[Interstitial collagenase and their endogenous regulators in squamous cell cervical carcinoma]. / Interstitsial'naia kollagenaza MMP-1 i ee éndogennye reguliatory v tele matki pri ploskokletochnoi kartsinome sheiki matki.

Interstitial collagenase (MMP-1) belongs to the family of matrix metalloproteinases (MMP), which play a key role in generalization processes of invasion and metastasis, which determine the degree of tumor malignancy. MMP-1 refers to secreted, inducible MMP, the expression of which in normal tissues is not defined. Induction of expression of MMP in CSS in the tumor occurs under the action of oncogenes of HPV, and in areas adjacent to the tumor normal tissue under the action of the inductor expression of MMP - EMMPRIN (CD147), which expressively on the surface of tumor cells. The aim of this study is to determine the possibility of expression ofMMP-1 and its regulators (tissue inhibitors TIMP-1 and activator - plasminogen activator - ADF) in morphologically normal body of the uterus during CSS. The study was carried out using on a tissue "tape" - postoperative specimens of the uterus when the diagnosis of CSS. All of the samples was expressed HPV16 gene E7. It was shown that: 1. The increase of MMP-1 expression, low expression (or lack thereof) of its inhibitors TIMP-1 and a very clear expression of the activator take place in the tumor when CSS that lead to increased activity of MMP-1, and aims to increase the destructive (invasive) potential of the tumor. 2. In morphologically normal tissue of the uterus during CSS the expression of MMP-1 can occur from the vaginal wall to the bottom of the uterine cavity, but at a much lower level than in the tumor. 3. These data indicate the possibility of development of a destructive process in morphologically normalnyh body tissues of the uterus during CSS, important for understanding the mechanism of tumor progression, and suggest participation in the process of expression of MMP-1 signaling by the type of epithelial-mesenchymal interaction .

Role of the angiotensin converting enzyme 1/angiotensin II/angiotensin receptor 1 axis in interstitial collagenase expression in human carotid atheroma.

BACKGROUND AND AIM: Angiotensin II (AII) receptor 1 (ATR1) and angiotensin converting enzyme 1 (ACE1) blockers have been shown to reduce acute cardiovascular events in patients, improve plaque stability and modify matrix metalloproteinase (MMP) expression. However, the role of the ACE1/AII/ATR1 axis in interstitial collagenase regulation has not been fully explored. In this study, we investigated the effect of ATR1 and ACE1 blockade on the expression and activity of MMP-1, -8 and -13 in human carotid atheroma. METHODS: Atheroma samples (n = 24) were obtained from patients undergoing carotid endarterectomy. The effects of ATR1 (irbesartan), ACE1 (quinapril), ACE2 (DX600) and MMP (GM6001) blockade on the expression of AII, the interstitial collagenases and soluble elastin fragments were investigated in explant culture supernatants. Paired atheroma samples were incubated with intervention or media control for 4 days. Protein levels (AII, MMP-1, -8, -13 and soluble elastin) were determined by ELISA. RESULTS: ATR1, but not ACE1, blockade significantly reduced MMP-1 and -8 concentrations in atheroma supernatants. ACE2 blockade significantly increased MMP-1 and -8 concentrations in atheroma supernatants. AII concentration in atheroma supernatants significantly increased after ATR1, ACE1 and ACE2 blockade. Release of soluble elastin fragments increased after ATR1 and ACE1 blockade, but was not changed by an MMP inhibitor. CONCLUSIONS: Our findings suggest that ATR1 blockade alters AII, MMP-1, MMP-8 expression and a marker of elastin degradation in human atheroma, but that the elastin degradation response is not MMP driven. This data contributes to the recognised ability of ATR1 blockade to modify plaque stability.

Changes of matrix metalloproteinase and cytokines and its clinical significance in children with juvenile idiopathic arthritis / 中华风湿病学杂志

Objective The purpose of the study was to investigate the changes and clinical significance of matrix metalloproteinase (MMP)-1,MMP-3,tissue inhibitor of metalloproteinase (TIMP),interleukin (IL)-1,tumor necrosis factor (TNF)-α and transforming growth factor(TGF)-β in juvenile idiopathic arthritis (JIA).Methods Thirty-two JIA subjects and 28 controls (traumatic arthritis patients) were included into this study.The MMP-1,MMP-3,TIMP,IL-1,TNF-α and TGF-β level in the serum and synovia were assessed by ELISA.The WBC count,the level of CRP,ESR,RF were also detected.Independent t-test and Pearson's analysis were adopted for data analysis.Results ① The level of MMP-1,MMP-3,IL-1 and TNF-α in the serum was (158±67) ng/ml,(212±89) ng/ml,(39±19) pg/ml,(26±10) pg/ml respectively,which was significantly higher than that of the control group (all P＜0.05) ; the ratio of MMP-3/TIMP-1 (0.86±0.32) was higher in the study group than that of the control group (P＜0.05),while the value of TIMP-1,TGF-β was (248±88),(17±9) ng/ml respectively,which was lower than that of the control group (P＜0.05).The value of seral MMP-3,MMP-3/TIMP-1 was positively correlated with that of WBC,CRP,ESR in the JIA group (all P＜0.05).② The value of MMP-1,MMP-3,IL-1 and TNF-α in the synovia was (216±78) ng/nl,(766±291)ng/ml,(56±21) pg/ml,(36±14) pg/ml respectively,which was higher than that of the control group (all P＜0.05); the ratio of MMP-3/TlMP-1 (2.68±0.89) was higher than that of the control group (P＜0.05),while the value of TIMP-1,TGF-β was (286±88) ng/ml,(12±4) ng/ml respectively,which was lower than that of the control group (all P＜0.05).③ The value of MMP-1,MMP-3,TIMP-1,IL-1 and TNF-α in the synovia was higher than that in the serum (all P＜0.05),while the value of TGF-β was lower than that in the serum (P＜0.05).Conclusion The value of MMP-1,MMP-3,IL-1 and TNF-α increases both in the serum and synovia,while the value of TIMP-1 decreases.The value of TGF-β decreases,which may have protective effect on JIA.The ratio of MMP-3/TIMP-1 in the serum is positively correlated to inflammation parameters,which may be used to judge the activity of illness in JIA.

Mechanism of tumor necrosis factor-like weak inducer of apoptosis on the synthesis of Matrix meta-lloproteinase-1 in fibroblast-like synoviocytes of rheumatoid arthritis / 中华风湿病学杂志

Objective To study whether p38 mitogen-activated protein kinases (p38MAPK) signal pathway were activated in the process of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) which then induces rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS) to synthesize matrix metalloproteinase-1 (MMP-1) and look for the relative mechanisms of how TWEAK was involved in the destruction of articular bones and cartilage. Methods RA FLS were primarily cultured and stimulated with TWEAK. FLS were pretreated with SB203580 or not. ELISA was used to detect the concentration of MMP-1 in cell-cultured supernatant. Western blotting was used to detect the expression of p-p38MAPK and P65 in RA FLS. Results TWEAK (100 ng/ml) could induce RA FIS to synthesize MMP-1. SB203580 could partially inhibite the expression of MMP-1 producted by RA FLS which was induced by TWEAK. TWEAK could make p38MAPK phosphorylated and increase the expression of P65 protein in the cell nucleus. Conclusion TWEAK induces RA FLS to synthesize MMP-1. In this process, p38MAPK signal transduction pathway is activated and then induce the expression of NF-κB.

Expression of collagenase in mice with hyperoxia-induced acute lung injury / 中华急诊医学杂志

Objective To investigate the role of interstitial collagenase in the pathogenesis of acute lung injury induced by hyperoxia outside of sealed cages and breath room air,and to study the mechanism of The severity of lung injury.Methods Seventy-two C57BL/6 mice were divided into normal control group,hyperoxia for 24 hours group,hyperoxia for 48 hours and hyperoxia for 72 hours group randomly,18 mice in each group.The hyperoxia group exposedin sealed cages with＞95%oxygen,and the control group were put in the inspiratory room.The expression of interstitial collagenase mRNA and protein in lung tissues was studied by reverse transcript-polymerase chain reaction(RT-PCR)and immunohistochemistry.Results Hyperoxia caused acute lung injury in mice.by The expression of interstitial collagenase mRNA in lung tissues was increased after 24 hours of hyperoxia compared with their control group[0.59±0.11 vs 0.07±0.01,q=3.t5 P＜0.01],the expression was higher at 72 hours of hyperoxia(0.68±0.12,q=3.78 P＜0.01).Immunohistochemistry study showed interstitial collagenase protein was mainly expressed in cytoplasm of airway epithelial cells,while Ⅱ type alveolar epithelial cells mainly and vascular smooth muscle cells in hyperoxia mice.The expression of interstitial collagenase protein in airway epithelium significantly increased at 24 hours of hyperoxia compared with their control group[(28.54±9.60) vs (13.48±4.32)q=2.62 P＜0.05],and the expression level was lower after 48 and 72 hours of hyperoxia(20.32±5.68) vs, (15.24±4.65).Conclusion Hyperoxia cause acute lung injury in mice;interstitial collagenase play an important role in the development of hyperoxia-induced lung injury in mice.

Effects of the EL-1 Receptor Antagonist on Matrix Metalloproteinase 1 Expression in UV-irradiated Fibroblasts / 中华皮肤科杂志

Objective To study the effects of the IL-1 receptor antagonist (IL-1Ra) on matrix metalloproteinase 1 (MMP-1) expression in UV-irradiated fibroblasts. Methods Simulating the impact of environmental ultraviolet (UV) light on human skin, UVA-irradiated human fibroblasts were cultured in medium obtained from UVB-irradiated HaCaT cells. MMP-1 was detected by ELISA in the culture medium of fibroblasts. After treatment with IL-1Ra, the mRNA expression levels of C-Jun, C-Fos and GAPDH (internal control) of fibroblasts were measured by real-time fluorescent quantitative RT-PCR. Results Production of MMP-1 by UVA (10 J/cm2)-irradiated fibroblasts was increased in culture medium from UVB-irradiated HaCaT cells. The fibroblasts produced significantly higher levels of MMP-1 in culture medium from HaCaT cells treated without UVB than those with 15 mJ/cm2 UVB (t = 8.413,P= 0.014). However, IL-1Ra inhibited MMP-1 production of fibroblasts in a dose-dependent manner. Standard curves of real-time fluorescent quantitative RT-PCR showed a linear correlation between the copy number and the threshold cycle (Tc). Melting curves confirmed the specificity of PCR products. The original copy numbers of C-Jun and C-Fos as well as the ratios of the numbers to the GAPDH copy number showed that IL-1Ra inhibited the C-Jun mRNA expression of fibroblasts in a dose-dependent manner but had no significant effects on C-Fos mRNA expression. Conclusions The culture medium from UVB-irradiated HaCaT cells can promote MMP-1 production by UVA-irradiated fibroblasts. IL-1Ra reduces MMP-1 production via inhibition of C-Jun mRNA expression.

REGULATION OF MMP_(13) GENE EXPRESSION IN RAT HEPATIC STELLATE CELLS BY IL-1? AND TNF-? / 解放军医学杂志

In order to investigate the influence of interleukin 1?(IL 1?) and tumor necrosis factor ? (TNF ?) on gene expression of rat interstitial collagenase (MMP 13 ) in hepatic stellate cells, cells of a hepatic stellate cell line (HSC T6) were cultured in medium containing IL 1? or TNF ? for different incubation periods. Total RNA of HSC was extracted and MMP 13 gene expression levels were measured by reverse transcription polymerase chain reaction. The results showed that MMP 13 gene expression level of the IL 1? group was much higher than that of the control group at 8h, 24h and 48h after exposure to IL 1?. The maximal value was 3 fold of the control group and was at 24h . MMP 13 gene expression level of the TNF ? group was also significantly higher than that of control group at 8h, 24h, 48h, 72h, and the maximum nalue was 4 fold of the control group at 48h. These results indicated that IL 1? and TNF ? might increase the gene expression of MMP 13 in hepatic stellate cells.

Expression of matrix metalloproteinase 1 and tissue inhibitor of metalloproteinase 1 in biopsy liver from patients with fibrosing cholestatic hepatitis / 中国医师杂志

Objective To explore the fibrosis mechanism of patients with fibrosing cholestatic hepatitis(FCH) in the way of degradation of collagen.Methods The expressions of matrix metalloproteinase 1(MMP1) and tissue inhibitor of metalloproteinase 1(TIMP1),and contents of type I,III collagen proteins were detected by immunohistochemical staining in the liver tissues of 9 cases with FCH associated with HBV developed following renal transplantation and 5 cases without liver disease as controls.Results The expressions of MMP1 and TIMP1,and type I,III collagen proteins in the patients with FCH were significantly higher than those in the control group.There was a positive correlation between the expressions of type I,III collagen proteins and TIMP1/ MMP1 ratio.Conclusion Hepatic fibrosis in the patients with FCH associated with HBV developed following renal transplantation may be relative to the increase of TIMP1 expression which inhibit the degradation of collagen.

Expression of Matrix Metalloproteinase (MMP)-1, MMP-3 Nitrotyrosine and Apoptosis in Articular Cartilage of Human Osteoarthritis

BACKGROUND: Matrix metalloproteinase (MMP)-1 and 3 are the most important degradating enzymes of the chondroid matrix. Chondrocytes may undergo apoptosis under various stimuli including nitric oxide (NO). We studied the expression rate and zone of MMP-1, MMP-3, nitrotyrosine, a marker of NO release, and apoptosis in the articular cartilage of human osteoarthritis. METHODS: To investigate the role of nitrotyrosine and apoptosis in the degradation of the chondroid matrix in human osteoarthritis, immunohistochemistry was done for MMP-1, MMP-3, and nitrotyrosine; and the terminal deoxynucleotidyl transferase mediated nick end labeling (TUNEL) method was performed for apoptosis using a total of 93 articular cartilages from 12 femoral heads and 17 knees obtained from total joint arthroplasty and 7 normal articular cartilages. RESULTS: In the normal control group, the expression rates for MMP-1, MMP-3, nitrotyrosine, and apoptosis were very low; and their expression zones were confined to the superficial layer of the articular cartilage. Their expression rates were low in the early stage of osteoarthritis and were moderate to high in the late stage (P<0.05). Their expression zones were confined to the superficial layer of the articular cartilage in the early stage of osteoarthritis and were expressed throughout the whole layer in the late stage and those of MMP-3 and nitrotyrosine were statistically significant (P<0.05). Their expression rates and zones were significantly correlated with the grade of osteoarthritis (P<0.05). Conclusion : The expression rate and zone of apoptosis and nitrotyrosine correlated well with those of MMP-1 and MMP-3. Therefore, NO and apoptosis may be related to the progression of human osteoarthritis.

Regulation of type I collagen and interstitial collagenase mRNA expression in human dermal fibroblasts by colchicine and D-penicillamine

Sclerosis is a disease process in which idiopathic hardening occurs in the skin and/or internal organs as a result of the accumulation of type I collagen, induced mainly by transforming growth factor-beta. Colchicine and D-penicillamine are widely used for its treatment. Their effects are known to be due to post-translational down-regulation of type I collagen synthesis, with colchicine also up-regulating interstitial collagenase. To determine whether or not they have any pre-translational effect on type I collagen and MMP-1, and also to observe their effects on the action of TGF-beta, cultured neonatal foreskin fibroblasts were treated with colchicine and D-penicillamine, singly and together. The amount of type I collagen and MMP-1 mRNA were quantitated by Northern blot hybridization. Colchicine suppresses the basal level of type I collagen mRNA but minimally stimulates the mRNA expression of MMP-1, whereas D-penicillamine does not have any significant effects on either. Colchicine was also able to significantly suppress the TGF-beta-induced up-regulation of type I collagen mRNA expression.