Elevated expression levels of matrix metalloproteinase-9 in placental villi and tissue inhibitor of metalloproteinase-2 in decidua are associated with prolonged bleeding after mifepristone-misoprostol medical abortion

Zhuang, Yaling; Qian, Zhida; Li-li, Huang

doi:10.1016/j.fertnstert.2013.09.027

Cited by 13 publications

(12 citation statements)

References 22 publications

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“…A role of MMPs in hemorrhage is also supported by the association between increased levels of certain MMPs and prolonged bleeding in human and animal studies, whereas genetic deletion of MMPs prevented bleeding in experimental models 17, 18. Furthermore, our research group recently demonstrated that acute and short‐term MMP inhibition is an effective and safe therapeutic strategy for the prevention of bleeding.…”

Section: Introductionmentioning

confidence: 85%

CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage

Rodríguez

Sobrino

López-Arias

et al. 2017

JAHA

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BackgroundIntracerebral hemorrhage (ICH) is an acute neurological disorder with high mortality and no effective treatment. In addition to the initial bleeding event, rebleeding and hematoma expansion are associated with poor outcome in these patients. We studied the effectiveness of the new antifibrinolytic agent CM352, a short‐half‐life matrix metalloproteinase inhibitor, for achieving early hemostasis and improving functional recovery in a rat model of collagenase‐induced ICH.Methods and Results ICH was induced by striatal injection of collagenase, and 1 hour later, rats received an intravenous injection of saline (n=6) or CM352 (1 mg/kg, n=6). Hematoma (basal and after 3 and 24 hours) and lesion (14 days) volumes were quantified on T2‐weighted (T2) magnetic resonance images. Neurological and functional recovery was evaluated by using Bederson score and a cylinder test (basal, 24 hours, and 14 days). Early treatment (1 hour) with CM352 was efficient reducing hematoma expansion at 3 hours (P<0.01) and, more markedly, at 24 hours (P<0.01). Decreased bleeding after antifibrinolytic treatment was accompanied by reduced interleukin‐6 levels at 3 hours (P<0.05) and smaller lesion volume at 14 days (P<0.01). CM352 drastically reduced sensorimotor impairment (cylinder test) after ICH in rats at 24 hours (P<0.01) and 14 days (P<0.01). Similarly, it also attenuated neurological deficit (Bederson scale) at 24 hours (P<0.01) and 14 days (P<0.01). Interestingly, late (3 hours) CM352 administration also resulted in reduced lesion size and better functional outcome.Conclusions CM352, a new antifibrinolytic agent and matrix metalloproteinase inhibitor, effectively prevented hematoma growth and reduced lesion size in ICH in association with improved functional and neurological recovery.

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Section: Introductionmentioning

confidence: 85%

CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage

Rodríguez

Sobrino

López-Arias

et al. 2017

JAHA

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“…[63] TIMP-1 has been found as an MMP-9 activity inhibitor through binding to its precursors and active form. [64] Increased expressions of MMP-9 and TIMP-1 and alveolar macrophages trigger larger amounts of MMP-9 with greater enzymatic activity in COPD patients. The imbalances between the levels of MMP-9 and TIMP-1 might result in the aberrant ECM degradation or the accumulation of ECM proteins in pulmonary alveoli and small airway walls, which would lead to COPD.…”

Section: Discussionmentioning

confidence: 99%

Relationships of MMP-9 and TIMP-1 proteins with chronic obstructive pulmonary disease risk: A systematic review and meta-analysis

et al. 2016

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Background:We performed this meta-analysis in order to collect all the relevant studies to clarify the correlations of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) with chronic obstructive pulmonary disease (COPD).Materials and Methods:After a literature search in electronic databases, pertinent case-control studies investigating the correlations of MMP-9 and TIMP-1 protein expressions within a COPD setting were enrolled based on our strict inclusion and exclusion criteria. We used key words such as “chronic obstructive pulmonary disease,” “COPD” or “COAD” or “chronic obstructive airway disease” and “matrix metalloproteinases” or “MMPs” to make a searching strategy in this study. STATA software (version 12.0, Stata Corporation, College Station, TX, USA) was utilized for statistical analysis.Results:A total of 20 studies were enrolled into this meta-analysis including 923 COPD patients and 641 healthy controls. The findings of this meta-analysis revealed that serum expression levels of MMP-9 and TIMP-1 protein in COPD patients were higher than those of healthy controls (MMP-9: SMD = 1.44, 95%CI = 0.85 ~ 2.04, P < 0.001; TIMP-1: SMD = 3.53, 95% CI = 2.31 ~ 4.75, P < 0.001). Subgroup analysis based on ethnicity revealed that both Caucasians and Asian COPD patients exhibited higher MMP-9 and TIMP-1 serum protein levels than healthy controls (MMP-9: SMD = 0.81, 95%CI = 0.15~1.48, P = 0.016; TIMP-1: SMD = 4.43, 95%CI = 1.98 ~ 6.87, P = 0.016) and in Caucasians (MMP-9: SMD = 2.30, 95%CI = 1.21 ~ 3.38, P < 0.001; TIMP-1: SMD = 2.86, 95%CI = 1.47 ~ 4.24, P < 0.001).Conclusion:The result of this meta-analysis indicates that elevated levels of MMP-9 and TIMP-1 proteins may be correlated with the pathogenesis of COPD, and the two proteins may represent important biological markers for the early diagnosis of COPD.

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“…23 Importantly, the role of MMPs in hemorrhaging is supported by the fact that increased levels of certain MMPs are associated with prolonged bleeding in human and animal studies, whereas genetic deletion of MMPs prevented bleeding in experimental models. 24,25 In this regard, fibrinolytic activity and bleeding time were found to be markedly reduced in Mmp10 -/-mice. 23 Also, MMP-3, which is a fibrinolytic MMP 18 that is 82% homologous to MMP-10, deserves particular attention as it has been consistently associated with intracranial hemorrhage.…”

Section: Introductionmentioning

confidence: 90%

Discovery and Safety Profiling of a Potent Preclinical Candidate, (4-[4-[[(3R)-3-(Hydroxycarbamoyl)-8-azaspiro[4.5]decan-3-yl]sulfonyl]phenoxy]-N-methylbenzamide) (CM-352), for the Prevention and Treatment of Hemorrhage

et al. 2015

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Discovery of potent and safe therapeutics that improve upon currently available antifibrinolytics, e.g., tranexamic acid (TXA, 1) and aprotinin, has been challenging. Matrix metalloproteinases (MMPs) participate in thrombus dissolution. Then we designed a novel series of optimized MMP inhibitors that went through phenotypic screening consisting of thromboelastometry and mouse tail bleeding. Our optimized lead compound, CM-352 (2), inhibited fibrinolysis in human whole blood functional assays and was more effective than the current standard of care, 1, in the tail-bleeding model using a 30 000 times lower dose. Moreover, 2 reduced blood loss during liver hepatectomy, while 1 and aprotinin had no effect. Molecule 2 displayed optimal pharmacokinetic and safety profiles with no evidence of thrombosis or coagulation impairment. This novel mechanism of action, targeting MMP, defines a new class of antihemorrhagic agents without interfering with normal hemostatic function. Furthermore, 2 represents a preclinical candidate for the acute treatment of bleeding.

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Elevated expression levels of matrix metalloproteinase-9 in placental villi and tissue inhibitor of metalloproteinase-2 in decidua are associated with prolonged bleeding after mifepristone-misoprostol medical abortion

Cited by 13 publications

References 22 publications

CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage

CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage

Relationships of MMP-9 and TIMP-1 proteins with chronic obstructive pulmonary disease risk: A systematic review and meta-analysis

Discovery and Safety Profiling of a Potent Preclinical Candidate, (4-[4-[[(3R)-3-(Hydroxycarbamoyl)-8-azaspiro[4.5]decan-3-yl]sulfonyl]phenoxy]-N-methylbenzamide) (CM-352), for the Prevention and Treatment of Hemorrhage

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