vasoactive-intestinal-peptide and Shock--Septic

Vasoactive intestinal peptide (VIP), a peptide produced by immune cells, exerts a wide spectrum of immunological functions that control the homeostasis of the immune system. In the last decade, VIP has been clearly identified as a potent anti-inflammatory factor, both in innate and adaptive immunity. In innate immunity, this peptide inhibits the production of inflammatory cytokines and chemokines from macrophages, microglia and dendritic cells. In addition, VIP reduces the expression of co-stimulatory molecules on antigen-presenting cells, and therefore reduces stimulation of antigen-specific CD4 T-cells. In terms of adaptive immunity, VIP promotes T-helper (Th)2-type responses, and reduces inflammatory Th1-type responses. Several of the molecular mechanisms involved in the inhibition of cytokine and chemokine expression, and in the preferential development and/or survival of Th2 effectors are known. Therefore, VIP and its analogs have been proposed as promising alternative candidates to existing therapies for the treatment of acute and chronic inflammatory and autoimmune diseases. The aim of this review is to update knowledge of the cellular and molecular events that are relevant to VIP function in the immune system. The central functions that VIP plays in cellular processes is being recognized and attention is being focused on this important peptide with regard to exciting new candidates for therapeutic intervention and drug development.

Topics: Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Autoimmunity; CD4-Positive T-Lymphocytes; Dendritic Cells; Drug Design; Homeostasis; Humans; Immunity, Innate; Inflammation; Lymphoid Tissue; Macrophages; Microglia; Neurodegenerative Diseases; Receptors, Vasoactive Intestinal Peptide; Shock, Septic; T-Lymphocyte Subsets; Th2 Cells; Vasoactive Intestinal Peptide

The structurally related neuropeptides VIP and PACAP are released within the lymphoid organs following antigenic stimulation, and modulate the function of inflammatory cells through specific receptors. In activated macrophages, VIP and PACAP inhibit the production of pro-inflammatory agents (cytokines, chemokines, and nitric oxide), and stimulate the production of the anti-inflammatory cytokine IL-10. These events are mediated through the VIP/PACAP effects on de novo expression or nuclear translocation of several transcription factors, i.e., NFkappaB, CREB, c-Jun, JunB, and IRF-1. The in vivo administration of VIP/PACAP results in a similar pattern of cytokine and chemokine modulation, which presumably mediates the protective effect of VIP/PACAP in septic shock. In addition, VIP/PACAP reduce the expression of the co-stimulatory molecules B7.1/B7.2, and the subsequent stimulatory activity of macrophages for T-helper cells. In T-cells expressing specific VIP/PACAP receptors, VIP and PACAP inhibit the expression of FasL through effects on NFkappaB, NFAT, and Egr2/3. The reduction of FasL expression has several biological consequences: inhibition of antigen-induced cell death in CD4 T-cells, inhibition of the FasL-mediated cytotoxicity of CD8 and CD4 effectors against direct and bystander targets, and promotion of long-term memory Th2 cells, through a positive effect on the survival of Th2, but not Th1, effectors. The various biological effects of VIP and PACAP are discussed within the range of a general anti-inflammatory model.

Topics: Adjuvants, Immunologic; Antigens; Antigens, Surface; B7-1 Antigen; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Death; Cell Survival; Chemokines; Cytokines; DNA-Binding Proteins; Early Growth Response Protein 2; Fas Ligand Protein; Humans; Immunity, Active; Immunity, Innate; Inducible T-Cell Co-Stimulator Ligand; Inflammation Mediators; Interleukin-10; Macrophage Activation; Membrane Glycoproteins; Neuropeptides; NF-kappa B; NFATC Transcription Factors; Nitric Oxide; Nuclear Proteins; Pituitary Adenylate Cyclase-Activating Polypeptide; Shock, Septic; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; Th2 Cells; Transcription Factors; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) and the structurally related neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP), present in the microenvironment of lymphoid organs, modulate the function of inflammatory cells through specific receptors. VIP and PACAP inhibit the production of pro-inflammatory agents and stimulate the production of anti-inflammatory cytokines in activated macrophages. The effect is mediated through specific receptors and involves shedding of the CD14 lipopolysaccharide (LPS) receptor and the transcriptional regulation of cytokine genes through effects on de novo expression or nuclear translocation of NFkappaB, cAMP-element binding protein (CREB), c-Jun, and interferon regulatory factor 1 (IRF-1). The in vivo administration of VIP/PACAP results in a similar pattern of cytokine modulation which, presumably, mediates the protective effect of VIP/PACAP in a high-endotoxic murine model for septic shock. VIP/PACAP reduce the expression of the costimulatory B7.1/B7.2 molecules and the subsequent stimulatory activity for T helper (Th) cells in stimulated macrophages. In contrast, in unstimulated macrophages, VIP/PACAP induce specific B7.2 expression and promote Th2 cell differentiation. We propose that VIP/PACAP act as endogenous factors that regulate immune homeostasis and that the physiological consequences of VIP/PACAP presence in the immune microenvironment depend on the timing of the neuropeptide release and the activation stage of the neighboring immune cells.

Topics: Animals; Antigen Presentation; Antigens, CD; B7-1 Antigen; B7-2 Antigen; Cytokines; Humans; In Vitro Techniques; Macrophages; Membrane Glycoproteins; Mice; Models, Biological; Neuroimmunomodulation; Neuropeptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Shock, Septic; Th1 Cells; Th2 Cells; Vasoactive Intestinal Peptide

Topics: Animals; Bradykinin; Catecholamines; Endorphins; Histamine; Histamine Release; Kallikreins; Kinins; Prostaglandins; Serotonin; Shock, Septic; Thromboxanes; Vasoactive Intestinal Peptide; Vasopressins

The vaginal epithelium provides a barrier to pathogens and recruits immune defenses through the secretion of cytokines and chemokines. Several studies have shown that mucosal sites are innervated by norepinephrine-containing nerve fibers. Here we report that norepinephrine potentiates the proinflammatory response of human vaginal epithelial cells to products produced by Staphylococcus aureus, a pathogen that causes menstrual toxic shock syndrome. The cells exhibit immunoreactivity for catecholamine synthesis enzymes and the norepinephrine transporter. Moreover, the cells secrete norepinephrine and dopamine at low concentrations. These results indicate that norepinephrine may serve as an autocrine modulator of proinflammatory responses in the vaginal epithelium.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Cell Line, Transformed; Dopamine; Epithelial Cells; Female; Humans; Immunomodulation; Interleukin-6; Interleukin-8; Neuroimmunomodulation; Neuropeptide Y; Norepinephrine; Peptide Fragments; Phentolamine; Propranolol; Shock, Septic; Staphylococcal Infections; Superantigens; Vagina; Vasoactive Intestinal Peptide

Tissue factor (TF), which is expressed on the surface of activated monocytes, is the major procoagulant that initiates thrombus formation in sepsis. Two endogenous neuropeptides, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP), are attractive candidates for the development of therapies against septic shock. The purpose of this study was to examine whether VIP or PACAP inhibit the LPS-induced TF expression in monocytes. Treatment of freshly isolated human monocytes or cultured monocytic THP-1 cells with VIP or PACAP leads to reduced LPS-induced TF protein, mRNA expression and activity, as demonstrated by Western blot, real-time polymerase chain reaction, and TF activity assay, respectively. In an endotoxemic model, VIP blunts the increase of LPS-induced TF expression in blood cells at the transcriptional level, as demonstrated by real-time polymerase chain reaction. However, neither neuropeptide affects the expression of TF pathway inhibitor in monocytes. In vitro, LPS increases the migration of c-Rel/p65 into the nucleus and the phosphorylation of p38 and JNK, all of which are essential for LPS-induced TF expression. In addition, interestingly, VIP and PACAP block both the migration of c-Rel/p65 and the phosphorylation of p38 and JNK, as demonstrated by Western blot analysis. These data indicate that VIP and PACAP inhibit LPS-induced TF expression in monocytes in vitro and in vivo, confirming these peptides as candidates for the multitarget therapy of septic shock.

Topics: Animals; Dose-Response Relationship, Drug; Endotoxemia; Humans; Lipopolysaccharides; Male; MAP Kinase Kinase 4; Mice; Mice, Inbred BALB C; Monocytes; p38 Mitogen-Activated Protein Kinases; Pituitary Adenylate Cyclase-Activating Polypeptide; Shock, Septic; Thromboplastin; Vasoactive Intestinal Peptide

To investigate the protective effects of vasoactive intestinal peptide (VIP) on septic shock rats and explore its possible mechanism.. Cecal ligation and puncture (CLP) was performed to produce septic shock rat model. Thirty adult Sprague-dawley rats were randomly divided into 3 groups with 10 animals in each group: sham operation group, CLP group and VIP group. The rats in VIP group were given intravenous injection of VIP (5 nmol per rat) instantly after the CLP operation. Then the mean arterial pressure (MAP) was monitored consistently and survival rate was observed. Blood samples were obtained from femoral artery for measuring the serum concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) by using enzyme-linked immunosorbent assays (ELISA). Organs (lung, kidney and intestine) were harvested for pathological examination.. At each time point after 8 h, the MAP of VIP rats was significantly higher than that in CLP rats (P<0.05). In VIP group rats, the serum TNF-alpha concentration was decreased meanwhile IL-10 level was increased with markedly alleviated organic pathological injuries and the survival rate was obviously raised.. VIP exerts protective effects on septic shock rats through inhibiting production of proinflammatory factors and stimulating the production of anti-inflammatory cytokines.

Topics: Animals; Blood Pressure; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Interleukin-10; Male; Neuroprotective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; Shock, Septic; Survival Rate; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is a neuro-peptide that can modulate immunity in several aspects. Previous reports showed that VIP attenuates the deleterious consequences of severe infection and septic shock by regulating production of inflammatory cytokines in immune activated cells. Intestine is one of the major organ of immune system and it may trigger multiple organ dysfunction syndrome in sepsis. The present study was planned to study the change of serum TNF-alpha, IL-1beta, IL-10 level and histopathological alteration of intestinal tract, and protective effects of VIP on endotoxic shock in rat.. Twenty eight SD rats were randomly divided into 3 groups, including control group (8 rats), LPS shock group (10 rats), and LPS + VIP group (10 rats). Endotoxic shock model was established by administration of a single dose of 10 mg/kg LPS in LPS shock group, a bolus of 5 nmol VIP intravenous injection following LPS in LPS + VIP group. The rats in the control group were given the same volume of normal saline injection. Blood samples were taken at time points of 1, 2, 4, and 6 hours after intervention from each group for measuring the level of TNF-alpha, IL-1beta and IL-10 by ELISA. Pathological changes of the intestine were observed by light microscope and electron microscope at the animals death or at the end of the experiment.. Serum TNF-alpha, IL-1beta and IL-10 levels elevated at each time point in LPS shock group and LPS + VIP group (P < 0.05 or P < 0.01). TNF-alpha concentration reached the peak level 2 h after LPS injection; IL-1beta and IL-10 increased continuously till the end of the experiment. In LPS + VIP group, TNF-alpha and IL-1beta elevated slightly and IL-10 increased significantly as compared with LPS shock group (P < 0.01). Leukocyte infiltration, ischemia, segmental hemorrhage or necrosis appeared in intestine under light microscope and cell swelling, cytoplasmic vacuoles and organelle damage were observed under electron microscope. However, pathological changes in LPS + VIP group were milder than those in LPS group.. VIP improved endotoxic shock-associated histopathological alteration of intestine, down-regulated pro-inflammatory cytokines production and up-regulated anti-inflammatory cytokines. These effects may suggest a protective mechanism of VIP in septic shock. VIP is a potential immunoregulatory substance in treatment of septic shock.

Topics: Animals; Biomarkers; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Interleukin-10; Interleukin-1beta; Intestines; Lipopolysaccharides; Male; Rats; Rats, Sprague-Dawley; Shock, Septic; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide

Septic shock is a systemic response to severe bacterial infections, generally caused by Gram-negative bacterial endotoxins, with multiple manifestations such as hypotension, tissue injury, disseminated intravascular coagulation, and multi-organ failure. All these effects, are induced by the generation of pro-inflammatory and vasodilator mediators, cell adhesion molecules, coagulation factors, and acute-phase proteins. Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two immunopeptides with anti-inflammatory properties exerted through type 1 and 2 VIP receptors (VPAC1 and VPAC2, respectively), and PACAP receptor (PAC1). The present results recapitulate the protective role of PAC1 in an experimental model of lethal endotoxemia using a knockout for the PAC1 receptor. Our results demonstrate that VIP and PACAP decrease lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) production, neutrophil infiltration and intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and fibrinogen expression through PAC1 receptor, providing an advantage to design more specific drugs complementing standard intensive care therapy in septic shock.

Topics: Animals; Mice; Mice, Knockout; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Shock, Septic; Survival Rate; Vasoactive Intestinal Peptide

Infections caused by Gram-negative bacteria constitute one of the major causes of septic shock, which results from the inability of the immune system to limit bacterial spread during the ongoing infection. In the last decade, it has been demonstrated that vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two endogenous immunopeptides, which together with three G protein-coupled receptors (VPAC1, VPAC2, and PAC1) exert a significant, therapeutic effect attenuating the deleterious consequences of septic shock by balancing pro- and anti-inflammatory factors. We have recently shown PAC1 receptor involvement in vivo as an anti-inflammatory receptor, at least in part, by attenuating lipopolysaccharide-induced production of proinflammatory interleukin-6. The present study deepens in the protective role of PAC1 receptor in septic shock, elucidating its involvement in the modulation of neutrophil recruitment and in the expression of different molecular sensors such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, fibrinogen, serum amyloid A, and nitric oxide as important, systemic players of the development of septic shock. Our results, using a mice deficient in PAC1 and a PAC1 antagonist, show that VIP and PACAP as well as the PAC1 receptor are involved in neutrophil recruitment in different target organs, in adhesion molecules expression, and in coagulation-related molecule fibrinogen synthesis. Thus, this study provides some important insights with respect to the involvement of PAC1 into the complexities of sepsis and represents an advantage for the design of more specific drugs complementing standard intensive care therapy in severe sepsis, confirming VIP and PACAP as candidates for multitarget therapy of septic shock.

Topics: Acute-Phase Reaction; Animals; Fibrinogen; Intercellular Adhesion Molecule-1; Intestines; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Growth Factors; Neuropeptides; Neurotransmitter Agents; Neutrophil Infiltration; Nitric Oxide; Peroxidase; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Cell Surface; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Serum Amyloid A Protein; Shock, Septic; Vascular Cell Adhesion Molecule-1; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two mediators synthesized by immune cells, specially under inflammatory and antigen stimulation conditions. Reports have shown that neuropeptides attenuate the deleterious consequences of septic shock both by down-regulating the production of proinflammatory mediators and by stimulating the production of anti-inflammatory cytokines by activated macrophages. In this study, we used a knockout for the PACAP receptor (PAC1(-/-)) to demonstrate an important protective role for PAC1 receptor in endotoxic shock. Moreover, our results indicate that PAC1 receptor acts in vivo as an anti-inflammatory receptor, at least in part, by attenuating lipopolysaccharide (LPS)-induced production of proinflammatory IL-6, which appears to be the main cytokine regulating the expression of the majority of the acute phase protein genes, which are an important deleterious component of septic shock. Besides, our findings point to endogenously produced VIP and PACAP as participants of the natural anti-inflammatory machinery. Because VIP and PACAP are two attractive candidates for the development of therapies against acute and chronic inflammatory diseases, septic shock, and autoimmune diseases, this paper represents a contribution to the understanding of the mechanism of action of these anti-inflammatory agents.

Topics: Animals; Female; Inflammation; Interleukin-6; Lipopolysaccharides; Male; Mice; Mice, Knockout; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Receptors, Pituitary Hormone; Shock, Septic; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) has potent protective activity against sepsis and increases the survival rate of septic rats and mice. The present study was planned to evaluate the effect of VIP on mast cell activity, histamine and methylhistamine levels and oxidative stress in the liver and kidneys of septic rats. The effect of VIP was compared to that of nitric oxide synthesis inhibition, previously tested extensively in septic shock models, with doubtful benefit. The present study showed that endotoxic shock did not lead to oxidative stress in either liver or kidney of the rats. On the other hand, mast cells, based on their location, displayed functional heterogeneity to the septic insults. VIP possibly modulated the specific reactions of the tissues to mediators released from mast cells during septic shock. The most prominent effect of VIP as compared to nitric oxide synthesis inhibition was related to mast cells. In conclusion, the prevention of mast cell reactivity by VIP could be a potential therapeutic strategy in controlling septic shock.

Topics: Animals; Antioxidants; Catalase; Cell Degranulation; Female; Histamine; Kidney; Lipid Peroxidation; Liver; Male; Mast Cells; Methylhistamines; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Sprague-Dawley; Shock, Septic; Superoxide Dismutase; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is a neuropeptide that can modulate several immune aspects. Previous reports showed that VIP attenuates the deleterious consequences of septic shock by inhibiting the production of pro-inflammatory agents and stimulating the production of anti-inflammatory cytokines in activated macrophages. In this study, by using selective VIP agonists, we investigated the differential involvement of the VIP receptors in the anti-inflammatory role of VIP. Both the type 1 VIP receptor (VPAC1) agonist, [K(15), R(16), L(27)] VIP 1-7-GRF 8-27, and the type 2 VIP receptor (VPAC2) agonist, Ro25-1553, protected mice from lethal endotoxemia by inhibiting the macrophage-derived pro-inflammatory mediators IL-6, TNF-alpha, IL-12 and NO, and by stimulating the production of the anti-inflammatory cytokine IL-10. In addition, both VIP and VPAC1 agonist, but not the VPAC2 agonist, reduced in vitro and in vivo the expression of the co-stimulatory B7. 1/B7.2 molecules, and the subsequent stimulatory activity for T helper cells in stimulated macrophages. The higher effectiveness of the VPAC1 agonist compared with the VPAC2 agonist suggests that VPAC1 is the major mediator of the anti-inflammatory action of VIP. Since VIP and the two agonists appear to affect multiple cytokines and inflammatory factors, they might provide a more efficient therapeutical alternative to the use of specific cytokine antibodies or antagonists.

Topics: Animals; Female; Immunity, Innate; Inflammation; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Receptors, Vasoactive Intestinal Peptide; Shock, Septic; Signal Transduction; Vasoactive Intestinal Peptide

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) down-regulate cytokine production. Because human septic shock involves excessive cytokine production, the effect of VIP/PACAP was investigated in a high endotoxemia murine model. Both peptides protect against endotoxin-induced lethality and prevent septic shock-associated histopathological alterations. VIP/PACAP reduce serum and peritoneal TNF-alpha and IL-6, suggesting that the protective effect is exerted by inhibiting the production of endogenous TNF-alpha/IL-6. Consistent with this mechanism, VIP does not protect against septic shock induced by exogenous TNF-alpha. The immunomodulatory role of VIP in vivo is supported by the appearance of high levels of VIP in serum and peritoneal fluid following LPS administration. Thus, the neuropeptides VIP/PACAP protect from the lethal effect of high endotoxemia, presumably by down-regulating TNF-alpha and IL-6 production, and may offer an alternative in the treatment of human septic shock syndrome.

Topics: Animals; Injections, Intraperitoneal; Interleukin-6; Lethal Dose 50; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Neuropeptides; Neuroprotective Agents; Pituitary Adenylate Cyclase-Activating Polypeptide; Shock, Septic; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide

High-output nitric oxide (NO) production from activated macrophages, resulting from the induction of inducible NO synthase (iNOS) expression, represents a major mechanism for macrophage cytotoxicity against pathogens. However, despite its beneficial role in host defense, sustained high-output NO production was also implicated in a variety of acute inflammatory diseases and autoimmune diseases. Therefore, the down-regulation of iNOS expression during an inflammatory process plays a significant physiological role. This study examines the role of two immunomodulatory neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), on NO production by LPS-, IFN-gamma-, and LPS/IFN-gamma-stimulated peritoneal macrophages and the Raw 264.7 cell line. Both VIP and PACAP inhibit NO production in a dose- and time-dependent manner by reducing iNOS expression at protein and mRNA level. VPAC1, the type 1 VIP receptor, which is constitutively expressed in macrophages, and to a lesser degree VPAC2, the type 2 VIP receptor, which is induced upon macrophage activation, mediate the effect of VIP/PACAP. VIP/PACAP inhibit iNOS expression and activity both in vivo and in vitro. Two transduction pathways appear to be involved, a cAMP-dependent pathway that preferentially inhibits IFN regulatory factor-1 transactivation and a cAMP-independent pathway that blocks NF-kappa B binding to the iNOS promoter. The down-regulation of iNOS expression, together with previously reported inhibitory effects on the production of the proinflammatory cytokines IL-6, TNF-alpha, and IL-12, and the stimulation of the anti-inflammatory IL-10, define VIP and PACAP as "macrophage deactivating factors" with significant physiological relevance.

Topics: Animals; Cyclic AMP; DNA-Binding Proteins; Drug Synergism; Enzyme Activation; Interferon Regulatory Factor-1; Interferon-gamma; Intracellular Fluid; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred BALB C; Neuropeptides; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Phosphoproteins; Pituitary Adenylate Cyclase-Activating Polypeptide; Protein Binding; Receptors, Vasoactive Intestinal Peptide; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; RNA, Messenger; Shock, Septic; Signal Transduction; Time Factors; Transcription, Genetic; Vasoactive Intestinal Peptide

Topics: Analysis of Variance; Animals; Blood Pressure; Escherichia coli; Female; Lipopolysaccharides; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Shock, Septic; Time Factors; Vasoactive Intestinal Peptide

Vasoactive intestinal polypeptide (VIP) and endotoxin (lipopolysaccharides, LPS) were measured in plasma samples from 11 patients with bacteriologically verified meningococcal disease. Five patients suffered fulminant septicaemia, developed severe septic shock, and 2 died due to circulatory collapse. Initially, all 5 had levels of VIP above 4 pM and plasma endotoxin above 200 ng/liter. Five patients were diagnosed as meningitis and 1 as having meningococcaemia, all with a normal circulatory state. None of these 6 patients had initially levels of VIP above 2.5 pM or endotoxin levels above 25 ng/liter (P less than 0.001). A correlation existed between plasma endotoxin and VIP levels (r = 0.735, P = 0.01). Sequentially collected samples from 3 patients showed rapidly declining VIP levels after initiation of antibiotic and fluid treatment. These results are in agreement with previous animal experiments, suggesting that endotoxin directly or indirectly stimulates the VIP-ergic nervous system in the initial phase of gram-negative septic shock in man.

Topics: Adult; Child; Endotoxins; Humans; Meningitis, Meningococcal; Meningococcal Infections; Neisseria meningitidis; Sepsis; Shock, Septic; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is a potent vasodilator that has been reported to be a mediator of the hemodynamic changes in endotoxin-induced hypodynamic septic shock. We investigated the release of VIP in a hyperdynamic model of sepsis in awake, conscious dogs similar to that of sepsis in human beings. Sepsis was induced by intraperitoneal implantation of a fibrin clot containing live Escherichia coli (0.9 +/- 0.2 X 10(9) organisms per kilogram of body weight). All dogs developed hyperdynamic sepsis with increased cardiac output and decreased systemic vascular resistance. During the first 24 hours of sepsis, VIP was released without a concomitant decrease in blood pressure, suggesting that during septic shock it was released by a direct mechanism rather than as a result of hypotension. During peak VIP release (2 to 4 hours after induction of sepsis) no decreases in systemic vascular resistance or mean arterial pressure were observed. This suggests that mediators other than VIP may be responsible for the vasodilation observed during sepsis. The precise role of VIP during sepsis is therefore yet to be clarified.

Topics: Animals; Blood Pressure; Cardiac Output; Disease Models, Animal; Dogs; Female; Heart Rate; Hemodynamics; Male; Portal Vein; Shock, Septic; Vascular Resistance; Vasoactive Intestinal Peptide

Plasma levels of catecholamines and neuropeptides (met-enkephalin, ME; neurotensin, NT; neuropeptide Y, NPY; peptide YY, PYY; vasoactive intestinal polypeptide, VIP; cholecystokinin, CCK; bombesin, BMB) were examined in the femoral artery (FA), adrenal vein (AD), and portal vein (PV), in eight cats under halothane anesthesia at baseline (S1), at the end of a 2-hr ligation period of the major splanchnic arteries (celiac trunk, superior and inferior mesenteric arteries) (S2), immediately (S3) and 30 min (S4) after splanchnic reperfusion, and after the administration of naloxone (1 mg/kg, i.v.) (S5). During S2, there was a significant increase in portal vein VIP levels, while the other variables (hemodynamics, hormone levels) remained unchanged. During early shock (S3), significant (10- to 30-fold) increases in adrenal secretion of all catecholamines, ME, NT, NPY, and PYY occurred, while VIP and PYY were significantly released into the PV, and two- to tenfold increases in femoral artery catecholamine and ME levels were observed. Later shock (S4) led to a further fivefold increase, compared to S3, in adrenal release of norepinephrine (NE), dopamine (DA), and ME. Following naloxone administration (S5), the adrenal medullary release of NE, epinephrine (EPI), DA, NT, and NPY was significantly (twofold) increased; however, the animals' hemodynamic situation did not improve.

Topics: Adrenal Glands; Animals; Bombesin; Catecholamines; Cats; Cholecystokinin; Enkephalin, Methionine; Hemodynamics; Intestinal Mucosa; Ischemia; Ligation; Mesenteric Arteries; Naloxone; Neuropeptide Y; Neuropeptides; Neurotensin; Peptide YY; Peptides; Shock, Septic; Vasoactive Intestinal Peptide

Topics: Animals; Blood Pressure; Cardiac Output; Escherichia coli; Humans; Kinetics; Lipopolysaccharides; Shock, Hemorrhagic; Shock, Septic; Swine; Vascular Resistance; Vasoactive Intestinal Peptide

Vasoactive intestinal polypeptide (VIP) is a highly potent vasodilatator. Cardiovascular changes and plasma VIP levels were studied during endotoxinaemia (Escherichia coli endotoxin 1 mg/kg) in a carefully monitored porcine model. Endotoxin infusion resulted in a profound but reversible shock and a substantial rise in plasma VIP levels. Increased levels of VIP could be demonstrated already after 30 min of endotoxin infusion and increased further during the infusion. Animals followed for a period of 60 h demonstrated slowly declining levels of VIP after endotoxin infusion but significantly elevated levels were usually found 24 h after infusion. Control animals did not show any changes in VIP during a similar procedure. Release of gastrointestinal peptides may be of importance during septic shock.

Topics: Animals; Chromatography, Gel; Endotoxins; Escherichia coli; Female; Hemodynamics; Leukocyte Count; Male; Shock, Septic; Swine; Vasoactive Intestinal Peptide

Plasma vasoactive intestinal polypeptide (VIP) increased significantly in the portal vein, the superior caval vein, the internal jugular vein, and the aorta during an intravenous infusion of E. coli endotoxin in six anesthetized pigs, which all developed a deep shock, with fall in aortic blood pressure and urinary output. Plasma VIP peaked simultaneously with the most pronounced shock symptoms, and the level in the portal vein was significantly higher than in blood from the other sampling sites. In contrast, no significant change in plasma secretin was noted. It is suggested that the gastrointestinal tract is the main source of the high plasma VIP levels seen during endotoxinemia and that VIP may play a significant role in endotoxin shock.

Topics: Animals; Endotoxins; Escherichia coli; Female; Infusions, Parenteral; Male; Secretin; Shock, Septic; Swine; Vasoactive Intestinal Peptide

Some of the many metabolic and cardiovascular activities and effects of vasoactive intestinal peptide are quite similar to the changes observed in endotoxin shock. The changes occurring in plasma vasoactive intestinal peptide levels during canine endotoxin shock were studied. Vasoactive intestinal peptide levels were markedly and significantly elevated following the administration of endotoxin, corresponding well with the drop in systemic blood pressure. In the dogs surviving the experiment, plasma vasoactive intestinal peptide levels returned to normal levels after 24 hours, corresponding well with the restoration of normal hemodynamic values. Surviving dogs exhibited significantly lower vasoactive intestinal peptide levels than did nonsurvivors. Many of the biologic activities of vasoactive intestinal peptide make it suitable for counteracting endotoxemia, thus acting as the defense of the body against endotoxin. However, the lower vasoactive intestinal peptide levels in the surviving dogs rather points to vasoactive intestinal peptide as a causative factor in canine endotoxemia.

Topics: Animals; Blood Pressure; Dogs; Gastrointestinal Hormones; Shock, Septic; Time Factors; Vasoactive Intestinal Peptide