Detection and monitoring of localized matrix metalloproteinase upregulation in a murine model of asthma

Felsen, Csilla N.; Savariar, Elamprakash N.; Whitney, Michael; Tsien, Roger Y.

doi:10.1152/ajplung.00371.2013

Cited by 24 publications

(20 citation statements)

References 46 publications

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“…These factors affect the airway structures and pulmonary functions (11,17). The present study identified exacerbated airway modeling in the OVA-induced asthma model, which was reduced by the administration of budesonide.…”

Section: Discussionmentioning

confidence: 99%

ORMDL3 is associated with airway remodeling in asthma via the ERK/MMP-9 pathway

Fang

Sun

et al. 2017

Molecular Medicine Reports

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ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) has been previously implicated in asthma pathogenesis, its effect on airway remodeling remains to be elucidated. The present study examined the expression levels of ORMDL3 in a mouse model of asthma. Mice were divided into three groups: Asthmatic model (n=10), budesonide-treated (n=10) and a control group (n=8). Asthma was induced by sensitization with ovalbumin (OVA) and aluminum hydroxide on day 1, 7 and 14. Subsequently mice were exposed to OVA three times per week from day 28. In order to investigate the mechanism of airway remodeling 100 µg/kg aerosol budesonide was administered to 6 animals prior to exposure to OVA. The condition of lung tissues was assessed through histology, and the expression levels of ORMDL3, phosphorylated-extracellular-signal regulated kinase (p-ERK) and matrix metallopeptidase-9 (MMP-9) were quantified using immunohistochemistry, reverse transcription-quantitative polymerase chain reaction and western blotting. A severe inflammatory response and airway remodeling were pretreatment with budesonide. Expression levels of ORMDL3, phosphorylated (p)-ERK and MMP-9 were significantly greater in the asthma-model group; however, in the group pretreated with budesonide their expression was reduced. Expression levels of ORMDL3, p-ERK and MMP-9 were significantly positively correlated with bronchial wall thickness. ORMDL3 expression was significantly positively correlated with p-ERK and MMP-9. Therefore, increased ORMDL3 expression may induce the p-ERK/MMP-9 pathway to promote pathological airway remodeling in patients with asthma.

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Section: Discussionmentioning

confidence: 99%

ORMDL3 is associated with airway remodeling in asthma via the ERK/MMP-9 pathway

Fang

Sun

et al. 2017

Molecular Medicine Reports

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“…Also the polycation is taken up and retained at or near the site of proteolysis, while the polyanion is subject to pharmacokinetic washout, reinforcing the high ratio of donor to acceptor emissions. As described in [ 19 ] the cleavable RACPP, with a PLGC(Me)AG linker sequence and referred to as RACPP1 in the cited paper, could be cut by MMP2 (Kcat/Km = 36429 s -1 M -1 ), MMP-9 (Kcat/Km = 13503 s -1 M -1 ), and somewhat by MMP14 (Kcat/Km = 17173 s -1 M -1 ), whereas the uncleavable control RACPP was resistant to such cleavage [ 19 , 20 ]. We also synthesized an RACPP with a cleavable sequence TLSLEH in the manner described above.…”

Section: Methodsmentioning

confidence: 99%

Impact of MMP-2 and MMP-9 enzyme activity on wound healing, tumor growth and RACPP cleavage

et al. 2018

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Matrix metalloproteinases-2 and -9 (MMP-2/-9) are key tissue remodeling enzymes that have multiple overlapping activities critical for wound healing and tumor progression in vivo. To overcome issues of redundancy in studying their functions in vivo, we created MMP-2/-9 double knockout (DKO) mice in the C57BL/6 background to examine wound healing. We then bred the DKO mice into the polyomavirus middle T (PyVmT) model of breast cancer to analyze the role of these enzymes in tumorigenesis. Breeding analyses indicated that significantly fewer DKO mice were born than predicted by Mendelian genetics and weaned DKO mice were growth compromised compared with wild type (WT) cohorts. Epithelial wound healing was dramatically delayed in adult DKO mice and when the DKO was combined with the PyVmT oncogene, we found that the biologically related process of mammary tumorigenesis was inhibited in a site-specific manner. To further examine the role of MMP-2/-9 in tumor progression, tumor cells derived from WT or DKO PyVmT transgenic tumors were grown in WT or DKO mice. Ratiometric activatable cell penetrating peptides (RACPPs) previously used to image cancer based on MMP-2/-9 activity were used to understand differences in MMP activity in WT or knockout syngeneic tumors in WT and KO animals. Analysis of an MMP-2 selective RACPP in WT or DKO mice bearing WT and DKO PyVmT tumor cells indicated that the genotype of the tumor cells was more important than the host stromal genotype in promoting MMP-2/-9 activity in the tumors in this model system. Additional complexities were revealed as the recruitment of host macrophages by the tumor cells was found to be the source of the tumor MMP-2/-9 activity and it is evident that MMP-2/-9 from both host and tumor is required for maximum signal using RACPP imaging for detection. We conclude that in the PyVmT model, the majority of MMP-2/-9 activity in mammary tumors is associated with host macrophages recruited into the tumor rather than that produced by the tumor cells themselves. Thus therapies that target tumor-associated macrophage functions have the potential to slow tumor progression.

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“…sputum from allergic asthmatics as compared to control subjects. This observation suggests that extracellular matrix can be aggressed after allergen contact and are linked to allergen-induced acute bronchial inflammation [18,19]. However, others reported that TIMP-1 levels did not vary significantly compared to controls [15,20].…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase-9 (MMP-9) and Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) as Non-Invasive Biomarkers of Remodelling in Asthma

Hassan¹,

Mohamed-Hussein²,

Mohammed³

et al. 2015

J Pulm Respir Med

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Rationale: Airway remodelling is clinically defined as persistent airflow obstruction despite aggressive antiinflammatory therapies. Assessment of airway remodelling by analysis of serum markers has been developed as minimally invasive procedures. Aim of the work: Evaluate the usefulness of estimation of serum MMP-9, TIMP-1 and their ratio, as non-invasive markers of airway remodelling in asthmatics. Patients and methods: The study included 68 asthmatics and 20 controls. Patients were classified according to levels of asthma control, severity and disease duration. Serum samples were taken to estimate levels of MMP-9, TIMP-1 and their ratio. Results: Serum MMP-9, TIMP-1, and MMP-9/TIMP-1 were significantly higher in asthmatics than controls, in uncontrolled vs. controlled asthma (P<0.001). Also they were significantly higher in severe and moderate asthma than in mild asthma (P<0.000), and in patients with disease duration >5 years vs. <5 years (P˂0.001). There was significant positive correlation between studied parameters (p<0.000) and significant negative correlation between the biomarkers and FEV 1 (p<0.001). Conclusion: Serum MMP-9, TIMP-1, and MMP-9/TIMP-1 could be considered as non-invasive markers of airway remodelling that can bypass biopsy sampling. Serum sample is easily handled and not subjected to technical error as sputum or BAL fluid.

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Detection and monitoring of localized matrix metalloproteinase upregulation in a murine model of asthma

Cited by 24 publications

References 46 publications

ORMDL3 is associated with airway remodeling in asthma via the ERK/MMP-9 pathway

ORMDL3 is associated with airway remodeling in asthma via the ERK/MMP-9 pathway

Impact of MMP-2 and MMP-9 enzyme activity on wound healing, tumor growth and RACPP cleavage

Matrix Metalloproteinase-9 (MMP-9) and Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) as Non-Invasive Biomarkers of Remodelling in Asthma

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