Assessment of Matrix Metalloproteinases-1 in Septic Acute Respiratory Distress Syndrome: A Report of Two Cases (original) (raw)
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Lack of matrix metalloproteinase-9 worsens ventilator-induced lung injury
2008
Matrix metalloproteinase-9 (MMP-9) is released by neutrophils at the sites of acute inflammation. This enzyme modulates matrix turnover and inflammatory response and its activity has been found increased after ventilator-induced lung injury. To clarify the role of MMP-9, mice lacking this enzyme and their wildtype counterparts were ventilated for two hours with high or low peak inspiratory pressures (25 and 15 cmH 2 O, respectively). Lung injury was evaluated by gas exchange, respiratory mechanics, wet-to-dry weight ratio and histologic analysis. The activity of MMP-9 and levels of interleukin-1 , interleukin-4 and macrophage inflammatory protein (MIP-2) were measured in lung tissue and bronchoalveolar lavage fluid (BALF). Cell count and myeloperoxidase activity were measured in BALF. There were no differences between wildtype and Mmp-9 -/animals after low-pressure ventilation. After high pressure ventilation, wildtype mice exhibited an increase in MMP-9 in tissue and BALF. Mice lacking MMP-9 developed more severe lung injury than wildtype mice, in terms of impaired oxygenation and lung mechanics, and higher damage in the histological study. These effects correlated with an increase in both cell count and myeloperoxidase activity in the BALF, suggesting an increased neutrophilic influx in response to ventilation. An increase in IL-1 and IL-4 in the BALF only in knockout mice could be responsible for the differences. There were no differences between genotypes in MMP-2, MMP-8 or tissue inhibitors of metalloproteinases.
Veterinary Research Communications, 2009
IntroductionMatrix metalloproteinases (MMPs) are zinc-dependent endopeptidases, mainly known for their ability to degrade various proteins of the cellular matrix (ECM), including proteoglycans and collagen. The expression of MMPs is crucial in many pathological events, and also plays significant roles in a number of physiological processes, such as remodeling of ECM, degradation of type IV collagen in the basement membrane and migration of leucocytes during immune response (Kobayashi et al., 1999).MMPs have been traditionally thought of an enzymes involved in long term remodelling processes, However they are now understood to act also acutely modulating early cellular response in cardiovascular diseases (Chow et al., 2007). The MMPs are synthesized and secreted in an enzymatically inactive form (zymogen, proMMP) by macrophages and fibroblasts. ProMMP activation requires the enzymatic dissociation of the binding between a pro-peptide in a specific domain in response to different factors ...
Dynamic changes of matrix metalloproteinases and their tissue inhibitors in severe sepsis
Journal of Critical Care, 2011
Purpose: Little is known about the dynamic changes of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in sepsis. Our aim was therefore to investigate the time course of MMPs and their inhibitors in patients experiencing severe sepsis. Methods: Our prospective controlled analysis included 38 patients with severe sepsis. Plasma levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured daily at a 5-day-long period with enzyme-linked immunosorbent assay. Seventeen healthy volunteers were invited as controls. Results: MMP-2 showed no difference compared to controls, whereas significantly elevated MMP-9 levels were detected on admission (P b .005). Significantly elevated but declining TIMP-1 levels were measured during the whole trial (P b .002-.004). Except for the second day, TIMP-2 levels were significantly lower than controls (P b .05-.009). MMP2/TIMP-1 ratios were significantly lower in septic patients (P b .03-.006), whereas MMP-2/TIMP-2 ratios were elevated throughout our study (P b .03-.006). MMP-9/TIMP-1 ratios were significantly lower at the first 3 days (P b .05-.008). MMP-9/TIMP-2 was significantly elevated on admission (P b .006). Conclusions: Our research is the first follow-up study dealing with MMPs, TIMPs, and their ratios in severe sepsis. Our results indicate that MMPs and TIMPs may play a crucial role in severe sepsis, especially TIMP-1, MMP-9, and possibly TIMP-2, after an extensive study.
Absence or Inhibition of Matrix Metalloproteinase–8 Decreases Ventilator-Induced Lung Injury
American Journal of Respiratory Cell and Molecular Biology, 2010
Mechanical ventilation is a life-saving therapy that can also damage the lungs. Ventilator-induced lung injury (VILI) promotes inflammation and up-regulates matrix metalloproteinases (MMPs). Among these enzymes, MMP-8 is involved in the onset of inflammation by processing different immune mediators. To clarify the role of MMP-8 in a model of VILI and their relevance as a therapeutic target, we ventilated wild-type and MMP-8-deficient mice with low or high pressures for 2 hours. There were no significant differences after low-pressure ventilation between wild-type and knockout animals. However, lack of MMP-8 results in better gas exchange, decreased lung edema and permeability, and diminished histological injury after high-pressure ventilation. Mmp8 2/2 mice had a different immune response to injurious ventilation, with decreased neutrophilic infiltration, lower levels of IFN-g and chemokines (LPS-induced CXC chemokine, macrophage inflammatory protein-2), and significant increases in anti-inflammatory cytokines (IL-4, IL-10) in lung tissue and bronchoalveolar lavage fluid. There were no differences in MMP-2, MMP-9, or tissue inhibitor of metalloproteinase-1 between wild-type and knockout mice. These results were confirmed by showing a similar protective effect in wild-type mice treated with a selective MMP-8 inhibitor. We conclude that MMP-8 promotes acute inflammation after ventilation with high pressures, and its short-term inhibition could be a therapeutic goal to limit VILI.
Critical Care, 2009
Introduction Matrix metalloproteinases (MMPs) play a role in infectious diseases through extracellular matrix (ECM) degradation, which favors the migration of immune cells from the bloodstream to sites of inflammation. Although higher levels of MMP-9 and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) have been found in small series of patients with sepsis, MMP-10 levels have not been studied in this setting. The objective of this study was to determine the predictive value of MMP-9, MMP-10, and TIMP-1 on clinical severity and mortality in a large series of patients with severe sepsis.
Metalloproteinase Inhibition Prevents Acute Respiratory Distress Syndrome
The Journal of Surgical Research, 2001
Background. The acute respiratory distress syndrome (ARDS) occurs in patients with clearly identifiable risk factors, and its treatment remains merely supportive. We postulated that patients at risk for ARDS can be protected against lung injury by a prophylactic treatment strategy that targets neutrophilderived proteases. We hypothesized that a chemically modified tetracycline 3 (COL-3), a potent inhibitor of neutrophil matrix metalloproteinases (MMPs) and neutrophil elastase (NE) with minimal toxicity, would prevent ARDS in our porcine endotoxin-induced ARDS model.
A novel role for matrix metalloproteinase-8 in sepsis*
Critical Care Medicine, 2012
Objectives-Matrix metalloproteinase-8 (MMP-8) mRNA expression was previously found to be increased in whole blood of children with septic shock. The impact of this finding on the severity and inflammatory response to sepsis is unknown. Here, we investigate the relationship between MMP-8 and disease severity in a children with septic shock. We further corroborate the role of MMP-8 in sepsis in a murine model. Design-Retrospective observational clinical study and randomized controlled laboratory experiments. Setting-Pediatric intensive care units and an animal research facility at an academic children's hospital. Patients/Subjects-Patients age ≤ 10 years admitted to the intensive care unit with a diagnosis of septic shock. For laboratory studies, we utilized male mice deficient for MMP-8 and male wild type C57/Bl6 mice. Interventions-Blood from children with septic shock was analyzed for MMP-8 mRNA expression and MMP-8 activity, and correlated with disease severity based on mortality and degree of organ failure. A murine model of sepsis was used to explore the effect of genetic and pharmacologic inhibition of MMP-8 on the inflammatory response to sepsis. Finally, activation of nuclear factor-κB (NF-κB) was assessed both in vitro and in vivo. Measurements and Main Results-Increased MMP-8 mRNA expression and activity in septic shock correlates with decreased survival and increased organ failure in pediatric patients. Genetic and pharmacologic inhibition of MMP-8 leads to improved survival and a blunted inflammatory profile in a murine model of sepsis. We also identify MMP-8 as a direct in vitro activator of the pro-inflammatory transcription factor, NF-κB. Conclusions-MMP-8 is a novel modulator of inflammation during sepsis and a potential therapeutic target.
The Tohoku Journal of Experimental Medicine, 2015
Sepsis-associated acute kidney injury (SA-AKI) severely impacts morbidity and mortality in surgical patients with sepsis. Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) have an important role in pathophysiology of sepsis but they have been unexplored in SA-AKI. We aimed to investigate the role of MMP-9 and TIMP-1 in septic surgical patients with SA-AKI and to evaluate them as diagnostic biomarkers of SA-AKI. This prospective observational study compared 53 major abdominal surgery patients with sepsis divided into SA-AKI (n = 37) and non-SA-AKI (n =16) group to 50 controls without sepsis matched by age, gender, comorbidities and type of surgery. Blood and urine samples from septic patients were collected on admission to ICU and 24, 48, 72 and 96 h later and once from the controls. The levels of MMP-9, TIMP-1, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1, urea and creatinine were measured. MMP-9/TIMP-1 ratio and disease severity scores, such as Sequential Organ Failure Assessment (SOFA), were calculated. Septic patients with SA-AKI had higher serum TIMP-1 levels and lower serum MMP-9 levels and lower MMP-9/TIMP ratio, compared to septic patients without SA-AKI and controls. The levels of these biomarkers did not change significantly over time. MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio correlated with urea, creatinine, NGAL, and SOFA scores. Moreover, using the area under ROC curve, we showed that TIMP-1 and MMP-9/TIMP-1 ratio, but not MMP-9, were good diagnostic biomarkers of SA-AKI. We report for the first time the potential diagnostic value of TIMP-1 and MMP-9/TIMP-1 ratio in SA-AKI.