Discovery of potent and selective matrix metalloprotease 12 inhibitors for the potential treatment of chronic obstructive pulmonary disease (COPD)

Wu, Yuchuan; Liu, Jianchang; Wu, Junjun; Morgan, Paul; Xu, Xin; Rancati, Fabio; Vallese, Stefania; Raveglia, Luca F.; Hotchandani, Rajeev; Fuller, Nathan O.; Bard, Joel; Cunningham, Kristina; Fish, Susan; Krykbaev, Rustem; Tam, Steve; Goldman, Samuel J.; Williams, Cara; Mansour, Tarek S.; Saiah, Eddine; Sypek, Joseph P.; Li, Wei

doi:10.1016/j.bmcl.2011.11.046

Cited by 31 publications

(26 citation statements)

References 17 publications

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“…In vivo detection of molecular and cellular processes that are involved in the pathogenesis of pulmonary disease can lead to early diagnosis and help track the effect of therapeutic interventions. Matrix metalloproteinases (MMPs) play prominent roles in pulmonary inflammation and remodeling and have recently emerged as promising novel therapeutic targets in lung disease 8–11 . A number of pro-inflammatory cytokines (e.g., IL-13) and growth factors induce MMP expression and activation 11–13 .…”

Section: Introductionmentioning

confidence: 99%

Matrix Metalloproteinase–Targeted Imaging of Lung Inflammation and Remodeling

Golestani

Razavian

et al. 2016

J Nucl Med

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Imaging techniques for detection of molecular and cellular processes that precede or accompany lung diseases are needed. Matrix metalloproteinases (MMPs) play key roles in the development of pulmonary pathology. Objectives Investigate the feasibility of in vivo MMP-targeted molecular imaging for detection of lung inflammation and remodeling. Methods Lung-specific IL-13 transgenic [Club cell 10-kDa protein (CC10)-IL-13Tg)] mice, and wild type (WT) littermates were used in this study. Lung structure, gene expression, and MMP activity were assessed by histology, real-time reverse transcription polymerase chain reaction, Western blot and zymography. MMP activation was imaged by in vivo micro single-photon emission computed tomography (SPECT)/CT followed by ex vivo planar imaging. Signal specificity was addressed using a control tracer. The correlation between in vivo MMP signal and gene expression was addressed. Results CC10-IL-13Tg mice developed considerable pulmonary tissue remodeling and inflammation. CD68, MMP-12 and MMP-13 were significantly higher in CC10-IL-13Tg lungs. On in vivo microSPECT/CT and ex vivo planar images, the MMP signal was significantly higher in the lungs of CC10-IL-13Tg mice than WT animals. Furthermore, a non-binding analog tracer showed significantly lower accumulation in CC10-IL-13Tg lungs relative to the specific tracer. There was a significant correlation between microSPECT/CT-derived MMP signal and CD68 expression in the lungs (r = 0.70, P < 0.01). Conclusions MicroSPECT/CT-based MMP-targeted imaging of the lungs is feasible and reflects pulmonary inflammation. If validated in humans, molecular imaging of inflammation and remodeling can potentially help early diagnosis and monitoring of the effects of therapeutic interventions in pulmonary diseases.

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Section: Introductionmentioning

confidence: 99%

Matrix Metalloproteinase–Targeted Imaging of Lung Inflammation and Remodeling

Golestani

Razavian

et al. 2016

J Nucl Med

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“…Smoking is also well known to be the major cause of COPD. Not only MMP-9, but also MMP-2, MMP-8, and MMP-12 are associated with COPD and emphysema in smokers (10,33,34). Inappropriate secretion of MMP-8, MMP-9, and MMP-12 by the stimulated inflammatory cells also play a role in asthmatic patients with smoking (35,36).…”

Section: Discussionmentioning

confidence: 99%

Correlation of matrix metalloproteinase-2 and -9 expression with recurrences in primary spontaneous pneumothorax patients

Chiu

Lee

et al. 2016

J. Thorac. Dis.

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Background: Primary spontaneous pneumothorax (PSP) is a common benign disorder. However, unpredictable recurrence is a major concern for most patients. The aim of the present study was to assess the role of matrix metalloproteinase-2 (MMP-2) and MMP-9 in alveolar macrophages of patients with PSP and its relationship with recurrence. Methods: Ninety-two patients who received needlescopic video-assisted thoracoscopic surgery (NVATS) wedge resection of lung with identifiable blebs for PSP were enrolled for the study. Immunohistochemistry was performed to evaluate the expression of MMP-2 and MMP-9 in lung tissues of patients with PSP. The result was correlated with clinicopathological variables and recurrence rates by the chi-square test. The value of MMP-2 and MMP-9 for overall recurrence was evaluated by univariate and multivariable Cox regression analyses. Results: The MMP-2 and MMP-9 staining was predominantly observed in alveolar macrophages of patients with PSP. We found that MMP-2 (recurrence: P<0.001; smoking status: P=0.029) and MMP-9 (recurrence: P=0.001; smoking status: P=0.045) expression in PSP, especially male patients, was significantly correlated with recurrence and smoking status. In the multivariate analyses, MMP-2 [hazard ratio (HR) =2.83; 95% confidence interval (CI): 1.37-5.85, P=0.005) and MMP-9 (HR =2.25; 95% CI: 1.19-4.24, P=0.013) were statistically significant risk factors for overall recurrence in PSP patients. Conclusions: High expression levels of MMP-2 and MMP-9 showed a positive correlation with recurrence in PSP patients. Further studies are required to test whether inhibition of MMP-2 and MMP-9 expression renders a promising approach for reducing the risk of PSP recurrence in the future.

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“…The orally administered MMP-9 and MMP-12 inhibitor AZD1236 was well tolerated by patients in two separate clinical trials but overall it was deemed to have no effect on clinical parameters [248] or disease related biomarkers in COPD patients [249]. In a recent study by Wu et al, several potential MMP-12 inhibitors were analysed in vivo, with one specific inhibitor, Compound 26, modulating cell infiltration into the lungs of mice with MMP-12 induced inflammation [250]. Similar findings were observed for a second MMP-12 inhibitor, Compound 14 [251].…”

Section: Synthetic and Semi-synthetic Engineered Protease Inhibitors mentioning

confidence: 99%

Antiproteases as Therapeutics to Target Inflammation in Chronic Obstructive Pulmonary Disease

McCarthy¹,

O’Dwyer²,

Bergin³

et al. 2014

COPD Clinical Perspectives

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Discovery of potent and selective matrix metalloprotease 12 inhibitors for the potential treatment of chronic obstructive pulmonary disease (COPD)

Cited by 31 publications

References 17 publications

Matrix Metalloproteinase–Targeted Imaging of Lung Inflammation and Remodeling

Matrix Metalloproteinase–Targeted Imaging of Lung Inflammation and Remodeling

Correlation of matrix metalloproteinase-2 and -9 expression with recurrences in primary spontaneous pneumothorax patients

Antiproteases as Therapeutics to Target Inflammation in Chronic Obstructive Pulmonary Disease

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