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1.
Nikolaos A Maniatis Eleftheria Letsiou Stylianos E Orfanos Matina Kardara Ioanna Dimopoulou Georgios Nakos Marilena E Lekka Charalambos Roussos Apostolos Armaganidis Anastasia Kotanidou 《Critical care (London, England)》2010,14(2):R70
Introduction
Activated Protein C (APC), an endogenous anticoagulant, improves tissue microperfusion and endothelial cell survival in systemic inflammatory states such as sepsis, but intravenous administration may cause severe bleeding. We have thus addressed the role of APC delivered locally by inhalation in preventing acute lung injury from alveolar overdistention and the subsequent ventilator-induced lung injury (VILI). We also assessed the effects of APC on the activation status of Extracellular- Regulated Kinase 1/2 (ERK) pathway, which has been shown to be involved in regulating pulmonary responses to mechanical stretch. 相似文献2.
Pérez-Casal M Thompson V Downey C Welters I Wyncoll D Thachil J Toh CH 《Critical care (London, England)》2011,15(4):R195-11
Introduction
Activated protein C (APC) induces release of microparticles (MP) from primary physiological cells, which are found in patients undergoing treatment with recombinant human APC (rhAPC) for severe sepsis. We hypothesised that APC on these circulating MPs activate endothelial protease-activated receptor 1 (PAR1) to induce anti-apoptotic and anti-inflammatory properties that can improve patient outcome. 相似文献3.
Yung-Yang Liu Cheng-Hung Lee Rejmon Dedaj Hang Zhao Hicham Mrabat Aviva Sheidlin Olga Syrkina Pei-Ming Huang Hari G Garg Charles A Hales Deborah A Quinn 《Critical care (London, England)》2008,12(4):1-11
Introduction
Mechanical ventilation with even moderate-sized tidal volumes synergistically increases lung injury in sepsis and has been associated with proinflammatory low-molecular-weight hyaluronan production. High-molecular-weight hyaluronan (HMW HA), in contrast, has been found to be anti-inflammatory. We hypothesized that HMW HA would inhibit lung injury associated with sepsis and mechanical ventilation.Methods
Sprague–Dawley rats were randomly divided into four groups: nonventilated control rats; mechanical ventilation plus lipopolysaccharide (LPS) infusion as a model of sepsis; mechanical ventilation plus LPS with HMW HA (1,600 kDa) pretreatment; and mechanical ventilation plus LPS with low-molecular-weight hyaluronan (35 kDa) pretreatment. Rats were mechanically ventilated with low (7 ml/kg) tidal volumes. LPS (1 or 3 mg/kg) or normal saline was infused 1 hour prior to mechanical ventilation. Animals received HMW HA or low-molecular-weight hyaluronan via the intraperitoneal route 18 hours prior to the study or received HMW HA (0.025%, 0.05% or 0.1%) intravenously 1 hour after injection of LPS. After 4 hours of ventilation, animals were sacrificed and the lung neutrophil and monocyte infiltration, the cytokine production, and the lung pathology score were measured.Results
LPS induced lung neutrophil infiltration, macrophage inflammatory protein-2 and TNFα mRNA and protein, which were decreased in the presence of both 1,600 kDa and 35 kDa hyaluronan pretreatment. Only 1,600 kDa hyaluronan completely blocked both monocyte and neutrophil infiltration and decreased the lung injury. When infused intravenously 1 hour after LPS, 1,600 kDa hyaluronan inhibited lung neutrophil infiltration, macrophage inflammatory protein-2 mRNA expression and lung injury in a dose-dependent manner. The beneficial effects of hyaluronan were partially dependent on the positive charge of the compound.Conclusions
HMW HA may prove to be an effective treatment strategy for sepsis-induced lung injury with mechanical ventilation. 相似文献4.
Cintia Tokio Reis Gon?alves Carlos Gustavo Reis Gon?alves Francine Maria de Almeida Fernanda Degobi Tenório Quirino dos Santos Lopes Ana Carolina Cardoso dos Santos Dur?o Fabiana Almeida dos Santos Luiz Fernando Ferraz da Silva Tania Marcourakis Hugo C Castro-Faria-Neto Rodolfo de Paula Vieira Marisa Dolhnikoff 《Critical care (London, England)》2012,16(5):R199
Introduction
The regular practice of physical exercise has been associated with beneficial effects on various pulmonary conditions. We investigated the mechanisms involved in the protective effect of exercise in a model of lipopolysaccharide (LPS)-induced acute lung injury (ALI).Methods
Mice were divided into four groups: Control (CTR), Exercise (Exe), LPS, and Exercise + LPS (Exe + LPS). Exercised mice were trained using low intensity daily exercise for five weeks. LPS and Exe + LPS mice received 200 µg of LPS intratracheally 48 hours after the last physical test. We measured exhaled nitric oxide (eNO); respiratory mechanics; neutrophil density in lung tissue; protein leakage; bronchoalveolar lavage fluid (BALF) cell counts; cytokine levels in BALF, plasma and lung tissue; antioxidant activity in lung tissue; and tissue expression of glucocorticoid receptors (Gre).Results
LPS instillation resulted in increased eNO, neutrophils in BALF and tissue, pulmonary resistance and elastance, protein leakage, TNF-alpha in lung tissue, plasma levels of IL-6 and IL-10, and IL-1beta, IL-6 and KC levels in BALF compared to CTR (P ≤0.02). Aerobic exercise resulted in decreases in eNO levels, neutrophil density and TNF-alpha expression in lung tissue, pulmonary resistance and elastance, and increased the levels of IL-6, IL-10, superoxide dismutase (SOD-2) and Gre in lung tissue and IL-1beta in BALF compared to the LPS group (P ≤0.04).Conclusions
Aerobic exercise plays important roles in protecting the lungs from the inflammatory effects of LPS-induced ALI. The effects of exercise are mainly mediated by the expression of anti-inflammatory cytokines and antioxidants, suggesting that exercise can modulate the inflammatory-anti-inflammatory and the oxidative-antioxidative balance in the early phase of ALI. 相似文献5.
BACKGROUND:
In cases of severe sepsis and septic shock, a series of pathophysiological changes lead to multiple organ dysfunction syndrome. This study aimed to investigate the expression of glucocorticoid receptor mRNA in the rat lung following endotoxin (LPS) induced shock.METHODS:
Totally 56 SD rats were randomly divided into 4 groups: LPS shock group (n=16), LPS+vasoactive intestinal peptide group(VIP) group, (n=16), LPS+VIP+ glucocorticoid (GC) group, (n=16),and control group (n=8). LPS shock was induced by intravenous injection of LPS (10 mg/kg) in rats. Within 15 minutes after LPS injection, rats in the treatment groups received VIP (5 nmol/kg) or VIP and methylprednisolone (3 mg/kg). The control group was given normal saline instead of LPS. The rats of the four groups were sacrificed at 6 hours,24 hours after injection respectively, and the lung tissues were collected. Pathological changes of the lungs were examined by light microscopy and electron microscopy. GRmRNA expression in the lung tissues was evaluated by RT-PCR.RESULTS:
In the LPS shock group, lung histopathology demonstrated destruction of the alveolar space,widening of the inter-alveolar space, inflammatory cell infiltration and interstitial edema. However,pathological changes in the LPS+ VIP group and LPS+ VIP+GC group were milder than those in the LPS shock group. Six hours after LPS injection, GR mRNA expression was down-regulated in the LPS group (0.72± 0.24) and LPS+ VIP group (0.88±0.27) (P<0.05) as compared with the control group (1.17±0.22). The LPS shock group showed a more significant down-regualtion than the LPS+VIP group, but the difference was not statistically significant (P>0.05). In contrast, GRmRNA expression in the LPS+ VIP+GC group was significantly up-regulated at 6 hours and further at 24 hours (1.45±0.32 and 1.91±0.46 respectively) (P<0.05).CONCLUSION:
GrmRNA expression decreased in LPS induced lung injury in rats. Combined treatment with VIP and GC mitigated lung injury ang inflammation. The mechanism may be related to up-regulation of GR mRNA expression.KEY WORDS: Glucocorticoid, GRmRNA, Vasoactive intestinal peptide, LPS, Shock, Inflammation, Lung injury, Rat 相似文献6.
Rosanna Vaschetto René JP Musters Etto C Eringa Francesco Della Corte Kanneganti Murthy AB Johan Groeneveld Frans B Plötz 《Critical care (London, England)》2010,14(2):R45
Introduction
Mechanical ventilation (MV) can injure the lungs and contribute to an overwhelming inflammatory response, leading to acute renal failure (ARF). We previously showed that poly(adenosine diphosphate-ribose) polymerase (PARP) is involved in the development of ventilator-induced lung injury (VILI) and the related ARF, but the mechanisms underneath remain unclear. In the current study we therefore tested the hypothesis that renal blood flow and endothelial, functional and tissue changes in the kidney of rats with lipopolysaccharide (LPS)-induced lung injury aggravated by MV, is caused, in part, by activation of PARP by peroxynitrite. 相似文献7.
Ville Pettilä Lea Kyhälä Marja-Leena Kylänpää Ari Leppäniemi Minna Tallgren Antti Markkola Pauli Puolakkainen Heikki Repo Esko Kemppainen 《Critical care (London, England)》2010,14(4):R139
Introduction
Previous human studies have shown low activity of protein C (APC) in severe acute pancreatitis (SAP). This, together with the findings in animal models, suggests that activated protein C (APC) may protect against pancreatic injury and ameliorate the disease. We, therefore, evaluated its effect on multiple organ dysfunction (MOD) measured by the SOFA (Sequential Organ Failure Assessment) and on organ-failure-free days, and the safety of APC in SAP. 相似文献8.
Dempfle CE Elmas E Link A Suvajac N Liebe V Janes J Borggrefe M 《Critical care (London, England)》2011,15(1):R23
Introduction
There are no published data on the status of endogenous activated protein C (APC) in pulmonary embolism (PE), and no data on the effect of drotrecogin alfa (activated) (DAA) given in addition to therapeutic dose enoxaparin. 相似文献9.
BACKGROUND:
Myeloid cell (TREM-1) is an important mediator of the signal transduction pathway in inflammatory response. In this study, a mouse model of acute lung injury (ALI) by intraperitoneal injection of lipopolysaccharide (LPS) was established to observe the expression pattern of TREM-1 in lung tissue and the role of TREM-1 in pulmonary inflammatory response to ALI.METHODS:
Thirty BALB/C mice were randomly divided into a normal control group (n=6) and an ALI group (n=24). The model of ALI was made by intraperitonal injection of LPS in dose of 10 mg/kg. Specimens from peripheral blood and lung tissue were collected 6, 12, 24 and 48 hours after LPS injection. RT-PCR was used to detect TREM-1 mRNA, and ELISA was employed for detection of TREM-1 protein and TNF-a protein, and HE staining was performed for the pathological Smith lung scoring under a light microscope.RESULTS:
The expressions of TREM-1 mRNA in lung tissue and blood of the ALI group 6, 12, 24, and 48 hours after injection of LPS were higher than those in the control group. The levels of TREM-1 protein and the levels of TNF-a protein in lung tissue of the ALI group 6, 12, 24, and 48 hours after LPS injection were higher than those of the control group; the level of TREM-1 protein peaked 12 hours after LPS injection, but it was not significantly correlated with the expression of TREM-1 mRNA (P=0.14); the TNF-a concentration was positively correlated with TREM-1 levels in lung tissue and with Smith pathological score (r=0.795, P=0.001:r=0.499, P=0.034), but not with the expression of TREM-1 mRNA (P=0.176).CONCLUSIONS:
The expression of TREM-1 mRNA in lung tissue of mice with ALI is elevated, and the expression of TREM-1 mRNA is related to the level of TNF-a and the severity of inflammatory response to ALI. The expressions of the TREM-1 gene are not consistent with the levels of TREM-1 protein, suggesting a new functional protein involved in immune regulation.KEY WORDS: Acute lung injury, Triggering receptor-1, Myeloid cell, Expression, Tumor necrosis factor, Pathological scoring 相似文献10.
Hagiwara S Iwasaka H Hidaka S Hishiyama S Noguchi T 《Critical care (London, England)》2008,12(2):R43-8
Introduction
Systemic inflammatory mediators, including high mobility group box 1 (HMGB1), play an important role in the development of sepsis. Anticoagulants, such as danaparoid sodium (DA), may be able to inhibit sepsis-induced inflammation, but the mechanism of action is not well understood. We hypothesised that DA would act as an inhibitor of systemic inflammation and prevent endotoxin-induced acute lung injury in a rat model.Methods
We used male Wistar rats. Animals in the intervention arm received a bolus of 50 U/kg of DA or saline injected into the tail vein after lipopolysaccharide (LPS) administration. We measured cytokine (tumour necrosis factor (TNF)α, interleukin (IL)-6 and IL-10) and HMGB1 levels in serum and lung tissue at regular intervals for 12 h following LPS injection. The mouse macrophage cell line RAW 264.7 was assessed following stimulation with LPS alone or concurrently with DA with identification of HMGB1 and other cytokines in the supernatant.Results
Survival was significantly higher and lung histopathology significantly improved among the DA (50 U/kg) animals compared to the control rats. The serum and lung HMGB1 levels were lower over time among DA-treated animals. In the in vitro study, administration of DA was associated with decreased production of HMGB1. In the cell signalling studies, DA administration inhibited the phosphorylation of IκB.Conclusion
DA decreases cytokine and HMGB1 levels during LPS-induced inflammation. As a result, DA ameliorated lung pathology and reduces mortality in endotoxin-induced systemic inflammation in a rat model. This effect may be mediated through the inhibition of cytokines and HMGB1. 相似文献11.
Upregulated but insufficient generation of activated protein C is associated with development of multiorgan failure in severe acute pancreatitis
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Introduction
Disturbed protein C (PC) pathway homeostasis might contribute to the development of multiple organ failure (MOF) in acute pancreatitis (AP). We therefore evaluated circulating levels of PC and activated protein C (APC), evaluated monocyte deactivation in AP patients, and determined the relationship of these parameters to MOF. 相似文献12.
In Kyoung Kim Chin Kook Rhee Chang Dong Yeo Hyeon Hui Kang Dong Gun Lee Sang Haak Lee Jin Woo Kim 《Critical care (London, England)》2013,17(3):R114
Introduction
Neutrophil recovery has been implicated in deterioration of oxygenation and exacerbation of preexisting acute lung injury (ALI). The aim of this study was to investigate whether imatinib or nilotinib was effective on lipopolysaccharide (LPS)-induced ALI during neutropenia recovery in mice.Methods
Mice were rendered neutropenic with cyclophosphamide prior to the intratracheal instillation of LPS. Imatinib or nilotinib was administrated by oral gavage during neutropenia recovery. In order to study the effects of drugs, mice were killed on day 5 and blood, bronchoalveolar lavage (BAL) fluid and lung tissue samples were obtained. The lung wet/dry weight ratio and protein levels in the BAL fluid or lung tissue were determined.Results
Treatment with imatinib or nilotinib significantly attenuated the LPS-induced pulmonary edema, and this result was supported by the histopathological examination. The concentrations of tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and myeloperoxidase in BAL fluid were significantly inhibited by imatinib or nilotinib in mice of ALI during neutropenia recovery. The mRNA expressions of platelet-derived growth factor receptor-β and c-KIT in imatinib or nilotinib group were significantly lower than LPS group.Conclusions
Our data indicated that imatinib or nilotinib effectively attenuated LPS-induced ALI during neutropenia recovery. These results provide evidence for the therapeutic potential of imatinib and nilotinib in ALI during neutropenia recovery. 相似文献13.
Olivier Joulin Sylvestre Marechaux Sidi Hassoun David Montaigne Steve Lancel Remi Neviere 《Critical care (London, England)》2009,13(1):R14-10
Introduction
Frequency-dependent acceleration of relaxation (FDAR) ensures appropriate ventricular filling at high heart rates and results from accelerated sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) activity independent of calcium removal from the cell. Because lipopolysaccharide (LPS) challenge may induce aberrations in calcium trafficking and protein phosphorylation, we tested whether LPS would abolish FDAR in rats. 相似文献14.
Yann K. Pittet Mette M. Berger Thomas-Thi Pluess Pierre Voirol Jean-Pierre Revelly Luc Tappy René L. Chioléro 《Intensive care medicine》2010,36(2):289-295
Objective
To test the dose response effect of infused fish oil (FO) rich in n-3 PUFAs on the inflammatory response to endotoxin (LPS) and on membrane incorporation of fatty acids in healthy subjects. 相似文献15.
Purpose
To investigate differences in cytokine/chemokine release in response to lipoteichoic acid (LTA) or lipopolysaccharide (LPS) and contributing cellular mechanisms, in order to improve understanding of the pathogenesis of sepsis. 相似文献16.
Bouazza Y Sennoun N Strub C Regnault V Gibot S Meziani F Lacolley P Levy B 《Intensive care medicine》2011,37(11):1857-1864
Purpose
To compare the effects of recombinant human activated protein C (APC) and glucocorticoids alone and in combination in non-anesthetized resuscitated septic shock induced by cecal ligation and puncture (CLP) on (a) survival, (b) hemodynamics, and (c) vascular reactivity. The effects of treatments on major cellular pathways likely implicated were also studied. 相似文献17.
José F Solsona Yolanda Díaz Antonia Vázquez Maria Pilar Gracia Ana Zapatero Jaume Marrugat 《Critical care (London, England)》2009,13(2):1-9
Introduction
In acute lung injury, repair of the damaged alveolar-capillary barrier is an essential part of recovery. Endostatin is a 20 to 28 kDa proteolytic fragment of the basement membrane collagen XVIII, which has been shown to inhibit angiogenesis via action on endothelial cells. We hypothesised that endostatin may have a role in inhibiting lung repair in patients with lung injury. The aims of the study were to determine if endostatin is elevated in the plasma/bronchoalveolar lavage fluid of patients with acute lung injury and ascertain whether the levels reflect the severity of injury and alveolar inflammation, and to assess if endostatin changes occur early after the injurious lung stimuli of one lung ventilation and lipopolysaccharide (LPS) challenge.Methods
Endostatin was measured by ELISA and western blotting.Results
Endostatin is elevated within the plasma and bronchoalveolar lavage fluid of patients with acute lung injury. Lavage endostatin reflected the degree of alveolar neutrophilia and the extent of the loss of protein selectivity of the alveolar-capillary barrier. Plasma levels of endostatin correlated with the severity of physiological derangement. Western blotting confirmed elevated type XVIII collagen precursor levels in the plasma and lavage and multiple endostatin-like fragments in the lavage of patients. One lung ventilation and LPS challenge rapidly induce increases in lung endostatin levels.Conclusions
Endostatin may adversely affect both alveolar barrier endothelial and epithelial cells, so its presence within both the circulation and the lung may have a pathophysiological role in acute lung injury that warrants further evaluation. 相似文献18.
Gavin D Perkins Nazim Nathani Alex G Richter Daniel Park Murali Shyamsundar Ritva Heljasvaara Taina Pihlajaniemi Mav Manji W Tunnicliffe Danny McAuley Fang Gao David R Thickett 《Critical care (London, England)》2009,13(2):R52
Introduction
In acute lung injury, repair of the damaged alveolar-capillary barrier is an essential part of recovery. Endostatin is a 20 to 28 kDa proteolytic fragment of the basement membrane collagen XVIII, which has been shown to inhibit angiogenesis via action on endothelial cells. We hypothesised that endostatin may have a role in inhibiting lung repair in patients with lung injury. The aims of the study were to determine if endostatin is elevated in the plasma/bronchoalveolar lavage fluid of patients with acute lung injury and ascertain whether the levels reflect the severity of injury and alveolar inflammation, and to assess if endostatin changes occur early after the injurious lung stimuli of one lung ventilation and lipopolysaccharide (LPS) challenge.Methods
Endostatin was measured by ELISA and western blotting.Results
Endostatin is elevated within the plasma and bronchoalveolar lavage fluid of patients with acute lung injury. Lavage endostatin reflected the degree of alveolar neutrophilia and the extent of the loss of protein selectivity of the alveolar-capillary barrier. Plasma levels of endostatin correlated with the severity of physiological derangement. Western blotting confirmed elevated type XVIII collagen precursor levels in the plasma and lavage and multiple endostatin-like fragments in the lavage of patients. One lung ventilation and LPS challenge rapidly induce increases in lung endostatin levels.Conclusions
Endostatin may adversely affect both alveolar barrier endothelial and epithelial cells, so its presence within both the circulation and the lung may have a pathophysiological role in acute lung injury that warrants further evaluation. 相似文献19.
Background
Activated protein C (APC) inhibits coagulation by degrading activated factor V (FVa) and factor VIII (FVIIIa), protein S (PS) functioning as a cofactor to APC.Methods
By mutagenesis of the vitamin K-dependent Gla domain of APC, we have recently created an APC variant having enhanced anticoagulant activity due to increased affinity for negatively charged phospholipid membranes. In the present study, the potential antithrombotic effects of this APC variant, and of a variant APC that is additionally mutated in the serine protease domain, have been evaluated in a blind randomized study in a rat model of arterial thrombosis. In this model, we have previously found the combination of bovine APC and PS to be highly antithrombotic. Four treatment groups each containing 10 rats were, in a blind random fashion, given intravenous bolus injections of wild-type or mutant variants of APC (0.8 mg/kg) together with human PS (0.6 mg/kg) or human PS (0.6 mg/kg) alone. A control group with 20 animals where given vehicle only.Results
A trend to increased patency rates was noted in a group receiving one of the APC variants, but it did not reach statistical significance.Conclusion
In conclusion, administration of human APC variants having enhanced anticoagulant efficacy together with human PS in a rat model of arterial thrombosis did not give an efficient antithrombotic effect. The lack of effect may be due to species-specific differences between the human protein C system and the rat hemostatic system. 相似文献20.
Takuro Arishima Takashi Ito Tomotsugu Yasuda Nozomi Yashima Hiroaki Furubeppu Chinatsu Kamikokuryo Takahiro Futatsuki Yutaro Madokoro Shotaro Miyamoto Tomohiro Eguchi Hiroyuki Haraura Ikuro Maruyama Yasuyuki Kakihana 《Thrombosis journal》2018,16(1):24