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

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Matrix metalloproteinase-12 is a therapeutic target for asthma in children and young adults. / Mukhopadhyay, Somnath (Lead / Corresponding author); Sypek, Joseph (Lead / Corresponding author); Tavendale, Roger; Gartner, Ulrike; Winter, John; Li, Wei; Page, Karen; Fleming, Margaret; Brady, Jeff; O'Toole, Margot; Macgregor, Donald F.; Goldman, Samuel; Tam, Steve; Abraham, William; Williams, Cara; Miller, Douglas K.; Palmer, Colin N. A.

In: Journal of Allergy and Clinical Immunology, Vol. 126, No. 1, 07.2010, p. 70-76.

Research output: Contribution to journalArticle

Harvard

Mukhopadhyay, S, Sypek, J, Tavendale, R, Gartner, U, Winter, J, Li, W, Page, K, Fleming, M, Brady, J, O'Toole, M, Macgregor, DF, Goldman, S, Tam, S, Abraham, W, Williams, C, Miller, DK & Palmer, CNA 2010, 'Matrix metalloproteinase-12 is a therapeutic target for asthma in children and young adults' Journal of Allergy and Clinical Immunology, vol 126, no. 1, pp. 70-76.

APA

Mukhopadhyay, S., Sypek, J., Tavendale, R., Gartner, U., Winter, J., Li, W., Page, K., Fleming, M., Brady, J., O'Toole, M., Macgregor, D. F., Goldman, S., Tam, S., Abraham, W., Williams, C., Miller, D. K., & Palmer, C. N. A. (2010). Matrix metalloproteinase-12 is a therapeutic target for asthma in children and young adults. Journal of Allergy and Clinical Immunology, 126(1), 70-76doi: 10.1016/j.jaci.2010.03.027

Vancouver

Mukhopadhyay S, Sypek J, Tavendale R, Gartner U, Winter J, Li W et al. Matrix metalloproteinase-12 is a therapeutic target for asthma in children and young adults. Journal of Allergy and Clinical Immunology. 2010 Jul;126(1):70-76.

Author

Mukhopadhyay, Somnath (Lead / Corresponding author); Sypek, Joseph (Lead / Corresponding author); Tavendale, Roger; Gartner, Ulrike; Winter, John; Li, Wei; Page, Karen; Fleming, Margaret; Brady, Jeff; O'Toole, Margot; Macgregor, Donald F.; Goldman, Samuel; Tam, Steve; Abraham, William; Williams, Cara; Miller, Douglas K.; Palmer, Colin N. A. / Matrix metalloproteinase-12 is a therapeutic target for asthma in children and young adults.

In: Journal of Allergy and Clinical Immunology, Vol. 126, No. 1, 07.2010, p. 70-76.

Research output: Contribution to journalArticle

Bibtex - Download

@article{843c213a69d1467bb70a38e1d8f8ccc2,
title = "Matrix metalloproteinase-12 is a therapeutic target for asthma in children and young adults",
author = "Somnath Mukhopadhyay and Joseph Sypek and Roger Tavendale and Ulrike Gartner and John Winter and Wei Li and Karen Page and Margaret Fleming and Jeff Brady and Margot O'Toole and Macgregor, {Donald F.} and Samuel Goldman and Steve Tam and William Abraham and Cara Williams and Miller, {Douglas K.} and Palmer, {Colin N. A.}",
year = "2010",
volume = "126",
number = "1",
pages = "70--76",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Matrix metalloproteinase-12 is a therapeutic target for asthma in children and young adults

A1 - Mukhopadhyay,Somnath

A1 - Sypek,Joseph

A1 - Tavendale,Roger

A1 - Gartner,Ulrike

A1 - Winter,John

A1 - Li,Wei

A1 - Page,Karen

A1 - Fleming,Margaret

A1 - Brady,Jeff

A1 - O'Toole,Margot

A1 - Macgregor,Donald F.

A1 - Goldman,Samuel

A1 - Tam,Steve

A1 - Abraham,William

A1 - Williams,Cara

A1 - Miller,Douglas K.

A1 - Palmer,Colin N. A.

AU - Mukhopadhyay,Somnath

AU - Sypek,Joseph

AU - Tavendale,Roger

AU - Gartner,Ulrike

AU - Winter,John

AU - Li,Wei

AU - Page,Karen

AU - Fleming,Margaret

AU - Brady,Jeff

AU - O'Toole,Margot

AU - Macgregor,Donald F.

AU - Goldman,Samuel

AU - Tam,Steve

AU - Abraham,William

AU - Williams,Cara

AU - Miller,Douglas K.

AU - Palmer,Colin N. A.

PY - 2010/7

Y1 - 2010/7

N2 - <p>Background: Matrix metalloproteinase (MMP)-12-mediated pathologic degradation of the extracellular matrix and the subsequent repair cycles influence the airway changes in patients with asthma and chronic obstructive pulmonary disease (COPD). The common serine variant at codon 357 of the MMP12 gene (rs652438) is associated with clinical manifestations consistent with more aggressive matrix degradation in other tissues.</p><p>Objective: We sought to explore the hypothesis that MMP12 represents a novel therapeutic target in asthma.</p><p>Methods: The role of the rs652438 variant on clinical phenotype was explored in young asthmatic patients and patients with COPD. Candidate MMP-12 inhibitors were identified on the basis of potency and selectivity against a panel of other MMPs. The role of MMP-12 specific inhibition was tested in vitro, as well as in animal models of allergic airway inflammation.</p><p>Results: The odds ratio for having greater asthma severity was 2.00 (95% CI, 1.24-3.24; P = .004) when comparing asthmatic patients with at least 1 copy of the serine variant with those with none. The carrier frequency for the variant increased in line with asthma treatment step (P = .000). The presence of the variant nearly doubled the odds in favor of asthmatic exacerbations (odds ratio, 1.90; 95% CI, 1.19-3.04; P = .008) over the previous 6 months. The serine variant was also associated with increased disease severity in patients with COPD (P = .016). Prior administration of an MMP-12 specific inhibitor attenuated the early airway response and completely blocked the late airway response with subsequent Ascaris suum challenge in sheep.</p><p>Conclusion: Studies on human participants with asthma and COPD show that the risk MMP12 gene variant is associated with disease severity. In allergen-sensitized sheep pharmacologic inhibition of MMP12 downregulates both early and late airway responses in response to allergic stimuli. (J Allergy Clin Immunol 2010;126:70-6.)</p>

AB - <p>Background: Matrix metalloproteinase (MMP)-12-mediated pathologic degradation of the extracellular matrix and the subsequent repair cycles influence the airway changes in patients with asthma and chronic obstructive pulmonary disease (COPD). The common serine variant at codon 357 of the MMP12 gene (rs652438) is associated with clinical manifestations consistent with more aggressive matrix degradation in other tissues.</p><p>Objective: We sought to explore the hypothesis that MMP12 represents a novel therapeutic target in asthma.</p><p>Methods: The role of the rs652438 variant on clinical phenotype was explored in young asthmatic patients and patients with COPD. Candidate MMP-12 inhibitors were identified on the basis of potency and selectivity against a panel of other MMPs. The role of MMP-12 specific inhibition was tested in vitro, as well as in animal models of allergic airway inflammation.</p><p>Results: The odds ratio for having greater asthma severity was 2.00 (95% CI, 1.24-3.24; P = .004) when comparing asthmatic patients with at least 1 copy of the serine variant with those with none. The carrier frequency for the variant increased in line with asthma treatment step (P = .000). The presence of the variant nearly doubled the odds in favor of asthmatic exacerbations (odds ratio, 1.90; 95% CI, 1.19-3.04; P = .008) over the previous 6 months. The serine variant was also associated with increased disease severity in patients with COPD (P = .016). Prior administration of an MMP-12 specific inhibitor attenuated the early airway response and completely blocked the late airway response with subsequent Ascaris suum challenge in sheep.</p><p>Conclusion: Studies on human participants with asthma and COPD show that the risk MMP12 gene variant is associated with disease severity. In allergen-sensitized sheep pharmacologic inhibition of MMP12 downregulates both early and late airway responses in response to allergic stimuli. (J Allergy Clin Immunol 2010;126:70-6.)</p>

KW - Asthma

KW - allergy

KW - chronic obstructive pulmonary disease

KW - metalloproteinase

KW - genetics

KW - exacerbation

KW - polymorphism

KW - animal studies

KW - FILAGGRIN NULL MUTATIONS

KW - LUNG-FUNCTION

KW - COPD

KW - METALLOELASTASE

KW - EXACERBATIONS

KW - POLYMORPHISMS

KW - INFLAMMATION

KW - EXPRESSION

KW - PROTEINS

KW - DISEASE

U2 - 10.1016/j.jaci.2010.03.027

DO - 10.1016/j.jaci.2010.03.027

M1 - Article

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 1

VL - 126

SP - 70

EP - 76

ER -

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