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PubMed2000

Role of c-jun expression increased by heat shock- and ceramide-activated caspase-3 in HL-60 cell apoptosis. Possible involvement of ceramide in heat shock-induced apoptosis.

Ceramide has emerged as a lipid mediator in apoptosis induced by a variety of stresses. As we previously showed that the activation of AP-1, a nuclear transcription factor was indispensable to ceramide-induced apoptosis in human leukemia HL-60 cells (Sawai, H., Okazaki, T., Yamamoto, H., Okano, H., Takeda, Y., Tashima, M., Sawada, H., Okuma, M., Ishikura, H., Umehara, H., and Domae, N. (1995) J. Biol. Chem. 270, 27326-27331), the role and mechanism of heat shock (HS)-increased c-jun expression in apoptosis was here investigated. HS increased morphological changes compatible with apoptosis in human leukemia HL-60 cells, and induced ceramide generation and sphingomyelin hydrolysis with an increase of neutral magnesium-dependent sphingomyelinase activity. When HS failed to induce apoptosis in HS-resistant HL-60 cells, ceramide generation was not detected, suggesting that ceramide was involved in downstream signals required for HS-induced apoptosis. Both HS and N-acetylsphingosine (C(2)-ceramide) increased the expression of c-jun/c-fos mRNAs with the peak 2 h after treatment. When we examined whether the inhibition of c-jun expression by its antisense oligodeoxynucleotides (AS) blocked HS- or C(2)-ceramide-induced apoptosis, AS of c-jun gene inhibited apoptotic morphological changes and DNA fragmentation whereas did not sense oligodeoxynucleotides. Moreover, a synthetic tetrapeptide, acetyl-Asp-Met-Gln-Asp-aldehyde (DMQD-CHO), which inhibited the formation of active form of caspase-3 more efficiently than those of caspase-4, -6, -7, and -8, blocked both caspase-3 like activity, c-jun expression and apoptosis induced by HS or C(2)-ceramide, although DMQD-CHO did not affect HS-induced ceramide generation. These results suggested that the ceramide was generated through sphingomyelin hydrolysis by HS-activated neutral, magnesium-dependent sphingomyelinase and that subsequent c-jun expression through activation of caspase-3 played a role in HS-induced HL-60 cell apoptosis.

Apoptosis↗
PubMed2001

Dissociation of heparan sulfate and receptor binding domains of hepatocyte growth factor reveals that heparan sulfate-c-met interaction facilitates signaling.

Hepatocyte growth factor (HGF) is a secreted, heparan sulfate (HS) glycosaminoglycan-binding protein that stimulates mitogenesis, motogenesis, and morphogenesis in a wide array of cellular targets, including hepatocytes and other epithelial cells, melanocytes, endothelial cells, and hematopoietic cells. NK1 is an alternative HGF isoform that consists of the N-terminal (N) and first kringle (K1) domains of full-length HGF and stimulates all major HGF biological activities. Within NK1, the N domain retains the HS binding properties of full-length HGF and mediates HS-stimulated ligand oligomerization but lacks significant mitogenic or motogenic activity. In contrast, K1 does not bind HS, but it stimulates receptor and mitogen-activated protein kinase activation, mitogenesis, and motogenesis, demonstrating that structurally distinct and dissociable domains of HGF are the primary mediators of HS binding and receptor activation. Despite the absence of HS-K1 binding, K1 mitogenic activity in HS-negative cells is strictly dependent on added soluble heparin, whereas K1-stimulated motility is not. We also found that, like the receptors for fibroblast growth factors, the HGF receptor c-Met binds tightly to HS. These data suggest that HS can facilitate HGF signaling through interaction with c-Met that is independent of HGF-HS interaction and that the recruitment of specific intracellular effectors that mediate distinct HGF responses such as mitogenesis and motility is regulated by HS-c-Met interaction at the cell surface.

Animals↗
PubMedDate not supplied

Heat-inducible vectors for use in gene therapy.

The objectives of this study were to quantity and compare the activities of a minimal heat shock (HS) promoter and other promoters used in gene therapy applications, and to identify strategies to amplify the heat inducibility of therapeutic genes. Human tumour cells were transiently or stably transfected with the HS promoter driving expression of reporter genes. HS promoter activity was induced transiently, with maximum activity 16-24 h after HS, and was dependent on temperature. The activity of the minimal HS promoter was similar, after 42 degrees C HS for 1 h, to that of the cytomegalovirus (CMV) promoter. To determine if the HS promoter could be used to activate a second conditional promoter, cells were transiently transfected with vectors containing both the HS and human immunodeficiency virus type 1 (HIV1) promoters. When the IL-2 gene was placed downstream of the HIV1 promoter. IL-2 production was temperature-independent. The addition of the HIV tat gene downstream of the HS promoter caused IL-2 to be induced more than 3 fold after a single 42 degrees C HS. These data indicate that the minimal HS promoter, following activation by clinically attainable temperatures (< or = 42 degrees C), can drive expression of therapeutic genes at levels comparable to the CMV promoter and be used in conjunction with a second conditional promoter to drive temperature-dependent, gene expression.

Genes, tat↗
PubMed2002

Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy.

In patients suffering from temporal lobe epilepsy (TLE), increased extracellular glutamate levels in the epileptogenic hippocampus both during and after clinical seizures have been reported. These increased glutamate levels could be the result of malfunctioning and/or downregulation of glutamate transporters (also known as EAATs; excitatory amino acid transporters). In this study, the distribution of protein and mRNA of EAAT subtypes was examined in the hippocampus of TLE patients with hippocampal sclerosis (HS group) and without hippocampal sclerosis (non-HS group), and in autopsy controls without neurological disorders. EAAT protein localization was studied by immunohistochemistry on paraffin sections using specific poly- and monoclonal antibodies against the glial glutamate transporters EAAT1 and EAAT2 and the neuronal glutamate transporter EAAT3. Antibody specificity was shown by immunoblotting. In the HS group, a small decrease in EAAT1-immunoreactivity (IR) was observed in CA4 and in the polymorphic and supragranular layer of the dentate gyrus, compared with the control group. The strongest changes were found for EAAT2 levels. In the non-HS group, increased EAAT2-IR was detected in the CA1 and CA2 field, compared with non-epileptic controls. EAAT2-IR was decreased in the HS compared with the non-HS group. Fewer EAAT3-positive cells were found in the HS group than in the non-HS and control group. In both TLE groups, increased EAAT3 levels were observed in individual neurones. In the HS group, the percentage of EAAT3-IR neurones was increased in CA2 and in the granule cell layer of the dentate gyrus. Radioactive in situ hybridization for EAAT1-3 confirmed our immunohistochemical results. Non-radioactive in situ hybridization showed that not only astrocytes, but also neurones express EAAT2 mRNA. Taken together, differences in both mRNA and protein levels of glutamate transporter subtypes were found in specific regions in the TLE hippocampus, with most severe changes found for EAAT2 and EAAT3 levels. The results indicate an upregulation of EAAT2 protein expression in CA1 and CA2 in neurones in the non-HS group. This is in line with decreased EAAT2 protein levels in the HS group, since these hippocampi are characterized by severe neuronal cell loss. The functional consequences (glutamate transport capacity) of the reported changes in EAAT2 and EAAT3 remain to be determined.

Adult↗
PubMed2005

High-sensitivity C-reactive protein: potential adjunct for risk stratification in patients with stable congestive heart failure.

AIMS: To determine the potential adjunct of high-sensitivity (hs) C-reactive protein for risk stratification in patients with stable congestive heart failure (CHF). METHODS AND RESULTS: We studied 546 consecutive patients clinically stable with an ejection fraction <45% who were referred to our centre for evaluation of left ventricular dysfunction. hs C-reactive protein levels were determined on blood samples obtained on entry into the study. Clinical follow-up (median 972 days) was obtained for 545 patients. Cardiovascular mortality was significantly increased (P=0.001) in patients with hs C-reactive protein >3 mg/L. By multivariable analysis, including clinical, biological, and echocardiographic variables, hs C-reactive protein >3 mg/L was an independent predictor of cardiovascular mortality [HR=1.78 (1.17-2.72); P=0.008]; the strongest predictive parameter in this model was B-type natriuretic peptide (BNP) (P=0.005). When peak VO(2) was included into the model, hs C-reactive protein >3 mg/L remained an independent predictor of cardiovascular mortality [HR=1.55 (1.02-2.38); P=0.04]; the strongest predictive parameter in this model was peak VO(2) (P<0.0001). In patients with ischaemic CHF, cardiovascular mortality was significantly increased in patients with hs C-reactive protein >3 mg/L (P=0.001), whereas in patients with non-ischaemic CHF, hs C-reactive protein >3 mg/L was not associated with cardiovascular mortality (P=0.098). By multivariable analysis, hs C-reactive protein >3 mg/L was an independent predictor of cardiovascular mortality in ischaemic patients [HR=2.16 (1.23-3.78)] but not in non-ischaemic patients [HR=1.05 (0.52-2.11)]. CONCLUSION: Cardiovascular mortality is increased in CHF patients with hs C-reactive protein >3 mg/L. The impact of hs C-reactive protein is independent of usual prognostic parameters, in particular BNP and peak VO(2). The interest of hs C-reactive protein determination appears to be especially marked in patients with ischaemic cardiomyopathy.

C-Reactive Protein↗
PubMed2002

Variant heparan sulfates synthesized in developing mouse brain differentially regulate FGF signaling.

Heparan sulfates (HSs) exert critical regulatory actions on many proteins, including growth factors, and are essential for normal development. Variations in their specific sulfation patterns are known to regulate binding and signaling of fibroblast growth factors (FGFs) via tyrosine kinase receptors (FGFRs). We previously reported differences in sulfation patterns between HS species expressed by embryonic day 10 (E10) and E12 mouse neural precursor cells. We have examined the abilities of the different HS species to support signaling of the relevant FGF-FGFR combinations expressed early during brain development. For FGF8, which only functions early (E8-E11), E10 HS showed preferential activation. The most potent signaling for FGF8 was via FGFR3c, for which E10 HS was strongly active and E12 HS had no activity. For FGF2, which functions from E10 to E13, HS from both stages showed similar activity and were more potent at activating FGFR1c than the other receptors. Thus, we find a stage-specific correlation with activation. To explore the potential mechanisms for the generation of these stage-specific HS species, we investigated the expression of the HS sulfotransferase (HSST) isozymes responsible for creating diverse sulfation motifs in HS chains. We find that there are stage-specific combinations of HSST isozymes that could underlie the synthesis of different HS species at E10 and E12. Collectively, these data lead us to propose a model in which differential expression of HSSTs results in the synthesis of variant HS species that form functional signaling complexes with FGFs and FGFRs and orchestrate proliferation and differentiation in the developing brain.

Alternative Splicing↗
PubMed2004

Role of heparan sulfate in dextral heart looping in chick.

Heparan sulfate (HS) has been shown to be involved in left-right asymmetry formation, including the process of dextral heart looping during embryonic development. The structural features of HS required in this process, however, have not been explored. In this study, we examined the structure of HS from the heart-forming regions (or heart fields) of Hamburger and Hamilton stage 5-9 chick embryos. No significant differences were found in HS to chondroitin sulfate (CS) ratio, HS chain length, or [35S] sulfate incorporation at HS disaccharide level between the left and the right heart fields. Compared to other parts of the embryo, however, lower ratio of HS to CS, shorter HS chain length, and higher [35S] sulfate incorporation at 6-O position of the glucosamine residue in the HS chains were observed in the heart-forming regions. Moreover, HS from the left and the right heart fields exhibit differential cleavage by heparanase, an endo-beta-d- glucuronidase that cleaves specific sequences within the HS chain. In embryo culture, microinjection of the active human heparanase enzyme into the right but not the left pericardial cavity at stage 7-8+ resulted in reversed heart looping in a dose-dependent manner. Heart reversal following microinjection of heparin or heparin derivatives suggests the involvement of N- and 6-O-sulfation but not 2-O-sulfation in the heart looping process.

Animals↗
PubMed2004

Exogenous estrogen boosts circulating estradiol concentrations and calcium uptake by duodenal tissue in heat-stressed hens.

In the hen, heat stress (HS) disrupts shell calcification and reproductive processes, including hormone synthesis and egg production. Two studies were conducted to investigate palliative effects of exogenous estrogen or dietary vitamin D3 on Ca homeostasis and reproductive physiology during HS. Study 1: Hy-Line W36 hens were randomly assigned to thermoneutral (TN) or HS treatments and to 1 of 7 estrogen treatments: zero (control) or one Compudose 200 implant given 1, 2, 3, 8, 9, or 10 d before onset of HS. With no implant, HS reduced plasma estradiol (E2) and total Ca absorbed (CaT) by duodenal cells (P < 0.05). In TN hens with implants, plasma E2 tripled within 24 h (P < 0.05) and remained elevated (P < 0.05) through d 9. In HS hens with implants, plasma E2 rose 6-fold (P < 0.05) to equal TN+E2 concentrations and remained elevated through d 10. In TN and HS hens with implants, the rate of Ca absorption (CaTR) and CaT increased dramatically; the responses were quadratic and essentially identical. Study 2: Hy-Line W36 hens were provided diets formulated either according to NRC requirements (NRC, 1994), or with the addition of 22,000 IU/kg vitamin D3 (+VD hens). A 24-h HS episode was imposed 2 wk after initiation of the dietary regimen. Duodenal samples were collected for Ca absorption assays after the 24-h HS episode. Both CaTR and CaT in +VD hens were approximately 3-fold higher than in hens in the NVD group (P = 0.102). The results lead to the conclusion that exogenous estrogen, high levels of dietary vitamin D, or both, before a HS episode, are efficacious in alleviating at least some of the effects of HS and should be further investigated.

Animals↗
PubMed1996

Complete recovery after normothermic hemorrhagic shock and profound hypothermic circulatory arrest of 60 minutes in dogs.

OBJECTIVE: We hypothesize that during severe normothermic hemorrhagic shock (HS), induction of profound hypothermic circulatory arrest (PHCA) of 60 minutes to allow repair of otherwise lethal injuries in a bloodless field, can be survived without brain damage. In previous dog studies, normothermic HS with mean arterial pressure (MAP) of 40 mm Hg for 30 minutes, followed by PHCA of 2 hours at brain (tympanic membrane) temperature of 5 to 10 degrees C and core temperature of 10 degrees C, induced and reversed with cardiopulmonary bypass, resulted in survival with mild histopathologic brain damage. This study was designed to determine the severity of HS that can safely allow 1 hour of PHCA. In pilot studies with HS at MAP 30 mm Hg for 90 minutes with or without subsequent PHCA of 60 minutes there were no survivors. METHODS: In the definitive study, outcomes in four groups of five dogs each were compared: group I, HS at MAP 30 mm Hg for 60 minutes and normothermic fluid resuscitation; group II, HS at MAP 30 mm Hg for 60 minutes, PHCA for 60 minutes, and resuscitation; group III, HS at MAP 40 mm Hg for 60 minutes and normothermic fluid resuscitation; and group IV, HS at MAP 40 mm Hg for 60 minutes, PHCA for 60 minutes, and resuscitation. Controlled ventilation was maintained for at least 20 hours and intensive care for 72 hours. RESULTS: In groups I and II, two of five dogs in each group survived to 72 hours. In groups III and IV, all ten dogs survived. All survivors were functionally normal, with neurologic deficit scores (0% = normal, 100% = brain dead) of < 10%. Light microscopic scoring of 18 brain regions revealed no ischemic changes. All nonsurvivors had a severe metabolic acidemia after HS and developed multiple organ failure, including pulmonary edema, pneumonia, and intestinal necrosis. CONCLUSIONS: The critical level of hypotension during 60 minutes normothermic HS that is compatible with survival in dogs is a MAP of between 30 and 40 mm Hg. After otherwise survivable severe normothermic HS of 60 minutes, PHCA of 60 minutes does not add brain damage or mortality, and may allow survival from injuries that would otherwise be irreparable.

Animals↗
PubMed1998

Hypertonic saline resuscitation reduces neutrophil margination by suppressing neutrophil L selectin expression.

UNLABELLED: Hypertonic saline (HS) reduces hemorrhage-induced lung injury by suppressing the neutrophil oxidative burst and reducing lung neutrophil influx. This study investigated whether this is caused by the effects of HS on endothelial adhesion molecule expression, the production of chemoattractants in the lung, or a direct effect of HS on neutrophil selectin expression. METHODS: BALB/c mice were made to hemorrhage to 40 mm Hg for 1 hour and resuscitated with shed blood and either 4 mL/kg 7.5% HS or two times the shed blood volume of lactated Ringer's solution (LRS). Neutrophil L selectin expression was determined by flow cytometry, total neutrophil counts were obtained by differential staining, and pulmonary endothelial P and E selectin expression was evaluated by immunohistochemistry. Chemoattractants in lung lavages were determined with a modified Boyden chamber migration assay. RESULTS: Chemotactic activity of lavage fluid of HS-treated animals was not significantly different from that of LRS-treated animals, and endothelial P and E selectin expression was not altered by HS resuscitation. Neutrophils of HS-treated animals, however, expressed significantly less L selectin than those of LRS-treated mice. Concomitantly, circulating neutrophil counts of LRS-treated animals were significantly decreased compared with those of HS-treated mice. CONCLUSION: HS had little effect on endothelial selectin expression and chemoattractant production in the lung. HS significantly decreased neutrophil L selectin expression, however. This suggests that HS resuscitation may reduce lung injury by preventing neutrophil L selectin expression and endothelial adhesion.

Animals↗
PubMed2001

Mild hypothermia increases survival from severe pressure-controlled hemorrhagic shock in rats.

BACKGROUND: In previous studies, mild hypothermia (34 degrees C) during uncontrolled hemorrhagic shock (HS) increased survival. Hypothermia also increased mean arterial pressure (MAP), which may have contributed to its beneficial effect. We hypothesized that hypothermia would improve survival in a pressure-controlled HS model and that prolonged hypothermia would further improve survival. METHODS: Thirty rats were prepared under light nitrous oxide/halothane anesthesia with spontaneous breathing. The rats underwent HS with an initial blood withdrawal of 2 mL/100 g over 10 minutes and pressure-controlled HS at a MAP of 40 mm Hg over 90 minutes (without anticoagulation), followed by return of shed blood and additional lactated Ringer's solution to achieve normotension. Hemodynamic monitoring and anesthesia were continued to 1 hour, temperature control to 12 hours, and observation without anesthesia to 72 hours. After HS of 15 minutes, 10 rats each were randomized to group 1, with normothermia (38 degrees C) throughout; group 2, with brief mild hypothermia (34 degrees C during HS 15-90 minutes plus 30 minutes after reperfusion); and group 3, with prolonged mild hypothermia (same as group 2, then 35 degrees C [possible without shivering] from 30 minutes after reperfusion to 12 hours). RESULTS: MAP during HS and initial resuscitation was the same in all three groups, but was higher in the hypothermia groups 2 and 3, compared with the normothermia group 1, at 45 and 60 minutes after reperfusion. Group 1 required less blood withdrawal to maintain MAP 40 mm Hg during HS and more lactated Ringer's solution for resuscitation. At end of HS, lactate levels were higher in group 1 than in groups 2 and 3 (p < 0.02). Temperatures were according to protocol. Survival to 72 hours was achieved in group 1 by 3 of 10 rats, in group 2 by 7 of 10 rats (p = 0.18 vs. group 1), and in group 3 by 9 of 10 rats (p = 0.02 vs. group 1, p = 0.58 vs. group 2). Survival time was longer in group 2 (p = 0.09) and group 3 (p = 0.007) compared with group 1. CONCLUSION: Brief hypothermia had physiologic benefit and a trend toward improved survival. Prolonged mild hypothermia significantly increased survival after severe HS even with controlled MAP. Extending the duration of hypothermia beyond the acute phases of shock and resuscitation may be needed to ensure improved outcome after prolonged HS.

Animals↗
PubMed2001

Hemorrhagic shock induced up-regulation of P-selectin expression is mediated by factors in mesenteric lymph and blunted by mesenteric lymph duct interruption.

BACKGROUND: Previous studies have shown that mesenteric lymph duct interruption prevents lung injury and decreases lung neutrophil sequestration after hemorrhagic shock (HS). Since endothelial cells rapidly express P-selectin after ischemia/reperfusion injury and HS-induced lung injury appears to involve neutrophil-endothelial cell interactions, we tested the following two hypotheses. First, that HS increases endothelial cell P-selectin expression and that interruption of mesenteric lymph flow in vivo would diminish this expression. Second, that incubation of human umbilical vein endothelial cells with post-HS mesenteric lymph but not sham shock (SS) lymph or postshock portal vein plasma would up-regulate P-selectin expression. METHODS: Pulmonary microvascular P-selectin expression was measured in male rats subjected to 90 minutes of HS (30 mm Hg), SS, or HS with lymphatic ligation, with a dual radiolabeled monoclonal antibody technique. The lungs from these animals were subsequently harvested and P-selectin expression was expressed as mean +/- SEM nanograms of monoclonal antibody per gram of tissue. RESULTS: Pulmonary P-selectin expression was 2.0 +/- 0.4 after SS, 9.7 +/- 3.0 after HS, but decreased to 2.3 +/- 0.3 after HS with lymph interruption (p < 0.05 HS vs. SS or HS plus lymph ligation). Incubation of human umbilical vein endothelial cells with shock lymph collected 3 to 4 hours after shock resulted in a nearly fivefold increase in P-selectin expression (p < 0.001) as compared with SS lymph, lymph collected 6 hours after shock, or postshock portal vein plasma. CONCLUSION: These results support the concept that gut-derived lymph promotes HS-induced lung injury through up-regulation of microvascular adhesion molecules and that intestinal lymph duct interruption may prevent distant organ injury by blunting the expression of these molecules.

Animals↗
PubMed1998

Nitric oxide in the liver may not be involved in blood redistribution during hemorrhagic shock in the dog.

We previously reported that nitric oxide (NO) in the brain cortex increases during hemorrhagic shock (HS) and then recovers to a baseline level by a retransfusion. Accordingly, we suggested that NO may play a role in blood redistribution during HS. To ascertain whether or not NO contributes to blood redistribution, we have investigated the changes in the liver's NO production during HS. Mongrel dogs were used in the study. After each dog was anesthetized with pentobarbital, an NO-selective electrode was placed in its liver, and a probe to measure hepatic blood flow (HF) was placed on the liver's surface. HS was induced until a mean arterial blood pressure of <40 mmHg was reached. In Group I (n=5), HS was maintained for 30 min. In Group II (n=7), shed blood was reinfused at 10 min after HS. In Group III (n=7), 10 min after NG-nitro-L-arginine methyl ester 30 mg/kg intravenously (i.v.), the same procedures were performed as in Group II. In Groups II and III, although 10 min of HS produced an increase in NO-related electrical current [Group II, 2,197+/-786 pA; Group III, 983+/-77 pA (mean+/-standard error)], reinfusion of shed blood restored the NO-related electrical current to its baseline value. HF in Groups I and II decreased continuously during HS, and it recovered to baseline after the restoration from HS in Group II. In Group III, NG-nitro-L-arginine methyl ester 30 mg/kg i.v. decreased HF 12.7+/-.7 to 10.2+/-.6 mL/min/100 g (mean+/-standard error, p < .05). In conclusion, although NO produced in the liver might play an important pathophysiologic role in HS, it may not affect the blood redistribution during HS, such as in mean arterial blood pressure <40 mmHg.

Animals↗
PubMed2004

Pretreatment with high-fat enteral nutrition reduces endotoxin and tumor necrosis factor-alpha and preserves gut barrier function early after hemorrhagic shock.

Gram-negative sepsis is a potentially fatal clinical syndrome characterized by a proinflammatory response (tumor necrosis factor-alpha) to bacterial (endo)toxins and gut barrier function loss. Recently, we found that high-fat enteral nutrition protects against late bacterial translocation in a model of hemorrhagic shock in rats. However, the basis for this protection is unknown. We hypothesized that the observed protection is the result of an early inhibition of endotoxin and the subsequent inflammatory response resulting in a preserved gut barrier function. Sprague-Dawley rats were divided into a group that was starved overnight (HS-S), fed with a low-fat enteral diet (HS-LF) or fed wih a high-fat enteral diet (HS-HF), and subsequently subjected to a nonlethal hemorrhagic shock. Ninety minutes after hemorrhage, arterial endotoxin significantly decreased in HS-HF rats (4.0 +/- 0.6 pg/mL) compared with HS-LF rats (10.7 +/- 0.9 pg/mL, P = 0.002) and HS-S rats (15.2 +/- 2.2 pg/mL P = 0.001). Interestingly, arterial tumor necrosis factor-alpha was also decreased in HS-HF rats (17.9 +/- 10.4 pg/mL) compared with HS-LF (83.5 +/- 16.7 pg/mL, P < 0.01) and HS-S rats (180.9 +/- 67.9 pg/mL, P < 0.02). Loss of tight junction structure (ZO-1) observed in ileum and colon of control hemorrhagic shock rats was prevented in HS-HF rats. In parallel, intestinal barrier function was preserved in HS-HF rats, evidenced by a reduced permeability to horseradish peroxidase (P < 0.05), less bacterial invasion, and a 10-fold reduction of bacterial translocation early after hemorrhagic shock. This report describes a new strategy to nutritionally prevent endotoxemia, the subsequent inflammatory response and gut barrier failure following hemorrhagic shock. High-fat enteral nutrition requires further evaluation as an intervention to prevent a potentially fatal systemic inflammatory response in patients at risk for sepsis.

Animal Feed↗
PubMed2005

Abnormal B-cell regulation in highly sensitized patients with sustained serum levels of antibody to HLA class I antigens.

BACKGROUND: There are anti-idiotypes in the sera of highly sensitized (HS) patients that stimulate B cells to produce antibody to HLA class I antigens. The purpose of this study is to determine if there is an abnormality in B cell responses to these anti-idiotypes. METHODS: Supernatants from normal and HS B cells exposed to either HLA-like anti-idiotypes or HS sera were tested for IgG and antibody to HLA class I antigens by ELISA and flow beads. RESULTS: When stimulated with HS sera, HS B cells produced antibody to HLA class I antigens (in vitro) (12/12) but normal B cells did not (0/10) (P<0.0001). When HS B cells were stimulated with isolated HLA-like anti-idiotypes, they produced more total IgG in the supernatant (603+/-105 ng/ml vs. 293+/-30 ng/ml; P<0.01) and more IgG1 (67+/-5.3 ng/ml vs. 32.3+/-5.4 ng/ml; P<0.001) and more IgG3 (33.3+/-9.2 vs. 2.03+/-0.2 ng/ml; P<0.0001) than normal B cells. The proliferative response to HLA-like anti-idiotypes was 1285+/-115 cpm from normal B cells and 1020+/-445 from HS B cells (p=NS). CONCLUSIONS: When exposed to HS sera, HS B cells produced antibody to HLA class I antigens and normal B cells did not. When exposed to isolated HLA-like anti-idiotypes, HS B cells produced more total IgG, primarily IgG1 and IgG3 with normal proliferation. This intrinsic abnormality in HS B cells permits antibody to HLA class I antigens to be produced and allows increased amounts of IgG1 and IgG3 to be secreted in the absence of an increase in proliferation.

Antibodies↗
PubMed1993

Lymphocyte transformation test with house dust mite (Dermatophagoides pteronyssinus) in normal children, asthmatic children and asthmatic children receiving hyposensitization.

In the first part of this study the proliferative response of lymphocytes (lymphocyte transformation test) to house dust mite (HDM) stimulation in cultures was studied in normal children (n = 16), asthmatic children who never received hyposensitization (HS) (n = 50) and asthmatic children receiving HS with HDM for at least 6 months (n = 20). The results are expressed as disintegrations per minute (d.p.m.) and as stimulation index (SI = d.p.m. in the presence of the allergen/d.p.m. in the control culture). A positive SI (> 2) was found in 54% of the asthmatic children who never received HS, in 30% of the asthmatics receiving HS and in none of the normal children. Furthermore, between asthmatics with and without HS, the SI was not statistically different, although asthmatics without HS tended to have a higher SI (median value: 2.13 vs 1.38) (P = 0.10). In a second series of experiments the effect of adding interleukin-2 (IL-2) to the lymphocyte cell culture was studied in asthmatic children with and without HS. Interleukin-2 induced an additional stimulatory effect on the lymphoproliferative response to HDM and to phytohaemagglutinin in patients who never received HS, but had no effect in patients receiving HS. We conclude that HS treatment seems to have an inhibiting effect upon this proliferative response, not only inhibiting the degree of the allergen-induced lymphocyte proliferation, but also inhibiting the sensitivity of proliferating lymphocytes for IL-2. These inhibiting effects upon lymphocytic activation could be responsible for the anti-inflammatory effects (i.e. suppression of the late asthmatic reaction) of HS.

Allergens↗
PubMed2004

Salicylic acid dependent signaling promotes basal thermotolerance but is not essential for acquired thermotolerance in Arabidopsis thaliana.

Salicylic acid (SA) is reported to protect plants from heat shock (HS), but insufficient is known about its role in thermotolerance or how this relates to SA signaling in pathogen resistance. We tested thermotolerance and expression of pathogenesis-related (PR) and HS proteins (HSPs) in Arabidopsis thaliana genotypes with modified SA signaling: plants with the SA hydroxylase NahG transgene, the nonexpresser of PR proteins (npr1) mutant, and the constitutive expressers of PR proteins (cpr1 and cpr5) mutants. At all growth stages from seeds to 3-week-old plants, we found evidence for SA-dependent signaling in basal thermotolerance (i.e. tolerance of HS without prior heat acclimation). Endogenous SA correlated with basal thermotolerance, with the SA-deficient NahG and SA-accumulating cpr5 genotypes having lowest and highest thermotolerance, respectively. SA promoted thermotolerance during the HS itself and subsequent recovery. Recovery from HS apparently involved an NPR1-dependent pathway but thermotolerance during HS did not. SA reduced electrolyte leakage, indicating that it induced membrane thermoprotection. PR-1 and Hsp17.6 were induced by SA or HS, indicating common factors in pathogen and HS responses. SA-induced Hsp17.6 expression had a different dose-response to PR-1 expression. HS-induced Hsp17.6 protein appeared more slowly in NahG. However, SA only partially induced HSPs. Hsp17.6 induction by HS was more substantial than by SA, and we found no SA effect on Hsp101 expression. All genotypes, including NahG and npr1, were capable of expression of HSPs and acquisition of HS tolerance by prior heat acclimation. Although SA promotes basal thermotolerance, it is not essential for acquired thermotolerance.

Acclimatization↗
PubMed2006

Comparison of biopsy samples obtained using standard endoscopic instruments and the harmonic scalpel during laparoscopic and laparoscopic-assisted surgery in normal dogs.

OBJECTIVES: To compare tissue specimens of canine abdominal organs collected by standard techniques (ST) and harmonic scalpel (HS) and to determine the effect of each technique on wound healing. STUDY DESIGN: Experimental. ANIMALS: Twelve dogs. METHODS: Paired biopsy samples (ST, HS) were collected from liver, spleen, adrenal gland, pancreas, stomach, jejunum, and bladder using laparoscopic or laparoscopic-assisted methods. Hemorrhage at biopsy sites was assessed (present or absent). Specimens were evaluated for diagnostic quality and histologic changes. Dogs were necropsied at 4 or 14 days postoperatively. RESULTS: HS incision caused less frequent hemorrhage of all organs except spleen. HS specimens had more coagulation necrosis than ST specimens, but both techniques yielded specimens that were sized similarly and were of diagnostic quality. At necropsy, HS biopsy sites of the stomach, jejunum, bladder, adrenal gland, and pancreas were more hyperemic than ST sites. There were more adhesions at jejunal and pancreatic ST biopsy sites. HS biopsy sites had more coagulation necrosis at days 4 and 14 postoperatively. Differences in fibrin deposition, inflammation, and fibrosis were present at biopsy sites of some organs at days 4 or 14 and in comparisons between days 4 and 14. CONCLUSIONS: Diagnostic quality biopsy specimens were obtained with HS and ST. Although HS-induced gross and histologic changes during the first 2 postoperative weeks, no clinical complications were observed. CLINICAL RELEVANCE: Both HS and ST can yield specimens with minimal hemorrhage and HS resulted in no apparent postoperative problems in normal dogs. Although HS caused more inflammation and adhesions at biopsy sites of the pancreas, adrenal gland, and jejunum, no clinical complications occurred.

Animal Structures↗