Matrix metalloproteinase-12 is a therapeutic target for asthma in children and young adults

Mukhopadhyay, Somnath; Sypek, Joseph P.; Tavendale, Roger; Gärtner, Ulrike; Winter, John; Li, Wei; Page, Karen; Fleming, Margaret; Brady, Jeffrey D.; O’Toole, Margot; MacGregor, David R.; Goldman, Samuel J.; Tam, Steve; Abraham, William M.; Williams, Cara; Miller, Douglas K.; Palmer, Colin N.A.

doi:10.1016/j.jaci.2010.03.027

Cited by 59 publications

(56 citation statements)

References 22 publications

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“…MMP12 (macrophage elastase) is important during COPD pathogenesis. Genetic analysis of human COPD patients showed that the common serine variant at codon 357 of the MMP12 gene (rs652438) is associated with clinical manifestations consistent with more aggressive matrix degradation and subsequent increased disease severity [61]. In contrast, the minor allele of a single-nucleotide polymorphism in MMP12 (rs2276109) is associated with a positive effect on lung function in adult smokers and with a reduced risk of COPD [93].…”

Section: Dysregulation Of Mmps In Different Lung Disorders and Its Thmentioning

confidence: 99%

“…The MMP12 gene variant (rs652438) results in more aggressive matrix degradation and was linked to increased asthma severity [61], while the rs227610 variant was associated with a positive effect on lung function in asthmatic children [93]. In a model of allergic airway inflammation induced by cockroach antigen, MMP12-deficient mice showed significant reduction in inflammatory injury [22].…”

Section: Dysregulation Of Mmps In Different Lung Disorders and Its Thmentioning

confidence: 99%

“…In a model of allergic airway inflammation induced by cockroach antigen, MMP12-deficient mice showed significant reduction in inflammatory injury [22]. Oral delivery of a potent and selective MMP12 inhibitor led to significant inhibition of both early and late airway responses to allergen challenge in an Ascaris suum-sensitised sheep asthma model [61,62]. Similarly, the MMP12 selective inhibitor S-1, an Nsulfonylamino acid derivative, inhibited the increase in eosinophils in the BAL fluid after antigen challenge in a mouse model of allergic airway inflammation [63].…”

Section: Dysregulation Of Mmps In Different Lung Disorders and Its Thmentioning

confidence: 99%

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A therapeutic role for matrix metalloproteinase inhibitors in lung diseases?

Vandenbroucke¹,

Dejonckheere²,

Libert³

2011

Eur Respir J

112

105

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Disruption of the balance between matrix metalloproteinases (MMPs) and their endogenous inhibitors is considered a key event in the development of pulmonary diseases such as chronic obstructive pulmonary disease, asthma, interstitial lung diseases and lung cancer. This imbalance often results in elevated net MMP activity, making MMP inhibition an attractive therapeutic strategy. Although promising results have been obtained, the lack of selective MMP inhibitors, together with limited knowledge regarding the exact functions of a particular MMP, hampers clinical application. This review discusses the involvement of different MMPs in lung disorders and future opportunities and limitations of therapeutic MMP inhibition.

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Section: Dysregulation Of Mmps In Different Lung Disorders and Its Thmentioning

confidence: 99%

Section: Dysregulation Of Mmps In Different Lung Disorders and Its Thmentioning

confidence: 99%

Section: Dysregulation Of Mmps In Different Lung Disorders and Its Thmentioning

confidence: 99%

See 1 more Smart Citation

A therapeutic role for matrix metalloproteinase inhibitors in lung diseases?

Vandenbroucke¹,

Dejonckheere²,

Libert³

2011

Eur Respir J

112

105

View full text Add to dashboard Cite

show abstract

“…Others propose that minor allelic single-nucleotide polymorphisms in the MMP-12 gene could affect FEV 1 among children with asthma (Hunninghake et al, 2009). Besides associating rs652438, a common gene variant of MMP-12, with disease severity in young asthmatic individuals, Mukhopadhyay et al show that pharmacologic inhibition of MMP-12 downregulates allergen-induced airway responses (Mukhopadhyay et al, 2010). In comparison to corticosteroid-treated asthmatics or healthy individuals, BAL resident TIMP-1 is increased in untreated asthma, implying that a potential MMP/TIMP imbalance could also orchestrate a pro-asthmatic phenotype (Mautino et al, 1999a;Mautino et al, 1999b).…”

Section: Asm and Disease Matrixmentioning

confidence: 99%

Airway Smooth Muscle: Is There a Phenotype Associated with Asthma?

Damera¹,

Panettieri²

2012

Bronchial Asthma - Emerging Therapeutic Strategies

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“…Genetic polymorphisms of MMP12 have been associated with the development of COPD and decline in lung function (Joos et al, 2002;Mukhopadhyay et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Endothelin Receptor B Protects Granulocyte Macrophage Colony-Stimulating Factor mRNA from Degradation

Jungck

Knobloch

Körber

et al. 2015

J Pharmacol Exp Ther

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Evidence is lacking on the differential effects of the two therapeutic concepts of endothelin receptor antagonists (ERAs): the blockade of only the endothelin receptor A (ET A R; selective antagonism) versus both ET A R and endothelin receptor B (ET B R; dual blockade). Ambrisentan, a selective ERA, and bosentan, a dual blocker, are both available for therapy. We hypothesized that there are differences in the potential of ERAs to ameliorate inflammatory processes in human airway smooth muscle cells (HASMCs) and aimed to unravel underlying mechanisms. We used HASMC culture, enzyme-linked immunosorbent assay, and quantitative reversetranscription polymerase chain reaction. Tumor necrosis factor a (TNFa) induced transcription and expression of chemokine (C-X-C motif) ligand 2 (CXCL2), chemokine (C-X-C motif) ligand 3 (CXCL3), granulocyte macrophage colony-stimulating factor (GM-CSF), and matrix metalloproteinase 12 (MMP12) in HASMCs. In concentrationresponse experiments, bosentan led to a significantly greater reduction of GM-CSF and MMP12 protein release than ambrisentan, whereas there was no significant difference in their effect on GM-CSF and MMP12 mRNA. Both ERAs reduced CXCL3 protein and mRNA equally but had no effect on CXCL2. Blocking mitogen-activated protein kinases revealed that both ET A R and ET B R signal through p38 mitogen-activated protein kinase, but ET B R also signals through extracellular signal-regulated kinase (ERK) 1/2 to induce GM-CSF expression. In the presence of the transcription inhibitor actinomycin D, bosentan, but not ambrisentan, reduced GM-CSF but not MMP12 or CXCL3 mRNA. In conclusion, blockade of each endothelin receptor subtype reduces GM-CSF transcription, but blocking ET B R additionally protects GM-CSF mRNA from degradation via ERK-1/2. Accordingly, blocking both ET A R and ET B R leads to a stronger reduction of TNFa-induced GM-CSF protein expression. This mechanism might be specific to GM-CSF. Our data stress the anti-inflammatory potential of ERA and warrant further investigation of their utility in chronic inflammatory airway diseases.

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Matrix metalloproteinase-12 is a therapeutic target for asthma in children and young adults

Cited by 59 publications

References 22 publications

A therapeutic role for matrix metalloproteinase inhibitors in lung diseases?

A therapeutic role for matrix metalloproteinase inhibitors in lung diseases?

Airway Smooth Muscle: Is There a Phenotype Associated with Asthma?

Endothelin Receptor B Protects Granulocyte Macrophage Colony-Stimulating Factor mRNA from Degradation

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