Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously we reported that alcohol abuse increases the incidence of the acute respiratory distress syndrome (ARDS) in septic patients, and that chronic ethanol ingestion in rats depletes alveolar epithelial glutathione and increases endotoxin-mediated lung edema. In this study we examined a potential mechanism by which ethanol-induced glutathione depletion could predispose to acute lung injury. We hypothesized that glutathione depletion activates matrix metalloproteinases (MMPs), thereby increasing degradation of the alveolar extracellular matrix (ECM) during sepsis. Ethanol-fed rats (20% vol/vol in water for 6 wk) were given endotoxin (2 mg/kg, intraperitoneally) followed 2 h later by lung isolation and ex vivo perfusion with n-formyl-methionyl-leucyl-phenylalanine (fMLP) (10(-)(7) M). Ethanol ingestion increased (p < 0.05) MMP-9 and MMP-2 activity, as determined by zymography, in the lung tissue and lavage fluid compared with control-fed rats, and increased (p < 0.05) levels of the 7S fragment of type IV collagen in the lung lavage fluid. Ethanol ingestion increased activation, but not production, of the MMP-9 and MMP-2 zymogens. Finally, although concomitant ingestion of N-acetylcysteine had no effect (p > 0.05) on MMP production, it increased (p > 0.05) lung glutathione levels, blocked (p < 0.05) MMP-9 and MMP-2 activation, and decreased (p < 0.05) levels of the 7S fragment of type IV collagen. We conclude that chronic ethanol ingestion, via glutathione depletion, activates MMPs during sepsis, thereby increasing degradation of the alveolar epithelial ECM. Lois M, Brown LAS, Moss IM, Roman J, Guidot DM. Ethanol ingestion increases activation of matrix metalloproteinases in rat lungs during acute endotoxemia.
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PMID:Ethanol ingestion increases activation of matrix metalloproteinases in rat lungs during acute endotoxemia. 1050 28

Matrix metalloproteinases (MMPs) are degradative enzymes, which act to remodel tissue. Their activity is regulated by the tissue inhibitors of metalloproteinases (TIMPs). An imbalance in the degradation/inhibition activities has been associated with many diseases, including sepsis. We have previously shown that TIMP-3 knockout animals develop spontaneous, progressive air space enlargement. The objectives of this study were to determine the effects of a septic lung stress induced by cecal ligation and perforation (CLP) on lung function, structure, pulmonary surfactant, and inflammation in TIMP-3 null mice. Knockout and wild-type animals were randomized to either sham or CLP surgery, allowed to recover for 6 h, and then euthanized. TIMP-3 null animals exposed to sham surgery had a significant increase in lung compliance when compared with sham wild-type mice. Additionally, the TIMP-3 knockout mice showed a significant increase in compliance following CLP. Rapid compliance changes were accompanied by significantly decreased collagen and fibronectin levels and increased gelatinase (MMP-2 and -9) abundance and activation. Additionally, in situ zymography showed increased airway-associated gelatinase activity in the knockout animals enhanced following CLP. In conclusion, exposing TIMP-3 null animals to sepsis rapidly enhances the phenotypic abnormalities of these mice, due to increased MMP activity induced by CLP.
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PMID:Negative impact of tissue inhibitor of metalloproteinase-3 null mutation on lung structure and function in response to sepsis. 1290 86

Enhanced cardiac generation of peroxynitrite contributes to septic cardiomyopathy. Since matrix metalloproteinases (MMPs) are activated in vitro by peroxynitrite, we hypothezised that MMPs may contribute to cardiac mechanical dysfunction in sepsis. Rats were injected (i.p.) with either lipopolysaccharide (LPS, 4 mg/kg) or vehicle. MMP inhibitors, either Ro 31-9790 (20 mg/kg), doxycycline (4 mg/kg), or vehicle were administered i.p. 30 min after LPS. At 6 h, when the symptoms of endotoxemia peak, hearts were excised and perfused as working hearts with Krebs-Henseleit buffer at 37 degrees C. Cardiac work (cardiac output x peak systolic pressure product) was measured. Perfusate and ventricle samples were analyzed by gelatin zymography to quantify MMP activity. Cardiac function was significantly depressed in LPS-treated rats compared to control rats (control: 55 +/- 4, LPS: 26 +/- 6 mmHg*mL*min(-1)). LPS also caused a loss of 72 kDa MMP-2 activity in the ventricles and the perfusate. Although MMP-9 activity was not detected in the ventricles, LPS resulted in an increase in perfusate 92 kDa MMP-9 activity. The MMP inhibitors significantly improved cardiac function of LPS-treated rats (Ro 31-9790: 38 +/- 3, doxycycline: 51 +/- 3 mmHg*mL*min(-1)), had no effect on the loss of MMP-2 activity, and significantly reduced the MMP-9 activity in the perfusate. These results demonstrate, for the first time, that LPS induced cardiac dysfunction is associated with a loss in ventricular MMP-2 activity and the release of MMP-9 from the heart. MMP inhibitors can significantly preserve cardiac mechanical function during septic shock.
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PMID:Matrix metalloproteinase inhibitors attenuate endotoxemia induced cardiac dysfunction: a potential role for MMP-9. 1457 5

Sepsis causes more than with 215,000 deaths per year in the United States alone. Death can be caused by multiple system organ failure, with the lung, in the form of the acute respiratory distress syndrome (ARDS), often being the first organ to fail. We developed a chronic porcine model of septic shock and ARDS and hypothesized that blocking the proteases neutrophil elastase (NE) and matrix metalloproteinases (MMP-2 and MMP-9) with the modified tetracycline, COL-3, would significantly improve morbidity in this model. Pigs were anesthetized and instrumented for hemodynamic monitoring and were then randomized to one of three groups: control (n = 3), laparotomy only; superior mesenteric artery occlusion (SMA) + fecal blood clot (FC; n = 7), with intraperitoneal placement of a FC; and SMA + FC + COL (n = 5), ingestion of COL-3 12 h before injury. Animals emerged from anesthesia and were monitored and treated with fluids and antibiotics in an animal intensive care unit continuously for 48 h. Serum and bronchoalveolar lavage fluid (BALF) were sampled and bacterial cultures, MMP-2, MMP-9, NE, and multiple cytokine concentrations were measured. Pigs were reanesthetized and placed on a ventilator when significant lung impairment occurred (PaO2/FiO2 < 250). At necropsy, lung water and histology were assessed. All animals in the SMA + FC group developed septic shock evidenced by a significant fall in arterial blood pressure that was not responsive to fluids. Lung injury typical of ARDS (i.e., a fall in lung compliance and PaO2/FiO2 ratio and a significant increase in lung water) developed in this group. Additionally, there was a significant increase in plasma IL-1 and IL-6 and in BALF IL-6, IL-8, IL-10, NE, and protein concentration in the SMA + FC group. COL-3 treatment prevented septic shock and ARDS and significantly decreased cytokine levels in plasma and BALF. COL-3 treatment also significantly reduced NE activity (P < 0.05) and reduced MMP-2 and MMP-9 activity in BALF by 64% and 34%, respectively, compared with the SMA + FC group. We conclude that prophylactic COL-3 prevented the development of ARDS and unexpectedly also prevented septic shock in a chronic insidious onset animal model of sepsis-induced ARDS. The mechanism of this protection is unclear, as COL-3 inhibited numerous inflammatory mediators. Nevertheless, COL-3 significantly reduced the morbidity in a clinically applicable animal model, demonstrating the possibility that COL-3 may be useful in reducing the morbidity associated with sepsis and ischemia/reperfusion injury in patients.
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PMID:Chemically modified tetracycline prevents the development of septic shock and acute respiratory distress syndrome in a clinically applicable porcine model. 1620 20

Despite continued investigation, the pathogenesis of tissue injury secondary to sepsis remains elusive. Further evaluation of the mechanisms by which endotoxemia and sepsis induce tissue injury is necessary to formulate rational and effective treatment strategies. The purpose of these studies was to evaluate the role of the matrix metalloproteinases MMP-2 and MMP-9 in gastric injury during lipopolysaccharide induced endotoxemia. Lipopolysaccharide increased gastric gelatinase activity as determined by in situ and gelatin zymography. Specifically, lipopolysaccharide induced MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) transcription, with subsequent increases in MMP-2 and TIMP-1 protein expression. Furthermore, selective metalloproteinase inhibition ameliorated gastric injury in this model. These data suggest that lipopolysaccharide-induced gastric injury is mediated, at least in part, by increased MMP-2 production.
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PMID:Rat gastric gelatinase induction during endotoxemia. 1661 66

The enzyme group of matrix metalloproteinases (MMPs) and their inhibitors, so-called tissue inhibitors of matrix-metalloproteinases (TIMPs), are crucial mediators responsible for wound repair after parenchymal damage. Little is known about the role of MMPs and TIMPs in severe sepsis. The aim of the present study was therefore to investigate their levels in patients with severe sepsis and to examine their association with prognosis. MMP-2, MMP-9, TIMP-1, TIMP-2 and interleukin-6 (IL-6) plasma levels were measured by ELISA methods in 37 patients on day 1 of severe sepsis. 37 healthy volunteers served as controls. Levels of MMP-9, TIMP-1, TIMP-2 and IL-6 in septic patients were significantly higher compared to healthy controls (p<0.001), whereas MMP-2 levels were not different in patients and controls. TIMP-1 levels were significantly higher in non-survivors (4675+/-435 ng/ml, mean+/-SEM) compared to survivors of severe sepsis (3201+/-249 ng/ml; p<0.01). Septic patients with TIMP-1 values >3200 ng/ml were 4.5 times more likely to die than patients with lower values (RR = 4.5; 95% CI 1.14-17.6, p = 0.014). Our results indicate that MMP-9, TIMP-2 and TIMP-1 are elevated in severe sepsis. Furthermore, TIMP-1 may serve as a useful laboratory marker to predict the clinical outcome of patients presenting with severe sepsis.
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PMID:Matrix-metalloproteinases and their inhibitors are elevated in severe sepsis: prognostic value of TIMP-1 in severe sepsis. 1700 30

Septic shock remains the leading cause of death in intensive care units in North America. Recent evidence implicates matrix metalloproteinases (MMP) in the pathogenesis of sepsis. MMP activity is upregulated in blood vessels exposed to bacterial lipopolysaccharide (LPS) or pro-inflammatory cytokines and contributes to vascular hyporeactivity to vasoconstrictors. The exact mechanism of MMP-mediated vascular hyporeactivity is unknown. We investigated the contribution of the endothelium in the MMP response to LPS-mediated vascular hyporeactivity in vitro. Tone induced by phenylephrine in isolated rat aortic rings with either intact or denuded endothelium was measured in the presence of LPS for 6 h. These rings were incubated with the nitric oxide (NO) synthase inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME), to determine whether NO synthase was involved in the response, or the MMP inhibitors, doxycycline or GM6001. MMP activity was measured after 6 h. LPS caused a greater reduction of phenylephrine-induced tone in endothelium-intact rings versus endothelium-denuded rings, indicating both endothelium-independent and -dependent mechanisms for LPS-induced vascular hyporeactivity. l-NAME abolished the response to LPS in both endothelium-intact and endothelium-denuded rings. MMP inhibitors prevented the LPS-induced loss of tone in endothelium-intact but not endothelium-denuded rings. LPS caused significantly greater MMP-2 activity in endothelium-intact aortae which was attenuated by doxycycline. MMP-2 activity in endothelium-denuded aortae was unchanged by LPS. The vascular endothelium contributes to MMP-mediated vascular dysfunction induced by LPS. The protective effect of MMP inhibition is endothelium-dependent and is a novel mechanism by which MMPs contribute to vascular dysfunction.
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PMID:Endothelial dependence of matrix metalloproteinase-mediated vascular hyporeactivity caused by lipopolysaccharide. 1824 97

Persistent arterial hypotension is a hallmark of sepsis and is believed to be caused, at least in part, by excess nitric oxide (NO). NO can combine with superoxide to produce peroxynitrite, which activates matrix metalloproteinases (MMPs). Whether MMP inhibition in vivo protects against vascular hyporeactivity induced by endotoxemia is unknown. Male Sprague-Dawley rats were administered either bacterial lipopolysaccharide (LPS, 4 mg/kg ip) or vehicle (pyrogen-free water). Later (30 min), animals received the MMP inhibitor doxycycline (4 mg/kg ip) or vehicle (pyrogen-free water). After LPS injection (6 h), animals were killed, and aortas were excised. Aortic rings were mounted in organ baths, and contractile responses to phenylephrine or KCl were measured. Aortas and plasma were examined for MMP activity by gelatin zymography. Aortic MMP and inducible nitric oxide synthase (iNOS) were examined by immunoblot and/or immunohistochemistry. Doxycycline prevented the LPS-induced development of ex vivo vascular hyporeactivity to phenylephrine and KCl. iNOS protein was significantly upregulated in aortic homogenates from endotoxemic rats; doxycycline did not alter its level. MMP-9 activity was undetectable in aortic homogenates from LPS-treated rats but significantly upregulated in the plasma; this was attenuated by doxycycline. Plasma MMP-2 activities were unchanged by LPS. Specific MMP-2 activity was increased in aortas from LPS-treated rats. This study demonstrates the in vivo protective effect of the MMP inhibitor doxycycline against the development of vascular hyporeactivity in endotoxemic rats.
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PMID:Inhibition of matrix metalloproteinase activity in vivo protects against vascular hyporeactivity in endotoxemia. 1983 53

Previous studies demonstrated that hepatic matrix metalloproteinase-9 (MMP-9) activity increased following cecal ligation and puncture (CLP) in rats, indicating liver injury in sepsis. The activity of MMP-9 in degrading extracellular matrix is controlled by activation of proenzymes and inhibition of tissue inhibitor of MMPs (TIMP-1). To further assess the proteolytic cascade imbalance in sepsis, hepatic MMP-9 and TIMP-1 expressions were examined in CLP rats. In this study, sepsis was induced in rats by CLP, and at 10 and 20 h after sepsis induction, liver samples were collected and MMP-2, MMP-9, and TIMP-1 gene and protein expressions were evaluated by real time PCR and Western blot analysis, respectively. Gene expression of MMP-9 was increased by 6.4-fold and 3.0-fold at 10 h and 20 h after CLP as compared to sham group, respectively. Likewise, MMP-9 protein expression was also significantly increased at both time points. In contrast, MMP-2 gene expression was not altered at 10 h and 20 h after CLP as compared to sham controls. Interestingly, TIMP-1 gene expression was elevated to 89-fold and 46-fold from sham levels at 10 h and 20 h after CLP, respectively. Similarly, TIMP-1 protein levels were also significantly increased at both time points. In addition, MMP-9/TIMP-1 protein ratio was lower at both 10 h and 20 h after CLP compared to sham rats. Results demonstrated an imbalance between MMP and TIMP, with a more evident role for MMP-9 than MMP-2, and high value of TIMP-1 was particularly evident in CLP rats. Our results indicate that MMP-9 and TIMP-1 expressions are increased and they may serve as useful markers to predict the outcome of sepsis.
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PMID:Modulation of matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 in sepsis. 2082 15

There is no description on the mechanisms associated with blood-brain barrier (BBB) disruption during sepsis development. Thus, we here determined changes in permeability of the BBB in an animal model of severe sepsis and the role of matrix metalloproteinase (MMP)-2 and MMP-9 in the dysfunction of the BBB. Sepsis was induced in Wistar rats by cecal ligation and perforation. BBB permeability was assessed using the Evans blue dye method. The content of MMP-2 and MMP-9 in the cerebral microvessels was determined by western blot. The activity of MMP-2 and MMP-9 was determined using zymography. An inhibitor of MMP-2 and MMP-9 or specific inhibitors of MMP-2 or MMP-9 were administered to define the role of MMPs on BBB permeability, brain inflammatory response, and sepsis-induced cognitive alterations. The increase of BBB permeability is time-related to the increase of MMP-9 and MMP-2 in the microvessels, both in cortex and hippocampus. Using an MMP-2 and MMP-9 inhibitor, or specific MMP-2 or MMP-9 inhibitors, the increase in the permeability of the BBB was reversed. This was associated with lower brain levels of interleukin (IL)-6 and lower oxidative damage. In contrast, only the inhibition of both MMP-9 and MMP-2 was able to improve acute cognitive alterations associated with sepsis. In conclusion, MMP-2 and MMP-9 activation seems to be a major step in BBB dysfunction, but BBB dysfunction seems not to be associated with acute cognitive dysfunction during sepsis development.
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PMID:Matrix metalloproteinase-2 and metalloproteinase-9 activities are associated with blood-brain barrier dysfunction in an animal model of severe sepsis. 2347 97


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