Plasma Matrix Metalloproteinase-9 Research Articles

Plasma matrix metalloproteinase 1, 3, and 7 levels and breast cancer risk in the Nurses' Health study.

Matrix metalloproteinases (MMPs), in particular MMP1, 3, and 7, are believed to be critical to breast cancer invasion and metastasis and also may have important functions earlier in breast carcinogenesis. However, the relationship between circulating levels of MMP1, 3, and 7 and breast cancer risk is uncertain. We examined associations between plasma MMP1, 3, and 7 and breast cancer risk in a prospective case-control study nested within the Nurses' Health Study. Blood samples were collected from 801 cases who developed breast cancer between 1992 and 2000 and 801 matched controls, and MMP levels were measured via immunofluorescence assay. No overall association was observed between any of these MMPs and breast cancer risk [top vs. bottom quintile; MMP1: odds ratio (OR) 0.9; 95% confidence interval (CI) 0.7, 1.3; p-trend=0.51; MMP3: OR 1.1; 95% CI 0.8, 1.5; p-trend=0.88; MMP7: OR=1.2; 95% CI 0.8, 1.7; p-trend=0.18]. Further, findings did not significantly vary by time since blood draw, body mass index, or postmenopausal hormone use, or by breast cancer subtypes. Circulating MMP1, 3, and 7 levels do not appear to be predictive of overall breast cancer risk.

Rac1 regulates platelet shedding of CD40L in abdominal sepsis

Matrix metalloproteinase-9 (MMP-9) regulates platelet shedding of CD40L in abdominal sepsis. However, the signaling mechanisms controlling sepsis-induced shedding of CD40L from activated platelets remain elusive. Rac1 has been reported to regulate diverse functions in platelets; we hypothesized herein that Rac1 might regulate platelet shedding of CD40L in sepsis. The specific Rac1 inhibitor NSC23766 (N6-[2-[[4-(diethylamino)-1-methylbutyl] amino]-6-methyl-4-pyrimidinyl]-2 methyl-4, 6-quinolinediamine trihydrochloride) was administered to mice undergoing cecal ligation and puncture (CLP). Levels of CD40L and MMP-9 in plasma, platelets, and neutrophils were determined by use of ELISA, western blot, and confocal microscopy. Platelet depletion abolished the CLP-induced increase in plasma levels of CD40L. Rac1 activity was significantly increased in platelets from septic animals. Administration of NSC23766 abolished the CLP-induced enhancement of soluble CD40L levels in the plasma. Moreover, Rac1 inhibition completely inhibited proteinase-activated receptor-4-induced surface mobilization and secretion of CD40L in isolated platelets. CLP significantly increased plasma levels of MMP-9 and Rac1 activity in neutrophils. Treatment with NSC23766 markedly attenuated MMP-9 levels in the plasma from septic mice. In addition, Rac1 inhibition abolished chemokine-induced secretion of MMP-9 from isolated neutrophils. Finally, platelet shedding of CD40L was significantly reduced in response to stimulation with supernatants from activated MMP-9-deficient neutrophils compared with supernatants from wild-type neutrophils, indicating a direct role of neutrophil-derived MMP-9 in regulating platelet shedding of CD40L. Our novel data suggest that sepsis-induced platelet shedding of CD40L is dependent on Rac1 signaling. Rac1 controls surface mobilization of CD40L on activated platelets and MMP-9 secretion from neutrophils. Thus, our findings indicate that targeting Rac1 signaling might be a useful way to control pathologic elevations of CD40L in the systemic circulation in abdominal sepsis.

Cleavage and reduced CD36 ectodomain density on heart and spleen macrophages in the Spontaneously Hypertensive Rat

Metabolic disease is accompanied by a range of cellular defects (“comorbidities”) whose origin is uncertain. To investigate this pathophysiological phenomenon we used the Spontaneously Hypertensive Rat (SHR), which besides an elevated arterial blood pressure also has many other comorbidities, including a defective glucose and lipid metabolism. We have shown that this model of metabolic disease has elevated plasma matrix metalloproteinase (MMP) activity, which cleaves the extracellular domain of membrane receptors. We hypothesize here that the increased MMP activity also leads to abnormal cleavage of the scavenger receptor and fatty acid transporter CD36. To test this idea, chronic pharmaceutical MMP inhibition (CGS27023A) of the SHR and its normotensive control, the Wistar Kyoto Rat (WKY), was used to determine if inhibition of MMP activity serves to maintain CD36 receptor density and function. Surface density of CD36 on macrophages from the heart, spleen, and liver was determined in WKY, SHR, CGS-treated WKY (CGS WKY), and CGS-treated SHR (CGS SHR) by immunohistochemistry with an antibody against the CD36 ectodomain. The extracellular CD36 density was lower in SHR heart and spleen macrophages compared to that in the WKY. MMP inhibition by CGS served to restore the reduced CD36 density on SHR cardiac and splanchnic macrophages to levels of the WKY. To examine CD36 function, culture assays with murine macrophages (RAW 264.7) after incubation in fresh WKY or SHR plasma were used to test for adhesion of light-weight donor red blood cell (RBC) by CD36. This form of RBC adhesion to macrophages was reduced after incubation in SHR compared WKY plasma. Analysis of the supernatant macrophage media by Western blot shows a higher level of CD36 extracellular protein fragments following exposure to SHR plasma compared to WKY. MMP inhibition in the SHR plasma compared to untreated plasma, served to increase the RBC adhesion to macrophages and decrease the number of receptor fragments in the macrophage media. In conclusion, these studies bring to light that plasma in the SHR model of metabolic disease has an unchecked MMP degrading activity which causes cleavage of a variety of membrane receptors, including CD36, which attenuates several cellular functions typical for the metabolic disease, including RBC adhesion to the scavenger receptor CD36. In addition to other cell dysfunctions chronic MMP inhibition restores CD36 in the SHR.

Dynamic changes of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 after burn injury

PurposeSevere burn is a life-threatening condition. Many trials discuss the role of matrix metalloproteinases and tissue inhibitor of metalloproteinases in diseases generating systemic inflammatory response syndrome, and in some, their prognostic importance has been established. We aimed to describe the time courses of the aforementioned system and to evaluate the difference between survivors and nonsurvivors in burns. MaterialsThirty-one patients were enrolled. Blood samples were collected on admission and on the 5 consecutive days. Circulating matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) have been measured. Healthy individuals were invited as controls. ResultsTissue inhibitor of metalloproteinase 1 increased in the burn group (P < .001) by day 2 and remained elevated thereafter. Plasma MMP-9 and MMP-9/TIMP-1 were already elevated on admission (P < .001) and decreased in tendency thereafter. In burned patients, significantly lower MMP-9 were noted on days 4 to 6 as MMP-9/TIMP-1 were also lower on days 3 to 6 (P < .01) compared with controls. We experienced difference regarding survival on days 5 and 6 by TIMP-1 (P < .05). ConclusionsOur research is the first follow-up study elucidating the dynamic changes of MMP-9–TIMP-1 system in severe burns. Alteration of MMP-9–TIMP-1 balance might influence systemic inflammatory response and related mortality. Matrix metalloproteinase 9 might be a good injury marker in burns after an extensive trial.

Supplementation with a single and double strain probiotic on the innate immune system for respiratory illness

Background and aimsThe immune mechanisms by which probiotics reduce susceptibility to upper respiratory tract illness is uncertain. The aim of this study was to examine purported cell-mediated immune mechanisms that might explain the reduction in respiratory illness observed following daily supplementation with Bifidobacterium animalis subsp. lactis Bl-04 (Bl-04) and a combined Lactobacillus acidophilus NCFM &B. animalis subsp. lactis BI-07 (NCFM & Bi-07). MethodsA cohort of 144 healthy physically active individuals were allocated to daily supplementation consumed as a beverage with Bl-04 (n = 46) supplemented at a dosage of 2.0 × 109 colony forming units (cfu) per day, NCFM & Bi-07 (n = 47) at a dosage of 5.0 × 109 CFU per day each, or a placebo (n = 51) over 150 d. Markers included plasma cytokines, metalloproteinases and neurotrophins, peripheral blood leucocyte numbers, antibody-dependent and antibody-independent NK cell activity (NKCA), and peripheral blood mononuclear cell (PBMC) phagocytosis. ResultsA total of 125 subjects were included in the final analysis. No significant effects were observed on cytokines, on white cell differentials, NKCA or PBMC phagocytosis from pre- to post-supplementation. The biomarkers that increased significantly from pre- to post-supplementation were the concentration of plasma macrophage inflammatory protein (MIP)-1δ which was higher in the Bl-04 than placebo group (Bl-04 25% ± 11%, placebo −3.3% ± 9.4%; mean ± SD, P = 0.003) while the concentration of plasma matrix metallo-proteinase (MMP)-1 decreased by 11% ± 16% in the NCFM & Bi-07 group and increased by 21% ± 17% in the placebo group, which was a significant 26% difference (8–41%; P = 0.02). ConclusionProbiotic supplementation had little effect on parameters of the innate immune system. Mechanisms explaining the beneficial effect of Bl-04 or NCFM & Bi-07 supplementation on respiratory illness remain unclear.

Imidapril and Enalapril Similarly Inhibit Plasma Matrix Metalloproteinase Activities and Attenuate Left Ventricular Remodeling in Patients With Acute Myocardial Infarction

Matrix metalloproteinase (MMP) plays a critical role in the development of ventricular remodeling after acute myocardial infarction (AMI). Imidapril, an angiotensin-converting enzyme inhibitor, has been shown to inhibit MMP activity. We investigated whether imidapril inhibits plasma MMP activities and attenuates ventricular remodeling in patients with AMI in comparison with enalapril. We enrolled 70 patients with AMI. All patients underwent primary percutaneous coronary intervention and were randomly assigned either to imidapril (n = 35) or to enalapril (n = 35) treatment. Left ventriculography was performed in acute (day 14) and chronic (6 months) phases, and plasma MMP-2 and MMP-9 activities were measured by zymography. Any changes in left ventricular end-diastolic volume index and ejection fraction from acute to chronic phases did not differ between the 2 groups. The plasma MMP-2 and MMP-9 activities at day 14 were both significantly decreased compared with those at day 1 in both groups (all P < 0.05). At 6 months, MMP-9 activity still remained decreased in both groups (P < 0.05 vs. day 1). Overall, there were no differences between the 2 groups both in plasma MMP-2 and MMP-9 activities. These results demonstrate that imidapril exerts inhibitory effects on plasma MMP activities and attenuates left ventricular remodeling in patients with AMI similar to enalapril.

51 Plasma MMP-3: A Novel Indicator of Left Ventricle Remodelling and Adverse Outcomes in Patients with Acute Heart Failure

PurposeChanges in the intercellular matrix have previously been found to be important in left ventricle (LV) remodelling in chronic heart failure (HF). We investigated whether plasma matrix metalloproteinase (MMP) 3...

Resection of Carotid Body Tumors reduces arterial blood pressure. An underestimated neuroendocrine syndrome

IntroductionCarotid Body Tumors (CBTs) are Paragangliomas (PGLs) located in the head and neck region which usually do not cause overt neuroendocrine symptoms and hypertension. Matrix Metalloproteinases (MMPs) have shown a strong correlation between CBTs and their clinical behavior. Aim of this study is to analyze the relationship between changes in arterial blood pressure and metalloproteinases levels after surgical resection of CBTs. MethodsWe performed a multicenter clinical study on 17 patients with benign and malignant CBTs (5 males; 12 females). Tumors were completely resected and biopsies, obtained at the time of surgery, were lysed for Western blot analysis to determine MMPs levels in tissues. An enzyme-linked immune sorbent assay (ELISA) kit was used to determine the concentration of MMPs in plasma fluid.Blood pressure values were measured at admission and at 10 days after surgery. ResultsAt the time of the admission, blood pressure values were higher in patients with CBTs respect to control patients; moreover in patients with malignant CBTs blood pressure values were higher (P < 0.01) respect to patients with benign CBTs. 10 days after the surgery, we documented a significant decrease (P < 0.01) in blood pressure values and in MMPs levels in all patients with CBTs. ConclusionThese results suggest that, despite the CTBs are considered non-functional tumors, an “underestimated” neuroendocrine activity on arterial blood pressure may be detected.

Effects of bosentan on pulmonary fibrosis

Objective To investigate the effects of bosentan on pulmonary fibrosis.Methods Forty-eight male Wistar rats were randomly and equally divided into control groups (C2,C4),model groups (F2,F4) and drug groups (D1,D2).Bleomycin was used to create pulmonary fibrosis model,while rats in D1 and D2 groups were treated by bosentan from day 2 and day 15.Plasma endothelin-I (ET-1),matrix metalloproteinase-9 (MMP-9) and tissue inhibitorof metalloproteinase (TIMP)-1 were measured.Alveolitis and fibrosis scores were assessed after 2 and 4 weeks.Results (1) The levels of ET-1 in F4 group were highest,followed by F2,C4 and C2 groups [(0.41 ±0.13),(0.28 ±0.08),(0.11 ±0.04),and (0.10 ±0.05) μg/L].Compared to F4 group,the levels of ET-1 in D1 group was reduced,but no significant difference was found between D2 and F4 groups; (2) Pathological assessment showed that alveolar structure was destroyed,and numerous inflammatory cells and fibroblasts could be seen in F2 group as well as collagen,most significantly in F4 group,and those were significantly reduced in D1 group as compared with F4 ; (3) The levels of ET-1 were positively associated with alveolitis and fibrosis scores,but MMP-9/TIMP-1 were negatively with them.Conclusion Bosentan can protect against the bleomycin-induced pulmonary fibrosis,and the improvement is more significant in early stage. Key words: Bosentan; Bleomycin ; Pulmonary fibrosis ; Endothelin-1

Effects of atorvastatin on plasma matrix metalloproteinase-9 concentration after glial tumor resection; a randomized, double blind, placebo controlled trial

BackgroundNeurosurgical procedures such as craniotomy and brain tumor resection could potentially lead to unavoidable cerebral injuries. Matrix metalloproteinase-9 (MMP-9) is up-regulated in neurological injuries. Statins have been suggested to reduce MMP- 9 level and lead to neuroprotection. Atorvastatin preoperatively administered to evaluate its neuroprotective effects and outcome assessment in neurosurgical-induced brain injuries after glial tumor resection. In this prospective, randomized, double-blind, placebo-controlled trial, 42 patients undergoing glial tumor surgery randomly received 40 mg atorvastatin or placebo twice daily from seven days prior to operation and continued for a 3 weeks period. Plasma MMP-9 concentration measured 4 times, immediately before starting atorvastatin or placebo, immediately before surgery, 24 hours and two weeks after the surgery. Karnofsky performance score was assessed before first dose of atorvastatin as a baseline and 2 months after the surgery.ResultsKarnofsky performance scale after surgery raised significantly more in Atorvastatin group (11.43 +/- 10.62 vs. 4.00 +/- 8.21) (p = 0.03). Atorvastatin did not significantly reduce MMP-9 plasma concentration 24 hours after surgery in comparison to placebo. No statistical significance detected regarding length of hospital stay among the groups. Significant reduction in MMP-9 plasma concentration was recorded in atorvastatin group two weeks after surgery (p = 0.048).ConclusionsSignificant statistical differences detected with atorvastatin group regarding MMP-9 plasma concentration, clinical outcome and Karnofsky performance score. Consequently, atorvastatin use may lead to better outcome after neurosurgical procedures.

Levels of plasma matrix metalloproteinases (MMP-2 and MMP-9) in response to INTEGRA® dermal regeneration template implantation.

BackgroundCutaneous wound healing results in scar formation. Matrix metalloproteinases (MMP) transform extracellular matrix proteins and modulate inflammation and cell signaling, thus determining scar outcome. To provide rapid wound closure and reduced scarring, dermal scaffolds were introduced. Little is known about the influence of these materials on MMPs levels.Material/MethodsIn this in vivo study the levels of MMP-2, MMP-9, and mediators of inflammation and fibrosis (IL-4 and TGF-β1) in patients treated with Integra® dermal regeneration template (IDRT) were investigated. In the group of 11 pediatric patients treated with IDRT, levels of selected molecules were analyzed before surgery and at day 1, 7, and 25 after scaffold implantation.ResultsThe mean IDRT take rate was 89.5±4.7% with 4 patients (36%) who developed local infection. Patients were divided into 2 groups according to presence of infection (1 group with complications and 1 group without complications). In the group with complications, the IDRT take rate was significantly reduced compared to the group without complications (71.5±5.4 vs. 100±0.1; p<0.005). Plasma levels of MMP-2 were significantly (p<0.05) elevated in both groups on day 7 after the scaffold placement compared to baseline. Positive correlations between IL-4 and MMP-2 (p=0.01) in the group with complications and TGF-β1 and MMP-9 (p=0.012) in both groups were observed.ConclusionsThese findings suggest that Integra® scaffold degradation is mainly caused by MMP-2, whereas inflammation associated with local infection increases levels of this molecule and it is not associated with elevation of MMP-9. This shows that dermal regeneration with Integra® uses molecular mechanisms other than scar formation during dermal wound healing.

S37 Matrix metalloproteinases drive collagen degradation and leukocyte migration in human tuberculosis: clinical and cellular studies

Introduction and ObjectivesTuberculosis (TB) causes disease worldwide and multi-drug resistance is rising. Matrix metalloproteinases (MMPs) cause immunopathological lung matrix destruction, which results in transmission, morbidity and mortality. We specifically investigated...

Doxycycline Reduces Cardiac Matrix Metalloproteinase-2 Activity but Does not Ameliorate Myocardial Dysfunction During Reperfusion in Coronary Artery Bypass Patients Undergoing Cardiopulmonary Bypass

Matrix metalloproteinase-2 proteolyzes intracellular proteins in the heart and induces acute myocardial contractile dysfunction in ischemia-reperfusion injury. Doxycycline, a matrix metalloproteinase inhibitor, prevented matrix metalloproteinase-2-induced troponin I cleavage in rat hearts and improved contractile function following ischemia-reperfusion. In patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass, increased atrial matrix metalloproteinase-2 activity was inversely correlated with cardiac mechanical function at 3 hours reperfusion. We performed a study in patients with coronary artery disease undergoing primary elective coronary artery bypass graft surgery with cardiopulmonary bypass to determine whether doxycycline reduces cardiac mechanical dysfunction, matrix metalloproteinase activity, and troponin I degradation after reperfusion. Randomized, double-blinded, placebo-controlled study. University of Alberta Hospital. Forty-two patients with coronary artery disease undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. Patients were randomized to receive either oral administration of 20 mg of doxycycline or matching placebo pill twice a day at least 2 days prior to surgery, on the day of surgery, and for the first 3 postoperative days. Left ventricular stroke work index was examined prior to cardiopulmonary bypass and at 24 hours reperfusion. Right atrial biopsies were collected before cardiopulmonary bypass and 10 minutes after aortic cross-clamp release to determine matrix metalloproteinase-2 activity and troponin I level. Blood was collected to determine matrix metalloproteinase activity and interleukin-6, C-reactive protein, and troponin I levels. Cardiac 72-kDa matrix metalloproteinase-2 activity was lower upon reperfusion in biopsies from the doxycycline group (p = 0.01), and the increase of matrix metalloproteinase-2 activity in the placebo group due to reperfusion did not appear in the doxycycline group (p = 0.05). Doxycycline, however, did not ameliorate cardiac mechanical dysfunction following reperfusion or the cardiopulmonary bypass-coronary artery bypass graft-induced increased plasma matrix metalloproteinase-9, interleukin-6, and C-reactive protein levels. Cardiopulmonary bypass-coronary artery bypass graft or doxycycline did not change tissue or plasma troponin I levels at 10 minutes reperfusion. Although doxycycline did not improve myocardial stunning following coronary artery bypass graft surgery with cardiopulmonary bypass, it reduced cardiac matrix metalloproteinase-2 activity in these patients. A larger trial and/or higher dose of doxycycline may yet be warranted.

Noninvasive Perioperative Evaluation of Right Ventricular Function in Children With Tetralogy of Fallot

Early and accurate noninvasive means of identifying right ventricular (RV) dysfunction in children with tetralogy of Fallot (TOF) are needed. RV function was examined using tissue Doppler imaging (TDI), strain rate (SR), and strain analysis (SA) in children before (N = 37) and after (6-12 months; N = 32) TOF repair, and in a control group of children (N = 37). Plasma concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) and matrix metalloproteinase 9 (MMP-9) were measured. TDI, SR, and SA revealed that RV systolic and diastolic function indices were lower preoperatively in the TOF group compared with the control group, and did not improve after TOF repair. Plasma NT-proBNP concentrations were significantly higher in the TOF group pre- and postoperatively compared with the control group. In the preoperative TOF group, NT-proBNP concentration was significantly correlated with peak systolic SR and systolic strain in the mid segments of RV free wall. Plasma MMP-9 concentrations were significantly increased in the preoperative TOF group compared with the control group, and significantly correlated with plasma NT-proBNP and logNT-proBNP concentrations. RV function correlated with plasma NT-proBNP concentrations in children with TOF. Assessment of this noninvasive measure may help identify RV dysfunction in patients with TOF before they become clinically symptomatic.

Using plasma matrix metalloproteinase-9 and monocyte chemoattractant protein-1 to predict future cardiovascular events in subjects with carotid atherosclerosis

Atherosclerosis is characterized by the gradual deposition of fat and cholesterol in the arterial wall, which over time can progress to yield inflammation and extracellular matrix-rich lesions that occlude vessels and restrict blood flow. During the formation of atherosclerotic lesions, monocytes are recruited through a mechanism that involves upregulation of the monocyte chemoattractant protein (MCP)-1/chemokine receptor CCR2 signaling pathway [1]. In addition to uptake of lipids, macrophages secrete high concentrations of inflammatory mediators and proteinases such as matrix metalloproteinases (MMPs), which contribute to atherosclerotic plaque progression [2].

Plasma Matrix Metalloproteinase-9 Response to Downhill Running in Humans

Matrix metalloproteinase-9 is a proteolytic enzyme capable of degrading proteins of the muscle extracellular matrix. Systemic levels of MMP-9 or its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), have the potential to serve as blood markers of exercise-induced muscle damage. The purpose of this study was to determine if an eccentrically-dominated task, downhill running (DHR), produces changes in plasma MMP-9 or TIMP-1 and examine the relationship between MMP-9/TIMP-1 levels and indirect indicators of muscle damage. Subjects were sedentary (SED, n=12) or had a history of concentrically-biased training (CON, n=9). MMP-9 and TIMP-1 were measured before (Pre-Ex), immediately after (Post-Ex), and 1-, 2-, 4-, and 7-days post-DHR (-10°), and compared to discomfort ratings, creatine kinase activity and strength loss. At 1-day Post-Ex, discomfort increased (5.6 ± 7.8 to 45.5 ± 19.9 mm; 0-100 mm scale), strength decreased (-6.9 ± 1.6%) and CK increased (162.9 ± 177.2%). MMP-9 was modestly but significantly increased at Post-Ex in both CONC and SED (32.7 ± 33.6%) and at 4-days in SED (66.9 ± 88.1%), Individual responses were variable, however. There were no correlations between MMPs and discomfort ratings, plasma CK or strength. While plasma MMP-9 changes may be detectable in the systemic circulation after DHR, they are small and do not correspond to other markers of damage.

Association between the Cerebral Inflammatory and Matrix Metalloproteinase Responses after Severe Traumatic Brain Injury in Humans

An increasing number of preclinical investigations have suggested that the degree of expression of the matrix metalloproteinase (MMP) family of endopeptidases may explain some of the variability in neurological damage after traumatic brain injury (TBI). As cytokines are a prominent stimulus for MMP expression in animals, we conducted a prospective multimodal monitoring study and determined their association with temporal MMP expression after severe TBI in eight critically ill adults. High cutoff, cerebral microdialysis (n=8); external ventricular drainage (n=3); and arterial and jugular venous bulb catheters were used to measure the concentration of nine cytokines and eight MMPs in microdialysate, cerebrospinal fluid (CSF), and plasma over 6 days. Severe TBI was associated with a robust central inflammatory response, which was largely similar between microdialysate and CSF. At all time points after injury, this response was predominated by the pro-inflammatory cytokines interleukin-6 (IL-6) and IL-8. Use of univariate generalized estimating equations suggested that the concentration of several MMPs varied with cytokine levels in microdialysate. The largest of these changes included increases in microdialysate concentrations of MMP-8 and MMP-9 with increases in the levels of IL-1α and -2 and IL-1α and -2 and TNF-α, respectively. In contrast, the microdialysate level of MMP-7 decreased with increases in microdialysate concentrations of IL-1β, -2, and -6. These findings support the observations of animal studies that cross-talk exists between the neuroinflammatory and MMP responses after acute brain injury. Further study is needed to determine whether this link between cerebral inflammation and MMP expression may have clinical relevance to the care of patients with TBI.

Relation of periprocedural plasma matrix metalloproteinase-8 and -9 levels to microvascular obstruction after primary percutaneous coronary intervention

Purpose: Reperfusion injury is central to the pathophysiology of microvascular obstruction (MVO) after primary percutaneous coronary intervention (p-PCI). Matrix metalloproteinases (MMPs) do not only regulate the release of proinflammatory cytokines and the expression of adhesion molecules but also facilitate leukocyte transmigration across the endothelium during an inflammatory response. The aim of this study was to investigate the relation of periprocedural plasma MMP- 8 and -9 levels to MVO after p-PCI in patients with acute ST segment elevation myocardial infarction (STEMI). Methods: Forty-two patients with acute STEMI who underwent p-PCI within 12 hours of the onset of symptoms were prospectively enrolled. Plasma samples for MMP-8 and-9 analysis were obtained on admission and at post-PCI 6th and 24th hours. MVO was assessed and quantified by the index of microcirculatory resistance (IMR) measured with the use of a guidewire tipped with pressure and temperature sensors on post-PCI day 4 to 5. Results: When we categorized the patients according to the mean value of IMR (30 U) and define MVO as IMR>30 U, baseline MMP 8 (21.1±18.6 vs 8.1±4.3, p=0.001) and baseline MMP 9 (108.8±76.4 vs 71.9±59.4, p=0.013) levels were significantly higher in patients with MVO. However, there was no difference between the two groups with respect to the MMP levels at the 6th and 24th hours (Figure 1). Plasma MMP-8 and -9 levels on admission were positively correlated with IMR (r=0.56 p<0.001 and r=0.47 p=0.002, respectively). However, magnitude of change (in percentages) in plasma MMP-8 and -9 levels between admission and post-PCI 6th hour was negatively correlated with IMR (r=-0.38 p=0.01 and r=-0.34 p=0.03, respectively). In addition to MMP-8 and -9, D-dimer (r = 0.38, p=0.016) and BNP (r =0.46, p=0.003) levels on admission, peak troponin level (r =0.27, p=0.077) and age (r =0.28, p=0.07) were also found to be significantly correlated with IMR. Multiple linear regression analysis revealed that MMP-8 level on admission (β=0.526, p=0.025) and BNP level on admission (β=0.056, p=0.038) were independently associated with IMR. Conclusions: Plasma MMP-8 level on admission is related to microvascular obstruction after p-PCI and significantly correlated with IMR. Furthermore, the presence of MVO seems to influence the dynamic nature of the MMPs after p-PCI. MMP inhibitors may be targets for future studies investigating alternative strategies for prevention of MVO.

The circulating level of MMP-9 and its ratio to TIMP-1 as a predictor of severity in patients with community-acquired pneumonia

BackgroundHere, we have examined the plasma levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1), the MMP-9/TIMP-1 molar ratio, the TIMP-1 single nucleotide polymorphisms (SNPs) 372C/T and the susceptibility to community-acquired pneumonia (CAP). MethodsAn enzyme-linked immunosorbent assay (ELISA) was used to measure plasma MMP-9 and TIMP-1 concentrations in 60 patients with CAP and 60 healthy individuals. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to detect the TIMP-1 SNPs 372C/T. ResultsThe plasma MMP-9, TIMP-1 levels and the MMP-9/TIMP-1 molar ratio were significantly increased in patients with CAP compared to normal controls. The MMP-9/TIMP-1 molar ratio decreased significantly in patients with CAP after treatment. Furthermore, the plasma TIMP-1 concentration was positively correlated with the pneumonia severity index (PSI), the CURB score, the results of the acute physiology and chronic health evaluation II (APACHE II) and the length of the hospital stay. No significant difference was found in the genotype distribution of TIMP-1 372C/T between patients with CAP and normal controls. ConclusionsWe hypothesize that MMP-9 levels and the MMP-9/TIMP-1 molar ratio play a role in the development of CAP and are related to the severity of CAP. Based on our data, we suggest that incorporating plasma MMP-9 levels and the MMP-9/TIMP-1 molar ratio into a clinical evaluation will aid in CAP diagnosis.

The anti-inflammatory effects of exercise training promote atherosclerotic plaque stabilization in apolipoprotein E knockout mice with diabetic atherosclerosis

Physical exercise is the cornerstone of cardiovascular disease treatment. The present study investigated whether exercise training affects atherosclerotic plaque composition through the modification of inflammatoryrelated pathways in apolipoprotein E knockout (apoE−/−) mice with diabetic atherosclerosis. Forty-five male apoE−/− mice were randomized into three equivalent (n=15) groups: control (CO), sedentary (SED), and exercise (EX). Diabetes was induced by streptozotocin administration. High-fat diet was administered to all groups for 12 weeks. Afterwards, CO mice were euthanatized, while the sedentary and exercise groups continued high-fat diet for 6 additional weeks. Exercising mice followed an exercise program on motorizedtreadmill (5 times/week, 60 min/session). Then, blood samples and atherosclerotic plaques in the aortic root were examined. A considerable (P<0.001) regression of the atherosclerotic lesions was observed in the exercise group (180.339±75.613×103µm2) compared to the control (325.485±72.302×103 µm2) and sedentary (340.188±159.108×103µm2) groups. We found decreased macrophages, matrix metalloproteinase-2 (MMP-2), MMP-3, MMP-8 and interleukin-6 (IL-6) concentrations (P<0.05) in the atherosclerotic plaques of the exercise group. Compared to both control and sedentary groups, exercise training significantly increased collagen (P<0.05), elastin (P<0.001), and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) (P<0.001) content in the atherosclerotic plaques. Those effects paralleled with increased fibrous cap thickness and less internal elastic lamina ruptures after exercise training (P<0.05), while body-weight and lipid parameters did not significantly change. Plasma MMP-2 and MMP-3 concentrations in atherosclerotic tissues followed a similar trend. From our study we can conclude that exercise training reduces and stabilizes atherosclerotic lesions in apoE−/− mice with diabetic atherosclerosis. A favorable modification of the inflammatory regulators seems to explain those beneficial effects.