A23187. In vitro, U0126 increased elastin synthesis and in vivo, 24 hours after an intravenous administration, elastin gene transcription and elastin mRNA levels were increased in the rat aorta. A chronic treatment, diffusing U0126 for 10 weeks, increased aortic elastin content without changing cell number and collagen content. In conclusion, calcium ionophore represses elastin gene transcription via activation of extracellular signal-regulated kinases 1/2 pathway and activator protein-1 transcription factors. Moreover, we provide strong evidence that inhibition of extracellular signal-regulated kinases 1/2 increases elastin synthesis and could thus be suitable for treating vascular pathologies characterized by diminished arterial elastin content. (Hypertension. 2014;64:423-430.) • Online Data Supplement

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Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-β on tropoelastin mRNA in lung fibroblasts

Abstract: . Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-␤ on tropoelastin mRNA in lung fibroblasts.

Cited by 33 publications

References 41 publications

Neutrophil elastase cleaves VEGF to generate a VEGF fragment with altered activity

Neutrophil elastase cleaves VEGF to generate a VEGF fragment with altered activity

Matrix Remodeling in Pulmonary Fibrosis and Emphysema

Inhibition of ERK1/2 Phosphorylation: A New Strategy to Stimulate Elastogenesis in the Aorta

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