Inhibition of elastase-induced acute inflammation and pulmonary emphysema in hamsters by a novel neutrophil elastase inhibitor FR901277

Fujie, Keiko; Shinguh, Yasuhiko; Yamazaki, Akiko; Hatanaka, Hiroshi; Okamoto, Masanori; Okuhara, Masakuni

doi:10.1007/s000110050440

Cited by 39 publications

(31 citation statements)

References 29 publications

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“…NE-I significantly inhibits elastase-induced paw edema in mice at 10 mg/kg with a median effective dose (ED 50 ) for inhibiting elastase-induced lung hemorrhage and pulmonary emphysema of about 8 mg/kg. 44 In preliminary studies, we observed 57% to 78% inhibition of NE in plasma and marrow between 1 and 8 hours after administration of G-CSF, and 78% to 85% inhibition of marrow NE on day 5, after 4 days of dosing with NE-I and our standard 4-day G-CSFmobilizing regimen. This dose of NE-I has also been shown to block CFU-GM mobilization and SDF-1 degradation in marrow in G-CSFmobilized mice.…”

Section: In Vivo Mmp-9 and Ne Neutralizationmentioning

confidence: 72%

Neutrophil-derived MMP-9 mediates synergistic mobilization of hematopoietic stem and progenitor cells by the combination of G-CSF and the chemokines GROβ/CXCL2 and GROβT /CXCL2Δ4

Pelus

Bian

King

et al. 2004

Blood

178

168

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Section: In Vivo Mmp-9 and Ne Neutralizationmentioning

confidence: 72%

Neutrophil-derived MMP-9 mediates synergistic mobilization of hematopoietic stem and progenitor cells by the combination of G-CSF and the chemokines GROβ/CXCL2 and GROβT /CXCL2Δ4

Pelus

Bian

King

et al. 2004

Blood

178

168

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“…An alternative approach is to develop small molecule inhibitors of neutrophil elastase [266] and ONO-5046 and FR901277 have high potency [267]. These drugs inhibit neutrophil elastase-induced lung injury in experimental animals, whether given by inhalation or systemically and also inhibit the other serine proteinases released from neutrophils, namely cathepsin G and proteinase-3, that may mediate features of COPD.…”

Section: Neutrophil Elastase Inhibitorsmentioning

confidence: 99%

COPD: current therapeutic interventions and future approaches

Barnes¹

2005

Eur Respir J

233

143

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Although long-acting bronchodilators have been an important advance for the management of chronic obstructive pulmonary disease (COPD), these drugs do not deal with the underlying inflammatory process. No currently available treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. Several new treatments that target the inflammatory process are now in clinical development. Some therapies, such as chemokine antagonists, are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD, whereas others target inflammatory cytokines such as tumour necrosis factor-a.Broad spectrum anti-inflammatory drugs are now in phase III development for COPD, and include phosphodiesterase-4 inhibitors. Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-activated protein kinase, nuclear factor-kB and phosphoinositide-3 kinase-c. More specific approaches are to give antioxidants, inhibitors of inducible nitric oxide synthase and leukotriene B 4 antagonists. Other treatments have the potential to combat mucus hypersecretion, and there is also a search for serine proteinase and matrix metalloproteinase inhibitors to prevent lung destruction and the development of emphysema.More research is needed to understand the cellular and molecular mechanisms of chronic obstructive pulmonary disease and to develop biomarkers and monitoring techniques to aid the development of new therapies.

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“…Elastolytic activity of carotid arteries (n ϭ 25) was assessed by Elastin-Congo red degradation assay as previously described 22,32 with some modification. For acidic protease activity of cathepsins, 21 100 g of total protein from each sample was incubated with 1 mg/ml ElastinCongo red containing 0.05% Triton X-100, 20 mmol/L sodium acetate, and 1 mmol/L EDTA, pH 5.5; for a study of MMP activity, the same amounts of total proteins were added to 1 mg/ml Elastin-Congo red and incubated in 10 mmol/L phosphate, pH 7.2, containing 150 mmol/L NaCl, 1% Triton-100, 15 mmol/L CaCl 2 , 0.1% SDS, 0.5% Na deoxycholate, and 0.2% Na azide.…”

Section: Elastase Assaymentioning

confidence: 99%

Increased Expression of Elastolytic Cysteine Proteases, Cathepsins S and K, in the Neointima of Balloon-Injured Rat Carotid Arteries

Cheng

Kuzuya

Sasaki

et al. 2004

The American Journal of Pathology

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The matrix-degrading activity of several proteases are involved in the accelerated breakdown of extracellular matrix associated with vascular remodeling during the development of atherosclerosis and vascular injury-induced neointimal formation. Previous studies have shown that the potent elastolytic cysteine proteases, cathepsins S and K, are overexpressed in atherosclerotic lesions in human and animal models. However, the role of these cathepsins in vascular remodeling remains unclear. In the present study, the expressions of cathepsin S and K and their inhibitor cystatin C were examined during arterial remodeling using a rat carotid artery balloon-injury model. The increase in both cathepsin S and K mRNA levels was observed from day 1 and day 3 through day 14 following the induction of balloon injury, respectively. Western blotting analysis revealed that both cathepsin S and K protein levels also increased in the carotid arteries during neointima formation, coinciding with an increase elastolytic activity assayed using Elastin-Congo red, whereas, no significant change in the expressions of cystatin C mRNA and protein was observed during follow-up periods after injury. Immunohistochemistry, Western blot, and in situ hybridization showed that the increase of cathepins S and K and the decrease of cystatin C occurred preferentially in the developing neointima. These findings suggest that cathepsin S and K may participate in the pathological arterial remodeling associated with restenosis.

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Inhibition of elastase-induced acute inflammation and pulmonary emphysema in hamsters by a novel neutrophil elastase inhibitor FR901277

Abstract: These results suggest that FR901277 inhibits the elastase activity potently both in vitro and in vivo, and that elastase may play a role at least in part in pathogenesis of pulmonary emphysema.

Cited by 39 publications

References 29 publications

Neutrophil-derived MMP-9 mediates synergistic mobilization of hematopoietic stem and progenitor cells by the combination of G-CSF and the chemokines GROβ/CXCL2 and GROβT /CXCL2Δ4

Neutrophil-derived MMP-9 mediates synergistic mobilization of hematopoietic stem and progenitor cells by the combination of G-CSF and the chemokines GROβ/CXCL2 and GROβT /CXCL2Δ4

COPD: current therapeutic interventions and future approaches

Increased Expression of Elastolytic Cysteine Proteases, Cathepsins S and K, in the Neointima of Balloon-Injured Rat Carotid Arteries

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