Matrix Metalloproteinase-9 In Lung Tissues Research Articles

Genipin inhibits allergic responses in ovalbumin-induced asthmatic mice

Genipin is a natural compound isolated from the fruit of Gardenia jasminoides with various pharmacological effects. In this study, we investigated whether genipin effectively alleviates allergic responses in a murine model of ovalbumin (OVA)-induced asthma. The mice were administered an intraperitoneal injection of OVA on day 0 and 14 to boost the immune response; genipin was then administered from day 18 to 23 by oral gavage. On days 21 to 23, mice were OVA-challenged using am ultrasonic nebulizer, and airway hyperresponsiveness (AHR) was determined on day 24 by plethysmography. Genipin significantly reduced the inflammatory cell count in bronchoalveolar lavage fluids (BALF) and AHR, which were accompanied by lower interleukin-5 (IL-5), IL-13 and OVA-specific immunoglobulin (Ig) E levels in the BALF or serum from OVA-induced asthmatic mice. In histology, genipin significantly decreased airway inflammation and mucus hypersecretion in OVA-induced asthmatic mice. Additionally, genipin inhibited OVA-induced increases in the expression of inducible nitric oxide synthase and cyclooxygenase-2 proteins. Further, genipin reduced the activity and protein levels of matrix metalloproteinase-9 in lung tissue from OVA induced asthmatic mice. Overall, genipin effectively alleviated the asthmatic inflammatory response in an OVA-induced asthmatic model. Therefore, our results suggest that genipin has therapeutic potential for treating asthma.

Abstract 606: Inhibitory effects of piceatannol on tumor angiogenesis and lung metastasis in the 4T1 mammary cancer model

Abstract Piceatannol (trans-3,4,3′,5′-tetrahydroxystilbene) is a polyphenol found in Rheum undulatum, grapes, red wine, and berries and has been shown to exert anticarcinogenic effects. In the present study, we determined whether oral administration of piceatannol inhibits solid tumor growth, angiogenesis, and lung metastasis of mammary cancer cells. 4T1 cells (5 x 104 cells) were injected into the mammary fat pad of syngeneic, 6-week old, female BALB/c mice. One day after, the mice were subjected to gavage for 30 days with piceatannol (0, 10, or 20 mg/kg body weight/day). Oral piceatannol treatment induced a significant reduction in the growth of solid tumors. Immunohistochemical staining of tumor tissues revealed that the expression of Ki67 (prototypic cell cycle related nuclear antigen), cyclin D1, cyclin A, cyclin-dependent kinase (CDK)4, CDK2, hypoxia-inducible factor 1, vascular endothelial growth factor, CD31 (platelet endothelial cell adhesion molecule-1) and LYVE-1 (lymphatic vessel endothelial receptor 1) was significantly decreased in the mice received 20 mg/kg piceatannol as compared to mice received vehicle. Piceatannol significantly increased the numbers of TUNEL-positive, apoptotic cells in tumor tissues, which was accompanied by increased Bax and cleaved caspase-3 expression and reduced Bcl-2 expression. Additionally, piceatannol feeding reduced the number and volume of pulmonary tumor nodules, which was accompanied by reduced expression of matrix metalloproteinase-9 in lung tissues. Piceatannol induced a significant reduction in the blood levels of chemokine ligand (CXCL) 16, CXCL13 (BCA-1), interleukin-16, macrophage colony-stimulating factor, monocyte chemoattractant protein-1, triggering receptor expressed on myeloid cells-1, stromal cell-derived factor-1, and plasminogen activator inhibitor-1 compared to the vehicle-fed mice. The present results indicate that piceatannol has an ability to inhibit breast cancer development and metastasis and this effect is attributable to its ability to inhibit tumor angiogenesis, lymphangiogenesis and reduce the blood levels of a broad variety of cytokines and chemokines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 606. doi:1538-7445.AM2012-606

Effect of spearmint oil on lipopolysaccharide induced emphysema-like changes and expression of matrix metalloproteinase-9

To investigate the effect of spearmint oil on emphysema-like changes and the expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta(IL-1beta), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-9) in lipopolysaccharide (LPS) treated rats. Emphysematous changes model was induced by intratracheal instillation of LPS once a week for up to 8 weeks in rats. Rats were divided into control, dexamethasone (0.3 mg x kg(-1)), and spearmint oil (10, 30,100 mg x kg(-1)) groups. Each group was treated with saline, dexamethasone, and spearmint of oil respectively for 4 weeks. Then total and different white blood cell counts in bronchoalveolar lavage fluid(BALF) were carried out. The pathologic changes of lung tissue such as alveolar structure, airway inflammation, and goblet cell metaplasia were observed by HE and AB-PAS staining. Expression of TNF-alpha, IL-1beta, TIMP-1 and MMP-9 were measured. Both spearmint and dexamethasone decreased the destruction of pulmonary alveolus. The total and different white blood cell counts in BALF including neutrophile and lymphocyte of spearmint oil 100 mg x kg(-1) and dexamethasone group were significantly reduced, and the goblet cell metaplasia was also inhibited. Dexamethasone had inhibitory effect on the expression of TNF-alpha, IL-1beta, TIMP-1 and MMP-9. Spearmint oil 30, 100 mg x kg(-1) significantly reduced TNF-alpha and IL-1beta respectively. Spearmint oil 10, 30 and 100 mg x kg(-1) had no effect on the expression of TIMP-1, but could decrease the expression of MMP-9 significantly in lung tissues. Spearmint oil has protective effect on rats with emphysematous changes, since it improves alveolar destruction, pulmonary inflammation, and goblet cell metaplasia. The mechanism may include reducing TNF-alpha, IL-1beta content and inhibiting overexpression of matrix metalloproteinase-9 in lung tissues.

Expression of thrombomodulin (TM) and matrix metalloproteinase-9(MMP-9) in the lung of rats with multiple organ dysfunction syndrome

Objective To determine the expressions of thrombomodulin (TM) and matrix metalloproteinase-9(MMP-9) in the lung of rats with multiple organ dysfunction syndrome (MODS) and to investigate the mechanism of lung injury in MODS. Method Forty adult mule Sprague-Dawley (SD) rats were randomly divided into two groups,namely the normal control group and the MODS model group. The rats of model group were further divided into four subgroups as per different intervals (6 h, 12 h, 24 h and 48 h) ,and there were 8 rats in each groups. The animal models of MODS were estabhshed by two hits,the left eyeball of each model rat was removed to bleed to 2 mL/100g,and four hours later, lipopolysaccharide (LPS 5 mg/kg) was injected into intraperitoneal cavity of model rats. The same volume of saline was injected intraperitoneally into rats of control group instead of LPS. All rats were sacrificed at various intervals. The histological changes in lung tissue were observed by naked eye and light microscope. The expressions of TM and MMP-9 proteins were deteceted by using immunohistechemistry. One-way ANOVA was used for comparison among multiple group. Results (1)There were no histopathological changes in lung of rats of control group, and the lung injury was serious in MODS rots. (2) Compared with the rots of con-trol group, the expression of TM in lung tissue of MODS rats increased 6 hours after LPS, reached peak 12 hours later(P <0.01),and then decreased during 24～48 period.There was no significant difference in expression of TM between two groups 48 hours later. Compared with control group, the expressions of MMP-9 in lung tissue of MODS rats didn't significantly increase 6 ～ 48 hours after LPS (P < 0.01). Conclusions There are endothelium damage and extracellular matrix damage found in the lung tissue of rats at the early phase of MODS. TM and MMP-9 are good biomarkers of endothelium and extracellular matrix damage, and they can be used for diagnosing and es-timating the severity of injury lungs at the early phase of MODS. Key words: Multiple organ dysfunction syndrome; Thrombomoduline; Matrix metalloproteinase-9; Endothe-lial cell; Extracellular matrix; Collagen Ⅳ; Lipopolysaccharide; Systemic inflammatory response syndrome

Inhibition of Matrix Metalloproteinase-9 with Doxycycline Reduces Pancreatitis-Associated Lung Injury

Background/Aims: Severe lung injury, responsible for up to 15% of mortality in acute necrotizing pancreatitis patients, is promoted by neutrophil (PMN) migration into the lung. We have previously demonstrated that pulmonary injury in acute pancreatitis is mediated by PMN-derived matrix metalloproteinase-9 (MMP-9). This study was conducted to evaluate the ability of the broad-spectrum MMP inhibitor doxycycline to prevent secondary pulmonary injury in acute pancreatitis. Methods: Eighteen rats were randomized into three groups: severe pancreatitis (SAP), severe pancreatitis + doxycycline (SAP+Dox) (30 mg/kg body mass) or control. Acute pancreatitis was induced by intraductal glycodesoxycholic acid and i.v. stimulation with cerulein. Lung sections were histologically graded for edema, microthrombi, atelectasis and hemorrhage. Active MMP-9 in lung tissue was measured with fluorescent assay (ELISA). Naphtol-AS-D-chloroacetate esterase staining was used to determine pulmonary PMN infiltration. The inhibitory effect of doxycycline on MMP-9-induced transmigration was confirmed in a Matrigel transmigration assay. Results: Addition of doxycycline significantly reduced TNF-α-induced PMN transmigration across Matrigel membrane (12.6 ± 2.6 vs. 20.1 ± 3.9 PMNs; p < 0.05). SAP+Dox showed decreased concentration of active MMP-9 in lung tissue (37.89 ± 1.75 vs. 46.29 ± 3.68 ng/ml; p < 0.05) and as a result decreased pulmonary infiltration of PMNs (21.2 ± 5.1 vs. 32.5 ± 6.8; p < 0.05). Histological evaluation revealed decreased pulmonary edema (1.83 ± 0.41 vs. 2.33 ± 0.51, p < 0.05), atelectasis (1.67 ± 0.52 vs. 2.33 ± 0.52; p < 0.05) and pulmonary hemorrhage (2.5 ± 0.55 vs. 1.83 ± 0.41; p < 0.05) in SAP+Dox vs. SAP. These findings were paralleled by reduced pulmonary expression of active MMP-9. Conclusions: Inhibition of MMP-9 activity with doxycycline reduced pancreatitis-associated lung injury and expression of MMP-9 in pulmonary tissue. Doxycycline reduced PMN migration in vitro and in vivo and therefore might represent a novel strategy for the prevention of secondary pulmonary complications in acute pancreatitis.