vasoactive-intestinal-peptide and Necrosis

Cutaneous necrotizing vasculitides (CNV) are a group of clinical disorders characterized by: 1) angiocentric segmental inflammation, 2) cellular infiltrate, 3) red cell extravasation, 4) fibrinoid necrosis of the blood vessels, and possibly 5) nuclear debris. There are many classifications of vasculitides based or on the diameter of the vessels or on the type of the cellular infiltrate. In this paper we outline the major key role played by the endothelium in this pathological process and the possible role of the regulatory peptides in the pathogenesis of CNV. Despite there are not direct yet clear evidences of the role of neuropeptides in the pathogenesis of cutaneous necrotizing vasculitis, we suggest a possible major role of them, on the basis of the activity of regulatory peptides on microvascular endothelium, on polymorphonuclear chemotaxys and on lymphocytic functions. Thus, neuropeptides and endothelins could act on the tone of the vessel, provoking vasodilation or vasoconstriction, determining a possible stimulus to inflammation and/or venular thrombosis. The release of neuropeptides at the sites of local inflammation could modulate the activity of nearby inflammatory cells and other tissue elements. Organs with neuropeptidergic fibers in high density, such as the skin, could be particularly susceptible to perturbations from inflammation-derived neuropeptides.

Topics: Animals; Calcitonin Gene-Related Peptide; Endothelins; Humans; Necrosis; Neuropeptides; Peptides; Skin Diseases, Vascular; Substance P; Vasculitis; Vasoactive Intestinal Peptide

To investigate the modulatory effect of recombinant-expressed vasoactive intestinal peptide (VIP) analogue (rVIPa) on trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats.. Forty-eight rats were randomized into six groups: normal control group (Control), model control group (TNBS), ethanol treatment group (ETOH), and VIP treatment groups with different dosage (rVIPa. Administration with 2 nmol rVIPa prevented TNBS-induced necrosis, hyperemia, swelling, inflammation,. rVIPa ameliorates TNBS-induced colonic injury and inflammation and effectively protected the intestinal mucosal barrier function in rats. The mechanism may be related to TLR4/NF-κB-mediated signaling pathway. rVIPa could be used as a new alternative therapy for intestinal inflammatory disorders.

Topics: Animals; Colon; Crohn Disease; Diarrhea; Disease Models, Animal; Gastrointestinal Agents; Humans; Intestinal Mucosa; Male; Necrosis; NF-kappa B; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Signal Transduction; Toll-Like Receptor 4; Treatment Outcome; Trinitrobenzenesulfonic Acid; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is a neuropeptide hormone that suppresses Th1-mediated cellular immunity. We previously reported that VIP-knockout (VIP-KO) mice have enhanced cellular immune responses and increased survival following murine cytomegalovirus (mCMV) infection in C57BL/6 mice. In this study, we tested whether treatment with a VIP receptor antagonistic peptide protects C57BL/6 and BALB/c mice from mCMV-infection. One week of daily subcutaneous injections of VIPhyb was non-toxic and did not alter frequencies of immune cell subsets in non-infected mice. VIPhyb administration to mCMV-infected C57BL/6 and BALB/c mice markedly enhanced survival, viral clearance, and reduced liver and lung pathology compared with saline-treated controls. The numbers of effector/memory CD8+ T-cells and mature NK cells were increased in VIPhyb-treated mice compared with PBS-treated groups. Pharmacological blockade of VIP-receptor binding or genetic blockade of VIP-signaling prevented the up-regulation of PD-L1 and PD-1 expression on DC and activated CD8+ T-cells, respectively, in mCMV-infected mice, and enhanced CD80, CD86, and MHC-II expression on conventional and plasmacytoid DC. VIPhyb-treatment increased type-I IFN synthesis, numbers of IFN-γ- and TNF-α-expressing NK cells and T-cells, and the numbers of mCMV-M45 epitope-peptide-MHC-I tetramer CD8+ T-cells following mCMV infection. VIP-treatment lowered the percentage of Treg cells in spleens compared with PBS-treated WT mice following mCMV infection, while significantly decreasing levels of serum VEGF induced by mCMV-infection. The mice in all treated groups exhibited similar levels of anti-mCMV antibody titers. Short-term administration of a VIP-receptor antagonist represents a novel approach to enhance innate and adaptive cellular immunity in a murine model of CMV infection.

Topics: Animals; Antiviral Agents; Cytokines; Cytomegalovirus; Cytomegalovirus Infections; Immunity, Cellular; Inflammation Mediators; Killer Cells, Natural; Liver; Lung; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Necrosis; Neurotensin; Receptors, Vasoactive Intestinal Peptide; Recombinant Fusion Proteins; T-Lymphocytes; Vasoactive Intestinal Peptide; Viral Load

Hepatic ischemia/reperfusion injury (IRI), an exogenous, antigen-independent, local inflammation response, occurs in multiple clinical settings, including liver transplantation, hepatic resection, trauma, and shock. The nervous system maintains extensive crosstalk with the immune system through neuropeptide and peptide hormone networks. This study examined the function and therapeutic potential of the vasoactive intestinal peptide (VIP) neuropeptide in a murine model of liver warm ischemia (90 minutes) followed by reperfusion. Liver ischemia/reperfusion (IR) triggered an induction of gene expression of intrinsic VIP; this peaked at 24 hours of reperfusion and coincided with a hepatic self-healing phase. Treatment with the VIP neuropeptide protected livers from IRI; this was evidenced by diminished serum alanine aminotransferase levels and well-preserved tissue architecture and was associated with elevated intracellular cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling. The hepatocellular protection rendered by VIP was accompanied by diminished neutrophil/macrophage infiltration and activation, reduced hepatocyte necrosis/apoptosis, and increased hepatic interleukin-10 (IL-10) expression. Strikingly, PKA inhibition restored liver damage in otherwise IR-resistant VIP-treated mice. In vitro, VIP not only diminished macrophage tumor necrosis factor α/IL-6/IL-12 expression in a PKA-dependent manner but also prevented necrosis/apoptosis in primary mouse hepatocyte cultures. In conclusion, our findings document the importance of VIP neuropeptide-mediated cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. Because the enhancement of neural modulation differentially regulates local inflammation and prevents hepatocyte death, these results provide the rationale for novel approaches to managing liver IRI in transplant patients.

Topics: Animals; Apoptosis; Caspase 3; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Flow Cytometry; Hepatocytes; Homeostasis; Immune System; Inflammation; Interleukin-10; L-Lactate Dehydrogenase; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Necrosis; Neutrophils; Peroxidase; Reperfusion Injury; Time Factors; Vasoactive Intestinal Peptide

The neuropeptide vasoactive intestinal peptide (VIP) is anti-inflammatory and protective in the immune and nervous systems, respectively. This study demonstrated in corneal endothelial (CE) cells injured by severe oxidative stress (1.4 mM H(2)O(2)) in bovine corneal organ cultures that VIP pre-treatment (0, 10(-10), 10(-8), and 10(-6) M; 15 min), in a VIP concentration-dependent manner, switched the inflammation-causing necrosis to inflammation-neutral apoptosis (showing annexin V-binding, chromatin condensation, and DNA fragmentation) and upheld ATP levels in a VIP antagonist (SN)VIPhyb-sensitive manner, while up-regulated mRNA levels of the anti-apoptotic Bcl-2 and the differentiation marker N-cadherin in a kinase A inhibitor-sensitive manner. As a result, VIP, in a concentration-dependent and VIP antagonist-sensitive manners, promoted long-term CE cell survival. ATP levels, a determining factor in the choice of apoptosis versus necrosis, measured after VIP pre-treatment and 0.5 min post-H(2)O(2) were 39.6 +/- 3.3, 50.8 +/- 6.2, 60.1 +/- 4.8, and 53.6 +/- 5.3 pmoles/microg protein (mean +/- SEM), respectively (p < 0.05, anova). VIP treatment alone concentration-dependently increased levels of N-cadherin (Koh et al. 2008), the phosphorylated cAMP-responsive-element binding protein and Bcl-2, while 10(-8) M VIP, in a VIP antagonist (SN)VIPhyb-sensitive manner, increased ATP level by 38% (p < 0.02) and decreased glycogen level by 32% (p < 0.02). VPAC1 (not VPAC2) receptor was expressed in CE cells. Thus, CE cell VIP/VPAC1 signaling is both anti-inflammatory and protective in the corneal endothelium.

Topics: Adenosine Triphosphate; Animals; Annexin A5; Apoptosis; Cadherins; Cattle; Cell Survival; Dose-Response Relationship, Drug; Endothelial Cells; Epithelium, Corneal; Gene Expression Regulation; Glycogen; Hydrogen Peroxide; In Vitro Techniques; Necrosis; Oxidants; Oxidative Stress; Propidium; Proto-Oncogene Proteins; RNA, Messenger; Vasoactive Intestinal Peptide

Topics: Animals; Blood Transfusion; Hemorrhage; Histamine Release; Ischemia; Kidney; Male; Malondialdehyde; Mast Cells; Necrosis; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Sprague-Dawley; Vasoactive Intestinal Peptide