S Kanwar, B L Tepperman, D Payne, L R Sutherland, P Kubes
The objective of this study was to correlate nitric oxide production with time of reperfusion of the post-ischemic feline small intestine. Epithelial permeability, quantitated as blood-to-lumen clearance of 51Cr-EDTA, following 1 hr of ischemia and 4 hr of reperfusion of the small intestine, increased approximately 10-fold. This increase was further augmented by L-NAME infusion between 60 and 120 min but not at 240 min. Ca(2+)-dependent nitric oxide synthase activity was reduced by approximately 50% at 3 and 4 hr of reperfusion, whereas Ca(2+)-independent nitric oxide synthase activity was undetectable throughout the experiment. Administration of L-arginine at the start of reperfusion attenuated the reperfusion-induced epithelial barrier dysfunction for the first 120 min but not at 180 or 240 min. Continuous infusion of a nitric oxide donor (CAS 754) following 1 hr of reperfusion reduced epithelial permeability at 4 hr of reperfusion. In conclusion, a reduction in nitric oxide production was observed with time of reperfusion, possibly due to reduced nitric oxide synthase levels.
{"title":"Time course of nitric oxide production and epithelial dysfunction during ischemia/reperfusion of the feline small intestine.","authors":"S Kanwar, B L Tepperman, D Payne, L R Sutherland, P Kubes","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The objective of this study was to correlate nitric oxide production with time of reperfusion of the post-ischemic feline small intestine. Epithelial permeability, quantitated as blood-to-lumen clearance of 51Cr-EDTA, following 1 hr of ischemia and 4 hr of reperfusion of the small intestine, increased approximately 10-fold. This increase was further augmented by L-NAME infusion between 60 and 120 min but not at 240 min. Ca(2+)-dependent nitric oxide synthase activity was reduced by approximately 50% at 3 and 4 hr of reperfusion, whereas Ca(2+)-independent nitric oxide synthase activity was undetectable throughout the experiment. Administration of L-arginine at the start of reperfusion attenuated the reperfusion-induced epithelial barrier dysfunction for the first 120 min but not at 180 or 240 min. Continuous infusion of a nitric oxide donor (CAS 754) following 1 hr of reperfusion reduced epithelial permeability at 4 hr of reperfusion. In conclusion, a reduction in nitric oxide production was observed with time of reperfusion, possibly due to reduced nitric oxide synthase levels.</p>","PeriodicalId":10280,"journal":{"name":"Circulatory shock","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1994-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19020126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
K Irita, H Okabe, A Koga, K Kurosawa, K Tagawa, M Yamakawa, J Yoshitake, S Takahashi
The changes in the concentrations of reduced (GSH) and oxidized glutathione (GSSG) in the plasma as well as in the liver were investigated in rats with endotoxin hepatitis. Hepatitis was induced by intraperitoneal co-administration of small doses of Escherichia coli endotoxin and D-galactosamine. In the liver, the concentration of GSH decreased and that of GSSG increased 12 hr later. In the plasma taken from the right atrium, the concentration of both GSH and GSSG increased. The GSH/GSSG ratio in the plasma decreased, as it did in the liver. The net sinusoidal efflux of GSH and GSSG from the liver was calculated by subtracting their concentrations in plasma of the infrahepatic, suprarenal inferior vena cava from those of the suprahepatic inferior vena cava. The efflux started to increase as early as 2-4 hr after the injection of the toxins. In contrast, a leakage of alanine aminotransferase, an elongation of prothrombin time, an inhibition of starvation ketosis, and an increase in serum concentration of total bilirubin were detected as late as 6-8 hr after the injection. We conclude that endotoxin/D-galactosamine hepatitis induced an increase in plasma concentrations of GSH as well as GSSG by increasing the efflux of these peptides from the liver, and that changes in plasma glutathione status might be useful and sensitive markers for liver damage.
研究了内毒素肝炎大鼠血浆和肝脏中还原性谷胱甘肽(GSH)和氧化性谷胱甘肽(GSSG)浓度的变化。腹腔注射小剂量大肠杆菌内毒素和d -半乳糖胺诱导肝炎。肝脏GSH浓度在12小时后下降,GSSG浓度升高。右心房血浆中GSH和GSSG浓度均升高。血浆中GSH/GSSG比值下降,肝脏中也是如此。通过从肝上下腔静脉中减去肝下、肾上下腔静脉血浆中GSH和GSSG的浓度,计算肝脏的净正弦流出量。早在注射毒素后2-4小时,外排开始增加。相反,在注射后6-8小时检测到丙氨酸转氨酶渗漏、凝血酶原时间延长、饥饿酮症抑制和血清总胆红素浓度升高。我们得出结论,内毒素/ d -半乳糖胺肝炎通过增加GSH和GSSG肽从肝脏的外排而引起血浆GSH和GSSG浓度的增加,血浆谷胱甘肽状态的变化可能是肝损伤的有用和敏感的标志物。
{"title":"Increased sinusoidal efflux of reduced and oxidized glutathione in rats with endotoxin/D-galactosamine hepatitis.","authors":"K Irita, H Okabe, A Koga, K Kurosawa, K Tagawa, M Yamakawa, J Yoshitake, S Takahashi","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The changes in the concentrations of reduced (GSH) and oxidized glutathione (GSSG) in the plasma as well as in the liver were investigated in rats with endotoxin hepatitis. Hepatitis was induced by intraperitoneal co-administration of small doses of Escherichia coli endotoxin and D-galactosamine. In the liver, the concentration of GSH decreased and that of GSSG increased 12 hr later. In the plasma taken from the right atrium, the concentration of both GSH and GSSG increased. The GSH/GSSG ratio in the plasma decreased, as it did in the liver. The net sinusoidal efflux of GSH and GSSG from the liver was calculated by subtracting their concentrations in plasma of the infrahepatic, suprarenal inferior vena cava from those of the suprahepatic inferior vena cava. The efflux started to increase as early as 2-4 hr after the injection of the toxins. In contrast, a leakage of alanine aminotransferase, an elongation of prothrombin time, an inhibition of starvation ketosis, and an increase in serum concentration of total bilirubin were detected as late as 6-8 hr after the injection. We conclude that endotoxin/D-galactosamine hepatitis induced an increase in plasma concentrations of GSH as well as GSSG by increasing the efflux of these peptides from the liver, and that changes in plasma glutathione status might be useful and sensitive markers for liver damage.</p>","PeriodicalId":10280,"journal":{"name":"Circulatory shock","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1994-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19020123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The effect of methylprednisolone on superoxide production by pulmonary and circulating blood neutrophils was investigated in rats after the intravenous injection of lipopolysaccharide. Superoxide production by both types of neutrophils was increased by lipopolysaccharide injection, and pretreatment with methylprednisolone inhibited this increase. The inhibitory effect of methylprednisolone on pulmonary neutrophils was greater than that on circulating blood neutrophils. Methylprednisolone also prevented the increase in pulmonary vascular permeability induced by lipopolysaccharide, but failed to inhibit intrapulmonary neutrophil accumulation. These results suggest that the suppression of superoxide production may be one mechanism by which methylprednisolone prevents endotoxin-induced lung damage.
{"title":"In vivo effect of methylprednisolone on lipopolysaccharide-induced superoxide production by pulmonary and circulating blood neutrophils in rats.","authors":"C Tsuji, S Shioya","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The effect of methylprednisolone on superoxide production by pulmonary and circulating blood neutrophils was investigated in rats after the intravenous injection of lipopolysaccharide. Superoxide production by both types of neutrophils was increased by lipopolysaccharide injection, and pretreatment with methylprednisolone inhibited this increase. The inhibitory effect of methylprednisolone on pulmonary neutrophils was greater than that on circulating blood neutrophils. Methylprednisolone also prevented the increase in pulmonary vascular permeability induced by lipopolysaccharide, but failed to inhibit intrapulmonary neutrophil accumulation. These results suggest that the suppression of superoxide production may be one mechanism by which methylprednisolone prevents endotoxin-induced lung damage.</p>","PeriodicalId":10280,"journal":{"name":"Circulatory shock","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1994-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19020125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
W A Arden, R R Fiscus, X Wang, L Yang, R Maley, M Nielsen, S Lanzo, D R Gross
Calcitonin gene-related peptide (CGRP) is a potent vasodilatory neuropeptide, which may play a role in vascular dysfunction during septic shock. Sixteen pigs (25-50 kg) were anesthetized with ketamine and isoflurane in O2, and administered 100 micrograms/kg Escherichia coli lipopolysaccharide i.v. (LPS; n = 8) or saline vehicle (n = 8). Pigs were instrumented for hemodynamic determinations and blood sampling for CGRP assay (pg/ml) from the portal vein (PV) and the pulmonary (PA) and carotid (CA) arteries. Blood samples were collected into EDTA and aprotinin before (baseline) and at 60, 120, and 180 min after LPS administration. LPS caused significant deterioration in indices of hemodynamic function and a significant increase in plasma CGRP concentration at all sampling sites by 120 min (P < 0.01). No significant difference between sampling sites was recorded at any time. Plasma CGRP concentrations displayed significant negative correlations with mean arterial pressure, cardiac index, and left ventricular stroke work. These data confirm our previous findings of CGRP elevations in endotoxemic rats, and indicate that 1) LPS is a potent stimulus for the systemic release of CGRP, 2) increasing plasma CGRP concentrations temporally correlates with cardiovascular deterioration during LPS shock, and 3) there is little evidence that the portal circulation is a major source of circulating CGRP levels during LPS shock. Vasoactive neuropeptides, such as CGRP, may interact with other documented mediators of vascular dysfunction in the pathogenesis of septic shock.
{"title":"Elevations in circulating calcitonin gene-related peptide correlate with hemodynamic deterioration during endotoxic shock in pigs.","authors":"W A Arden, R R Fiscus, X Wang, L Yang, R Maley, M Nielsen, S Lanzo, D R Gross","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Calcitonin gene-related peptide (CGRP) is a potent vasodilatory neuropeptide, which may play a role in vascular dysfunction during septic shock. Sixteen pigs (25-50 kg) were anesthetized with ketamine and isoflurane in O2, and administered 100 micrograms/kg Escherichia coli lipopolysaccharide i.v. (LPS; n = 8) or saline vehicle (n = 8). Pigs were instrumented for hemodynamic determinations and blood sampling for CGRP assay (pg/ml) from the portal vein (PV) and the pulmonary (PA) and carotid (CA) arteries. Blood samples were collected into EDTA and aprotinin before (baseline) and at 60, 120, and 180 min after LPS administration. LPS caused significant deterioration in indices of hemodynamic function and a significant increase in plasma CGRP concentration at all sampling sites by 120 min (P < 0.01). No significant difference between sampling sites was recorded at any time. Plasma CGRP concentrations displayed significant negative correlations with mean arterial pressure, cardiac index, and left ventricular stroke work. These data confirm our previous findings of CGRP elevations in endotoxemic rats, and indicate that 1) LPS is a potent stimulus for the systemic release of CGRP, 2) increasing plasma CGRP concentrations temporally correlates with cardiovascular deterioration during LPS shock, and 3) there is little evidence that the portal circulation is a major source of circulating CGRP levels during LPS shock. Vasoactive neuropeptides, such as CGRP, may interact with other documented mediators of vascular dysfunction in the pathogenesis of septic shock.</p>","PeriodicalId":10280,"journal":{"name":"Circulatory shock","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1994-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19020128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The effect of methylprednisolone on superoxide production by pulmonary and circulating blood neutrophils was investigated in rats after the intravenous injection of lipopolysaccharide. Superoxide production by both types of neutrophils was increased by lipopolysaccharide injection, and pretreatment with methylprednisolone inhibited this increase. The inhibitory effect of methylprednisolone on pulmonary neutrophils was greater than that on circulating blood neutrophils. Methylprednisolone also prevented the increase in pulmonary vascular permeability induced by lipopolysaccharide, but failed to inhibit intrapulmonary neutrophil accumulation. These results suggest that the suppression of superoxide production may be one mechanism by which methylprednisolone prevents endotoxin-induced lung damage.
{"title":"In vivo effect of methylprednisolone on lipopolysaccharide-induced superoxide production by pulmonary and circulating blood neutrophils in rats.","authors":"C. Tsuji, S. Shioya","doi":"10.11501/3083092","DOIUrl":"https://doi.org/10.11501/3083092","url":null,"abstract":"The effect of methylprednisolone on superoxide production by pulmonary and circulating blood neutrophils was investigated in rats after the intravenous injection of lipopolysaccharide. Superoxide production by both types of neutrophils was increased by lipopolysaccharide injection, and pretreatment with methylprednisolone inhibited this increase. The inhibitory effect of methylprednisolone on pulmonary neutrophils was greater than that on circulating blood neutrophils. Methylprednisolone also prevented the increase in pulmonary vascular permeability induced by lipopolysaccharide, but failed to inhibit intrapulmonary neutrophil accumulation. These results suggest that the suppression of superoxide production may be one mechanism by which methylprednisolone prevents endotoxin-induced lung damage.","PeriodicalId":10280,"journal":{"name":"Circulatory shock","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1994-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84894412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Protective effects of SDZ MRL 953, a monosaccharidic lipid A analog with a reduced toxicity, were investigated in models of experimental septic shock caused by injections of LPS, and inoculations of heat-killed or live bacteria. Female B6D2F1 mice were challenged with a combination of galactosamine (800 mg/kg) plus various doses of heat-killed isolates of Escherichia coli, Pseudomonas aeruginosa, Salmonella typhimurium, and Staphylococcus aureus or LPS from Salmonella abortus equi. In some experiments, isolates of living bacteria at sublethal inocula were also combined with galactosamine. More than 90% of the animals died within 24 hr when the challenge was performed either simultaneously with or up to 4 hr after an intraperitoneal administration of galactosamine. No death was observed when galactosamine was omitted or administered after the microbial or LPS challenge. Pretreatment of the animals with SDZ MRL 953 (1-10 mg/kg) rendered the animals resistant to the lethal effects of both bacterial and LPS challenge in a time- and dose-dependent manner. The levels of TNF-alpha in control mice rose to greater than 600 pg/ml 2 hr postbacterial or LPS challenge, but were below detection in animals pretreated with SDZ MRL 953. Protection against both the infection and the toxicity of heat-killed bacteria or LPS was also achieved when murine anti-TNF-alpha monoclonal antibody was administered prophylactically. Together, these data suggest that SDZ MRL 953 enhances the resistance of mice against the toxicity of heat-killed gram-negative bacteria and S. aureus, and attenuates host responses to living bacteria which may lead to irreversible shock and death.
{"title":"Protection of mice from mortality caused by living and heat-killed bacteria by SDZ MRL 953.","authors":"E Schütze, J Hildebrandt, E Liehl, C Lam","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Protective effects of SDZ MRL 953, a monosaccharidic lipid A analog with a reduced toxicity, were investigated in models of experimental septic shock caused by injections of LPS, and inoculations of heat-killed or live bacteria. Female B6D2F1 mice were challenged with a combination of galactosamine (800 mg/kg) plus various doses of heat-killed isolates of Escherichia coli, Pseudomonas aeruginosa, Salmonella typhimurium, and Staphylococcus aureus or LPS from Salmonella abortus equi. In some experiments, isolates of living bacteria at sublethal inocula were also combined with galactosamine. More than 90% of the animals died within 24 hr when the challenge was performed either simultaneously with or up to 4 hr after an intraperitoneal administration of galactosamine. No death was observed when galactosamine was omitted or administered after the microbial or LPS challenge. Pretreatment of the animals with SDZ MRL 953 (1-10 mg/kg) rendered the animals resistant to the lethal effects of both bacterial and LPS challenge in a time- and dose-dependent manner. The levels of TNF-alpha in control mice rose to greater than 600 pg/ml 2 hr postbacterial or LPS challenge, but were below detection in animals pretreated with SDZ MRL 953. Protection against both the infection and the toxicity of heat-killed bacteria or LPS was also achieved when murine anti-TNF-alpha monoclonal antibody was administered prophylactically. Together, these data suggest that SDZ MRL 953 enhances the resistance of mice against the toxicity of heat-killed gram-negative bacteria and S. aureus, and attenuates host responses to living bacteria which may lead to irreversible shock and death.</p>","PeriodicalId":10280,"journal":{"name":"Circulatory shock","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1994-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19020124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The sensitivity of rat cremaster muscle arterioles to topically applied arginine vasopressin (AVP) is greatly increased by endotoxin (ENDT) [1]. The hypothesis is that the increase in vasoconstrictor sensitivity is in part due to modification of the AVP responses by endothelial compounds such as nitric oxide (NO) and endothelin. Reactivity of left cremaster muscle microvessels of pentobarbital anesthetized Sprague-Dawley rats was measured using videomicroscopy. Femoral arterial pressure as well as second and third order arteriolar (A2 and A3) vasoconstrictor threshold responses were determined for topical AVP (10(-15)-10(-6) M). These measurements were repeated in the presence of ENDT (6 mg/kg) alone and in the presence of the NO synthase inhibitor L-NAME (N omega-nitro-L-arginine methyl ester; 1 mg/kg) and ENDT (group 1). The control threshold (M)(-log) for arteriolar constriction by AVP was 9.4 +/- 0.7. After ENDT the threshold decreased significantly (P < 0.05) to 13.8 +/- 0.5, but returned to 9.0 +/- 0.5 after i.v. injected L-NAME. Acetylcholine (ACh) injected i.a. during AVP constriction significantly increased diameters at control and after ENDT, but not after L-NAME. In group 2 the AVP threshold was determined at control, after L-NAME plus hydroquinone (HQ), and at 30, 90, and 120 min post-ENDT in the presence of L-NAME + HQ. The AVP threshold at control was 9.0 +/- 0.3, after L-NAME 9.0 +/- 0.6, and after HQ 8.0 +/- 0.7. After L-NAME + HQ, the threshold was significantly increased to 7.3 +/- 0.2. After ENDT, in the presence of both antagonists, the threshold remained elevated at 7.4 +/- 0.2.(ABSTRACT TRUNCATED AT 250 WORDS)
{"title":"Modification of vasopressin microvascular responses by endotoxin, endothelin, and nitric oxide.","authors":"C H Baker, E T Sutton","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The sensitivity of rat cremaster muscle arterioles to topically applied arginine vasopressin (AVP) is greatly increased by endotoxin (ENDT) [1]. The hypothesis is that the increase in vasoconstrictor sensitivity is in part due to modification of the AVP responses by endothelial compounds such as nitric oxide (NO) and endothelin. Reactivity of left cremaster muscle microvessels of pentobarbital anesthetized Sprague-Dawley rats was measured using videomicroscopy. Femoral arterial pressure as well as second and third order arteriolar (A2 and A3) vasoconstrictor threshold responses were determined for topical AVP (10(-15)-10(-6) M). These measurements were repeated in the presence of ENDT (6 mg/kg) alone and in the presence of the NO synthase inhibitor L-NAME (N omega-nitro-L-arginine methyl ester; 1 mg/kg) and ENDT (group 1). The control threshold (M)(-log) for arteriolar constriction by AVP was 9.4 +/- 0.7. After ENDT the threshold decreased significantly (P < 0.05) to 13.8 +/- 0.5, but returned to 9.0 +/- 0.5 after i.v. injected L-NAME. Acetylcholine (ACh) injected i.a. during AVP constriction significantly increased diameters at control and after ENDT, but not after L-NAME. In group 2 the AVP threshold was determined at control, after L-NAME plus hydroquinone (HQ), and at 30, 90, and 120 min post-ENDT in the presence of L-NAME + HQ. The AVP threshold at control was 9.0 +/- 0.3, after L-NAME 9.0 +/- 0.6, and after HQ 8.0 +/- 0.7. After L-NAME + HQ, the threshold was significantly increased to 7.3 +/- 0.2. After ENDT, in the presence of both antagonists, the threshold remained elevated at 7.4 +/- 0.2.(ABSTRACT TRUNCATED AT 250 WORDS)</p>","PeriodicalId":10280,"journal":{"name":"Circulatory shock","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1994-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18523599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To study the clinical significance of the decrease of glucocorticoid receptor (GR) in stress and shock, GR was blocked about 80% by mifepristone (RU38486), and the effects of the blockade on the pathological changes of endotoxemia were studied in rats. The results revealed that GR blockade may exacerbate the pathological and pathophysiological changes of endotoxemia: (1) the more rapid drop in arterial blood pressure, (2) the more severe pathological changes involving multiple organs, especially the lung and small intestine, (3) the increase of leukocyte adherence in venules and more pronounced rheological changes in the mesenteric microcirculation, and (4) the striking elevation of serum acid phosphatase (ACP), phospholipase A2 (PLA2) activity, and lipoperoxide (LPO). The changes of serum ACP, PLA2, and LPO in the rats with 80% GR blockade were more marked than in those with 50% GR blockade. Based on these findings, we propose that the decrease in GR during stress and shock might be a contributing factor in the pathogenesis of shock and multiple organ failure (MOF). The possible mechanisms of the above noted findings are discussed.
{"title":"Effect of glucocorticoid receptor (GR) blockade on endotoxemia in rats.","authors":"J Fan, X Q Gong, J Wu, Y F Zhang, R B Xu","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>To study the clinical significance of the decrease of glucocorticoid receptor (GR) in stress and shock, GR was blocked about 80% by mifepristone (RU38486), and the effects of the blockade on the pathological changes of endotoxemia were studied in rats. The results revealed that GR blockade may exacerbate the pathological and pathophysiological changes of endotoxemia: (1) the more rapid drop in arterial blood pressure, (2) the more severe pathological changes involving multiple organs, especially the lung and small intestine, (3) the increase of leukocyte adherence in venules and more pronounced rheological changes in the mesenteric microcirculation, and (4) the striking elevation of serum acid phosphatase (ACP), phospholipase A2 (PLA2) activity, and lipoperoxide (LPO). The changes of serum ACP, PLA2, and LPO in the rats with 80% GR blockade were more marked than in those with 50% GR blockade. Based on these findings, we propose that the decrease in GR during stress and shock might be a contributing factor in the pathogenesis of shock and multiple organ failure (MOF). The possible mechanisms of the above noted findings are discussed.</p>","PeriodicalId":10280,"journal":{"name":"Circulatory shock","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1994-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19007523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Hydrazine sulfate selectively modulates the TNF response to endotoxin in mouse macrophages.","authors":"F Jia, D C Morrison, R Silverstein","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":10280,"journal":{"name":"Circulatory shock","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1994-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19007560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
R Saladino, C Garcia, C Thompson, B Hammer, J Parsonnet, T Novitsky, G Siber, G Fleisher
Gram-negative bacterial sepsis is associated with endotoxemia and a high mortality rate. In previous studies, we demonstrated the therapeutic benefit of an anti-lipopolysaccharide factor isolated from amebocytes of Limulus polyphemus, and of a recombinant version of this protein, termed endotoxin neutralizing protein (ENP), in rabbits challenged with purified lipopolysaccharides. To assess the benefit of ENP in treating a live bacterial infection, we established a rabbit model of Escherichia coli (E. coli) peritonitis and bacteremia with high mortality despite gentamicin treatment. Twenty-four pairs of New Zealand white rabbits were challenged intraperitoneally (IP) with E. coli O18ac K1 in 5% porcine mucin (mean bacteria per dose = 2.5 x 10(8)). The animals were treated with intravenous (i.v.) gentamicin (2.5 mg/kg), and with either ENP (5 mg/kg) or saline i.v. at 1 hr after E. coli challenge. All rabbits were bacteremic 1 hr after challenge (geometric mean 4.1 +/- 1.2 x 10(4) cfu/mL). Peak geometric mean serum endotoxin (2.62 v 10.54 EU/mL, P = .013) and tumor necrosis factor (TNF) (2540 v 6438 TNF units/mL, P = .046) concentrations were lower in ENP-treated animals as compared to control animals. Seven of 24 animals treated with ENP survived 24 hr compared with 4 of 24 controls (Kaplan-Meier analysis, P = .19). However, in the subgroup of 13 paired animals in whom bacteremia was eliminated by gentamicin treatment, 5 of 13 ENP-treated animals survived 24 hr, compared with 1 of 13 controls (Kaplan-Meier analysis, P = .032).(ABSTRACT TRUNCATED AT 250 WORDS)
革兰氏阴性细菌性败血症与内毒素血症和高死亡率有关。在之前的研究中,我们证明了从多足鲎变形细胞中分离的抗脂多糖因子,以及该蛋白的重组版本,称为内毒素中和蛋白(ENP),在纯化脂多糖刺激的兔子中具有治疗作用。为了评估ENP治疗活细菌感染的益处,我们建立了一种大肠杆菌腹膜炎和菌血症的兔子模型,尽管庆大霉素治疗,但死亡率很高。24对新西兰大白兔腹腔注射含5%猪黏液的大肠杆菌O18ac K1(每剂量平均细菌数= 2.5 × 10(8))。小鼠在大肠杆菌攻毒后1小时静脉注射庆大霉素(2.5 mg/kg)和ENP (5 mg/kg)或生理盐水。所有家兔在攻毒后1小时呈菌血症(几何平均值4.1 +/- 1.2 × 10(4) cfu/mL)。enp处理动物的峰值几何平均血清内毒素(2.62 v 10.54 EU/mL, P = 0.013)和肿瘤坏死因子(TNF) (2540 v 6438 TNF单位/mL, P = 0.046)浓度低于对照动物。24只接受ENP治疗的动物中有7只存活了24小时,而24只对照组中有4只存活了24小时(Kaplan-Meier分析,P = .19)。然而,在庆大霉素治疗消除菌血症的13只配对动物亚组中,13只接受enp治疗的动物中有5只存活了24小时,而13只对照组中有1只存活了24小时(Kaplan-Meier分析,P = 0.032)。(摘要删节250字)
{"title":"Efficacy of a recombinant endotoxin neutralizing protein in rabbits with Escherichia coli sepsis.","authors":"R Saladino, C Garcia, C Thompson, B Hammer, J Parsonnet, T Novitsky, G Siber, G Fleisher","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Gram-negative bacterial sepsis is associated with endotoxemia and a high mortality rate. In previous studies, we demonstrated the therapeutic benefit of an anti-lipopolysaccharide factor isolated from amebocytes of Limulus polyphemus, and of a recombinant version of this protein, termed endotoxin neutralizing protein (ENP), in rabbits challenged with purified lipopolysaccharides. To assess the benefit of ENP in treating a live bacterial infection, we established a rabbit model of Escherichia coli (E. coli) peritonitis and bacteremia with high mortality despite gentamicin treatment. Twenty-four pairs of New Zealand white rabbits were challenged intraperitoneally (IP) with E. coli O18ac K1 in 5% porcine mucin (mean bacteria per dose = 2.5 x 10(8)). The animals were treated with intravenous (i.v.) gentamicin (2.5 mg/kg), and with either ENP (5 mg/kg) or saline i.v. at 1 hr after E. coli challenge. All rabbits were bacteremic 1 hr after challenge (geometric mean 4.1 +/- 1.2 x 10(4) cfu/mL). Peak geometric mean serum endotoxin (2.62 v 10.54 EU/mL, P = .013) and tumor necrosis factor (TNF) (2540 v 6438 TNF units/mL, P = .046) concentrations were lower in ENP-treated animals as compared to control animals. Seven of 24 animals treated with ENP survived 24 hr compared with 4 of 24 controls (Kaplan-Meier analysis, P = .19). However, in the subgroup of 13 paired animals in whom bacteremia was eliminated by gentamicin treatment, 5 of 13 ENP-treated animals survived 24 hr, compared with 1 of 13 controls (Kaplan-Meier analysis, P = .032).(ABSTRACT TRUNCATED AT 250 WORDS)</p>","PeriodicalId":10280,"journal":{"name":"Circulatory shock","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1994-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19007559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}