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1. |
APPLICATION OF GENE THERAPY TO ACUTE INFLAMMATORY DISEASES |
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Shock,
Volume 12,
Issue 2,
1999,
Page 83-101
Lyle Moldawer,
Paul Edwards,
Michael Josephs,
Rebecca Minter,
Edward Copeland,
Sally MacKay,
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摘要:
The application of gene therapy to acute inflammation has not received as much research attention as has the treatment of genetically-based diseases, cancer, and viral infections. However, gene therapy as a drug delivery system offers several theoretical and practical advantages over current protein delivery systems. These include the ability to target therapies to individual tissues or cell types, to locally produce proteins that can act intracellularly or in an autocrine, juxtacrine, or paracrine fashion, and to sustain new protein synthesis for periods up to several weeks after a single administration. Although retrovirus, herpes simplex, and adeno-associated virus have been proposed for gene therapy in cancer and in genetic diseases, nonviral and adenovirus approaches appear most applicable as drug delivery systems due to their rapid onset and short duration of transgene expression. The relative modest transduction efficiencies obtained at present with nonviral approaches, and the inherent inflammatory properties of first-generation adenovirus constructs, however, have limited their usefulness to date. The present review discusses the theoretical and practical benefits of specific gene therapy approaches for the treatment of acute inflammatory diseases, as well as our experiences with liposome:plasmid DNA and adenovirus-based approaches. Although a number of technical and theoretical hurdles remain before it can be evaluated in humans with acute inflammation, gene therapy offers a novel approach for the treatment of acute inflammation, and will likely enter the armamentarium of critical care physicians in the near future.
ISSN:1073-2322
出版商:OVID
年代:1999
数据来源: OVID
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2. |
PLASMA GELSOLIN IS REDUCED IN TRAUMA PATIENTS |
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Shock,
Volume 12,
Issue 2,
1999,
Page 102-104
Benny Dahl,
Frank Schiødt,
Peter Ott,
Robert Gvozdenovic,
Helen Yin,
William Lee,
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摘要:
Tissue injury results in the release of the intracellular protein actin which is cleared from the circulation by the plasma proteins gelsolin and Gc-globulin, constituting the Extracellular Actin Scavenger System (EASS). Experimental studies have shown that excessive amounts of actin in the circulation can lead to a condition resembling multiple organ dysfunction syndrome (MODS), and we have previously demonstrated that the level of Gc-globulin is decreased after severe trauma. The purpose of the present study was to determine whether the plasma levels of gelsolin were altered in the early phase after trauma. Twenty-three consecutive trauma patients were studied. Plasma samples were assayed for gelsolin by immunonephelometry with polyclonal rabbit antihuman gelsolin prepared in our own laboratory. The median time from injury until the time the first blood sample was taken was 52 min (range 20–110) and the median Injury Severity Score (ISS) was 20 (range 4–50). The gelsolin level on admission was reduced significantly in the trauma patients compared with normal controls. The median level was 51 mg/L (7–967) vs. 207 mg/L (151–621),P< 0.0001. There was no correlation between admission levels of gelsolin and ISS or survival. This study illustrates that the plasma concentration of gelsolin is significantly diminished immediately after traumatic injury. Further studies are necessary to establish a role for gelsolin or EASS in the development of MODS in trauma patients. The level of serum or plasma gelsolin can be determined rapidly and accurately using a nephelometric assay.
ISSN:1073-2322
出版商:OVID
年代:1999
数据来源: OVID
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3. |
PROTECTIVE EFFECT OF TYRPHOSTIN AG‐556 ON SHOCK INDUCED BY ENDOTOXIN OR GRAM POSITIVE BACTERIA |
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Shock,
Volume 12,
Issue 2,
1999,
Page 105-110
Shinji Ogura,
Osamu Umegaki,
Francesco Genovese,
Lawrence Fernando,
Joel Cochran,
Cristina Romeo,
James Cook,
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摘要:
The effects of tyrphostin AG-556 (TYR), a tyrosine kinase inhibitor, were evaluated on shock induced by lipopolysaccharide (LPS) or group B streptococcus (GBS) in rats. Mortality and mean survival time were monitored. Plasma 6-keto prostaglandin F1α(6-keto PGF1α) was also measured at four hours after LPS injection. The effects of TYR on the production of 6-keto PGF1α, thromboxane B2(TXB2) and nitrite (NO) from LPS or GBS stimulatedin vitroperitoneal rat macrophage were also examined.Salmonella enteritidisLPS (12 mg/kg, i.v.) (n=6) produced severe shock (100% mortality). Simultaneous treatment with TYR (n=6) significantly (p < 0.01) extended mean survival time and 33% of rats survived. Plasma 6-keto PGF1α. concentrations were increased in LPS controls, whereas TYR (5 mg/kg) significantly (p < 0.05) decreased the production. Animals treated with GBS/D-galactosamine (n=9) also exhibited shock with 100% lethality and TYR again prolonged survival time (p< 0.05) with 55% of the animals surviving. To evaluate direct effects of TYR on mediator production induced by LPS or GBS, rat macrophages were stimulated with heat-killed GBS or LPS with or without TYR. Supernatants were collected at 24 h for determination of TXB2, 6-keto PGF1αand NO. All mediators measured were significantly increased (p< 0.05) with LPS or GBS. TYR inhibited (p< 0.05) the production of all mediators from macrophages induced by LPS or GBS. The decrease in eicosanoids was associated with a reduction of the content of cyclooxygenase-2 (COX-2) as determined by western blotting. Collectively, these results suggest that TYR ameliorates toxic shock induced by LPS or gram positive bacteria. This protection is associated with suppression of macrophage mediator production.
ISSN:1073-2322
出版商:OVID
年代:1999
数据来源: OVID
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4. |
ENDOTHELIAL CELL DETERMINANTS OF SUSCEPTIBILITY TO NEUTROPHIL‐MEDIATED KILLING |
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Shock,
Volume 12,
Issue 2,
1999,
Page 111-117
Hedwig Murphy,
Roscoe Warner,
Natalie Bakopoulos,
Michael Dame,
James Varani,
Peter Ward,
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摘要:
Vascular endothelial cell injury plays an important role in the pathogenesis of inflammatory-mediated tissue injury. In the current study, we assessed injury in primary cultures of endothelial cells obtained from different sites within the same species, comparing rat dermal microvascular and rat lung microvascular endothelial cells. Dermal microvascular-derived endothelial cells were more sensitive to killing by PMA (phorbol myristate acetate)-activated human neutrophils than were endothelial cells derived from lung microvasculature. Lung endothelial cells stimulated with interferon-γ plus lipopolysaccharide (IFNγ + LPS) generated high levels of nitric oxide (*NO), while dermal endothelial cells stimulated with IFNγ + LPS generated significantly lower levels of *NO. Under conditions of *NO generation (IFNγ + LPS stimulation), or in the presence of the *NO donor,S-nitroso-N-acetyl penicillamine (SNAP), endothelial cell killing by PMA-activated neutrophils was reduced. Lung endothelial cells stimulated with PMA generated less superoxide (O2*-) than dermal endothelial cells. Under conditions of *NO generation (IFNγ + LPS stimulation), or in the presence of SNAP, O2*-release from endothelial cells was reduced. Endothelial cell-derived *NO appeared to play a significant role in attenuating the neutrophil-mediated killing. The differences in the ability of endothelial cells to generate *NO and O2*-underlies, at least in part, the differences in susceptibility of these cells to injury by activated neutrophils.
ISSN:1073-2322
出版商:OVID
年代:1999
数据来源: OVID
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5. |
IMMUNOPATHOLOGIC RESPONSES TO NON‐LETHAL SEPSIS |
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Shock,
Volume 12,
Issue 2,
1999,
Page 118-126
Samuel Ebong,
Douglas Call,
Gerald Bolgos,
David Newcomb,
Jill Granger,
Michael O'Reilly,
Daniel Remick,
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摘要:
Although sepsis causes significant morbidity and mortality, its basic pathology is still not well understood. We investigated the inflammatory and physiologic alterations of non-lethal sepsis using cecal ligation and puncture (CLP), a model that induces peritonitis due to mixed intestinal flora, reproducing the complex immunology of sepsis. Groups of mice were subjected to CLP (25G needle) or sham surgery, had minimitters implanted to continuously monitor temperature and activity, and were sacrificed daily for 6 days. There was significant hypothermia (6–13 hrs post-surgery), and decreases in activity (to day 4) and weight (to day 3) but no mortality in the CLP group. Blood analyses of the CLP-treated mice showed reduced hemoglobin, platelets, lymphocytes, monocytes, and neutrophils, compared to sham animals. Both groups had nearly equivalent neutrophil influx into the peritoneum. Plasma and peritoneal G-CSF, IL-6, as well as the murine chemokines KC and MIP2-α were significantly higher in the CLP-treated mice at day 1. Plasma and peritoneal TNF were low (<70 pg/mL). While there was elevated IL-1β in the peritoneum of the CLP-treated mice, this cytokine was not detected in the plasma in either treatment group. Cytokines were not detected in the pulmonary airspace of the CLP-treated mice and PMNs were not recruited to this site. Our data shows altered immunopathology in non-lethal sepsis with significant blood and cytokine alterations. Since there was 100% survival, the inflammatory response was appropriate and probably even protective.
ISSN:1073-2322
出版商:OVID
年代:1999
数据来源: OVID
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6. |
EFFECT OF MESENTERIC ISCHEMIA AND REPERFUSION OR HEMORRHAGIC SHOCK ON INTESTINAL MUCOSAL PERMEABILITY AND ATP CONTENT IN RATS |
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Shock,
Volume 12,
Issue 2,
1999,
Page 127-133
Somkiat Wattanasirichaigoon,
Michael Menconi,
Russell Delude,
Mitchell Fink,
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摘要:
In a reductionistin vitrosystem, intestinal epithelial permeability appears to be dependent on cellular ATP content. In order to extend these prior observations, we used rat models of mesenteric ischemia/reperfusion (I/R) and pressure-controlled hemorrhagic shock to test the hypothesis that intestinal barrier function is directly proportional to tissue ATP content. I/R was induced by clamping the mesenteric vessels for 60 min followed by 60 min of reperfusion. Normal, ischemic, and reperfused ileal segments were prepared from each rat (n = 12). Hemorrhagic shock was induced by bleeding rats (n = 9) to a mean arterial pressure of 30 mmHg and maintaining this pressure for 4 h by infusing Ringer's lactate solution as necessary. Ileal segments were harvested before induction of hemorrhage and at 1 h intervals thereafter. Everted gut sacs were prepared to measure the mucosal-to-serosal passage of fluorescein-conjugated dextran (FD4; M.W. = 4 kDa). Tissue ATP levels were determined using a luciferase assay. FD4 clearance rates were plotted as a function of tissue ATP content. Linear regression analyses showed a strong inverse relationship between intestinal permeability and tissue ATP level in rats subjected to I/R (r2= 0.78;P< 0.001) or hemorrhage (r2= 0.82;P< 0.001). These data support the idea that ATP content is a determinant of intestinal epithelial barrier functionin vivo.
ISSN:1073-2322
出版商:OVID
年代:1999
数据来源: OVID
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7. |
DIFFERENTIAL EFFECTS OF HEPARIN ON THE EARLY AND LATE PHASES OF HEPATIC ISCHEMIA AND REPERFUSION INJURY IN THE PIG |
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Shock,
Volume 12,
Issue 2,
1999,
Page 134-138
Wei Liu,
David Pitcher,
Sheri Morris,
Jonathan Pugmire,
Jaimie Shores,
Courtney Ingram,
Robert Glew,
Don Morris,
Donald Fry,
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摘要:
The mechanisms by which heparin protects the liver during induced episodes of liver ischemia-reperfusion are poorly understood. Previous work in a swine model demonstrated that serum levels of glycohydrolases and lipid peroxide peaked within 3 h after 45 minutes of hepatic ischemia followed by reperfusion. Serum levels of lactate dehydrogenase and aspartate aminotransferase peaked 20–24 h later. The aim of this study was to evaluate the effect of heparin on these two-phases of enzyme release, using a pig model of hepatic ischemia-reperfusion injury. Twenty male swine were divided into control (n = 8) and heparin (n = 12) groups. In the heparin group, heparin was administered prior to and concurrent with ischemia-reperfusion. Following 45 min of hepatic ischemia, the levels of β-galactosidase, β-glucosidase, acid phosphatase, purine nucleoside phosphorylase, lipid peroxides, lactate dehydrogenase, and aspartate aminotransferase in serum were monitored for up to 166 h and compared to pre-ischemic and control levels. With heparin infusion, the peak levels of β-galactosidase, β-glucosidase, and the lipid peroxide were reduced to 50–60% of the control levels. Acid phosphatase and purine nucleoside phosphorylase activities in serum were reduced to 25% and 60%, respectively. The peak concentrations of lactate dehydrogenase and aspartate aminotransferase were reduced to about 25% of the control level. In addition, the serum enzymes of control pigs did not return to pre-ischemic levels until 2 weeks after hepatic ischemia, while they normalized in less than 1 week in the heparin-treated animals. Systemic heparinization had different protective effects on the first and secondary phases of liver injury. These differences may reflect heparin protection of different types of liver cells. The protection of the parenchymal cells may be the combined result of reduced sinusoidal cell injury and the anticoagulant properties of heparin.
ISSN:1073-2322
出版商:OVID
年代:1999
数据来源: OVID
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8. |
INJURY PRIMES THE IMMUNE SYSTEM FOR AN ENHANCED AND LETHAL T‐CELL RESPONSE AGAINST BACTERIAL SUPERANTIGEN |
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Shock,
Volume 12,
Issue 2,
1999,
Page 139-144
Malcolm Kell,
Eamon Kavanagh,
Andreas Goebel,
Christopher Soberg,
James Lederer,
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摘要:
We previously reported the high lethality of CD4+ T-cell activation in burn-injured T-cell receptor (TCR) transgenic mice. This suggested to us that T-cells may play a role in the development of the systemic inflammatory response syndrome (SIRS) which can occur after severe injury. In this study, we sought a more clinically relevant model to test the hypothesis that naturally produced bacterial toxins that are known to act as potent polyclonal T-cell activating agents may induce a similar lethal shock-like response in injured, non-TCR transgenic mice. Accordingly, sham- or burn-injured mice were treated with various doses of staphylococcal enterotoxin A (SEA), then observed for 48-hour mortality. We observed 94% and 56% 48-h mortality when burn-injured mice were given 15 μg and 10 μg of SEA, respectively, while neither SEA dose caused mortality in sham-injured mice. The assessment of serum cytokine levels demonstrated significantly elevated interleukin 2 (IL-2) and tumor necrosis factor α (TNFα) levels when compared to sham mice (P< 0.01).In vitrostudies confirmed ourin vivoresults and also demonstrated elevated levels of interferon γ (IFNγ) (P< 0.01). We also observed a novel injury-dependent switch from CD4+ to CD8+ T-cells as the dominant T-cell type producing TNFα and IFNγ in response to SEA stimulationin vitro.Taken together, our findings indicate that injury primes the immune system for an augmented early T-cell response that can result in a lethal shock-like syndrome.
ISSN:1073-2322
出版商:OVID
年代:1999
数据来源: OVID
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9. |
CARDIOVASCULAR ASPECTS OF EXPERIMENTAL MENINGOCOCCAL SEPSIS IN YOUNG AND OLDER AWAKE PIGLETSAGE‐RELATED DIFFERENCES |
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Shock,
Volume 12,
Issue 2,
1999,
Page 145-154
Jan Hazelzet,
René Stubenitsky,
Alexander Petrov,
Gerda van Wleringen,
Edwin van der Voort,
John Hess,
Wim Hop,
Lambertus Thijs,
Dirk Duncker,
Jan Poolman,
Pieter Verdouw,
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摘要:
Severe meningococcal disease is characterized by: a high load of specific endotoxin, capillary leakage and coagulation disorders. We studied the possible age-related differences in global hemodynamic and regional blood flow responses to different dosages (1 and 10 μg/kg body weight) of rough meningococcal endotoxin in young (8 kg) and older piglets (40 kg). Animals were chronically instrumented and studied in the awake state. The response to plasma infusion (30 mL/kg in 30 min) was evaluated after placebo and endotoxin infusion. The clinical picture was similar in all groups. The mortality was 0/8, 3/8, 1/8, 4/9 in young-low, young-high, old-low, and old-high dose respectively. Most important findings were that cardiac index (Cl) decreased in the young animals after endotoxin infusion, while it was well preserved in the older animals; in the older animals the systemic vascular resistance dropped 20%, while in the younger ones there was no change in resistance. Conductance to the kidneys, intestines, and spleen decreased significantly more in the young animals, while the increase in conductance and flow to the liver was higher in the old animals; subsequent volume loading resulted only partly in a recovery of the hemodynamic parameters, but failed to improve oxygen delivery.
ISSN:1073-2322
出版商:OVID
年代:1999
数据来源: OVID
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10. |
MODULATION OF HEMORRHAGIC SHOCK BY INTESTINAL MUCOSAL NG‐NITRO‐L‐ARGININE AND L‐ARGININE IN THE ANESTHETIZED RAT |
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Shock,
Volume 12,
Issue 2,
1999,
Page 155-160
David Mailman,
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摘要:
Maintaining intestinal function protects against shock of various origins. Nitric oxide (NO) can protect tissues. The present research examined whether the presence of 50 μM NG-nitro-L-arginine (NOLARG), a nitric oxide synthase (NOS) inhibitor, or L-arginine (LARG), the substrate of NOS, in the jejunal lumen of the anesthetized rat could affect the progress of hemorrhagic shock. The jejunai lumen was perfused with saline containing14C-inulin and3H2O to measure net H2O absorption and absorptive site blood flow (ASBF). Luminal NOx (NO3-+NO2-) secretion into the gut effluent and blood pressure (BP) were also measured. The animals were bled to and maintained at 40 mmHg for 60 min and then reinfused. Survival time was significantly decreased in luminally-perfused NOLARG animals, but was significantly increased in LARG perfused animals. Most deaths occurred during the hemorrhage periods. Animals perfused with LARG through the ileal lumen required significantly less blood to be reinfused to maintain blood pressure during the hemorrhage periods. There were not significant differences in BP among surviving animals. Net H2O absorption and ASBF were significantly decreased only in NOLARG-perfused animals in the period just before and after reinfusion. There were no significant differences in luminal NOx secretion among the groups. Thus, intestinal mucosal NOS substrates or antagonists modulate the progress of hemorrhagic shock, but the mechanism was not defined in these experiments.
ISSN:1073-2322
出版商:OVID
年代:1999
数据来源: OVID
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