Selective Inhibition of Matrix Metalloproteinase Isozymes and in Vivo Protection against Emphysema by Substituted γ-Keto Carboxylic Acids

Ma, Dawei; Jiang, Yongwen; Chen, Fangping; Gong, Likun; Ding, Ke; Xu, Yong; Wang, Renxiao; Ge, Ai‐hua; Ren, Jin; Li, Jingya; Jia, Lee; Ye, Qizhuang

doi:10.1021/jm051101g

Cited by 24 publications

(11 citation statements)

References 12 publications

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“…In an animal model of emphysema and in patients with COPD, several MMPs, including MMP-9, are elevated in sputum, BALF, and lung tissue specimens [2, 30, 44, 45] and are related to poor lung function. MMP inhibition attenuates emphysema and small-airway remodeling in guinea pigs and hamsters [46, 47]. However, D’Armiento et al .…”

Section: Discussionmentioning

confidence: 99%

Protective effect of Galectin-9 in murine model of lung emphysema: Involvement of neutrophil migration and MMP-9 production

et al. 2017

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PurposeChronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction and pulmonary emphysema. Persistent inflammation and remodeling of the lungs and airways result in reduced lung function and a lower quality of life. Galectin (Gal)-9 plays a crucial role as an immune modulator in various diseases. However, its role in the pathogenesis of pulmonary emphysema is unknown. This study investigates whether Gal-9 is involved in pulmonary inflammation and changes in emphysema in a porcine pancreatic elastase (PPE)-induced emphysema model.Materials and methodsGal-9 was administered to mice subcutaneously once daily from 1 day before PPE instillation to day 5. During the development of emphysema, lung tissue and bronchoalveolar lavage fluid (BALF) were collected. Histological and cytological findings, concentrations of chemokines and matrix metalloproteinases (MMPs) in the BALF, and the influence of Gal-9 treatment on neutrophils were analyzed.ResultsGal-9 suppressed the pathological changes of PPE-induced emphysema. The mean linear intercept (Lm) of Gal-9-treated emphysema mice was significantly lower than that of PBS-treated emphysema mice (66.1 ± 3.3 μm vs. 118.8 ± 14.8 μm, respectively; p < 0.01). Gal-9 decreased the number of neutrophils and levels of MMP-9, MMP-2 and tissue inhibitor of metalloproteinases (TIMP)-1 in the BALF. The number of neutrophils in the BALF correlated significantly with MMPs levels. Interestingly, Gal-9 pretreatment in vitro inhibited the chemotactic activity of neutrophils and MMP-9 production from neutrophils. Furthermore, in Gal-9-deficient mice, PPE-induced emphysema progressed significantly compared with that in wild–type (WT) mice (108.7 ± 6.58 μm vs. 77.19 ± 6.97 μm, respectively; p < 0.01).ConclusionsThese results suggest that Gal-9 protects PPE-induced inflammation and emphysema by inhibiting the infiltration of neutrophils and decreasing MMPs levels. Exogenous Gal-9 could be a potential therapeutic agent for COPD.

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Section: Discussionmentioning

confidence: 99%

Protective effect of Galectin-9 in murine model of lung emphysema: Involvement of neutrophil migration and MMP-9 production

et al. 2017

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“…MMPs are considered to be crucial for tissular remodeling processes in most organs, including the lung, and a role of MMPs in the development of pulmonary emphysema has been suspected. A gain-of-function polymorphism in the promoter of MMP-9 is linked to the occurrence of pulmonary emphysema in humans (9), and the pharmacological inhibition of MMPs protects against emphysema in hamsters exposed to elastase (15). It was therefore interesting that while an elevation in MMP-2 and MMP-9 activity was initially detected at similar levels in BALF of mice early after elastase instillation (6th hour and day 1), MMP activation resolved much faster in KGF-treated mice.…”

Section: Discussionmentioning

confidence: 99%

Keratinocyte growth factor protects against elastase-induced pulmonary emphysema in mice

Plantier¹,

Marchand-Adam²,

Antico³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pulmonary emphysema is characterized by persistent inflammation and progressive alveolar destruction. The keratinocyte growth factor (KGF) favorably influences alveolar maintenance and repair and possesses anti-inflammatory properties. We aimed to determine whether exogenous KGF prevented or corrected elastase-induced pulmonary emphysema in vivo. Treatment with 5 mg x kg(-1) x day(-1) KGF before elastase instillation prevented pulmonary emphysema. This effect was associated with 1) a sharp reduction in bronchoalveolar lavage fluid total protein and inflammatory cell recruitment, 2) a reduction in the pulmonary expression of the chemokines CCL2 (or monocyte chemoattractant protein-1) and CXCL2 (or macrophage inflammatory protein-2alpha) and of the adhesion molecules ICAM-1 and VCAM-1, 3) a reduction in matrix metalloproteinase (MMP)-2 and MMP-9 activity at day 3, and 4) a major reduction in DNA damage detected by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) in alveolar cells at day 7. Treatment with KGF after elastase instillation had no effect on elastase-induced emphysema despite the conserved expression of the KGF receptor in the lungs of elastase-instilled animals as determined by immunohistochemistry. In vitro, KGF abolished the elastase-induced increase in CCL2, CXCL2, and ICAM-1 mRNA in the MLE-12 murine alveolar epithelial cell line. We conclude that KGF pretreatment protected against elastase-induced pulmonary inflammation, activation of MMPs, alveolar cell DNA damage, and subsequent emphysema in mice.

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“…By optimization of the benzoxazole substitution, selective MMP-13 (exemplified by 857081-53-9) [105] and aggrecanase ADAMTS [106] nM inhibitors were made. The γ -ketocarboxylate (second structure of this figure) is an MMP-2, -9 and -12 selective inhibitor (although only with μM potency) with efficacy in a hamster PPE-induced emphysema model [107].…”

Section: New Generation Hydroxamate-based Mmp Inhibitorsmentioning

confidence: 99%

Recent advances in MMP inhibitor design

Fisher

Mobashery

2006

Cancer Metastasis Rev

237

205

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The search for an MMP inhibitor with anticancer efficacy is a nearly three-decade endeavor. This inhibitor is yet to be found. The reasons for this failure include shortcomings in the chemistry of these compounds (including broad MMP sub-type selectivity, metabolic lability, and toxicity) as well as the emerging, and arguably extraordinary, complexity of MMP cell (and cancer) biology. Together these suggest that the successful anticancer inhibitor must possess MMP selectivity against the MMP subtype whose involvement is critical, yet highly temporally (with respect to metastatic progression) and mechanistically (with respect to matrix degradation) regulated. This review summarizes the progression of chemical structure and mechanistic thinking toward these objectives, with emphasis on the disappointment, the perseverance, and the resilient optimism that such an inhibitor is there to be discovered.

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Selective Inhibition of Matrix Metalloproteinase Isozymes and in Vivo Protection against Emphysema by Substituted γ-Keto Carboxylic Acids

Cited by 24 publications

References 12 publications

Protective effect of Galectin-9 in murine model of lung emphysema: Involvement of neutrophil migration and MMP-9 production

Protective effect of Galectin-9 in murine model of lung emphysema: Involvement of neutrophil migration and MMP-9 production

Keratinocyte growth factor protects against elastase-induced pulmonary emphysema in mice

Recent advances in MMP inhibitor design

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