vasoactive-intestinal-peptide and Inflammation

In this review, we discuss sympathetic regulation in normal and diabetic wound healing. Experimental denervation studies have confirmed that sympathetic nerve endings in skin have an important and complex role in wound healing. Vasoconstrictor neurons secrete norepinephrine (NE) and neuropeptide Y (NPY). Both mediators decrease blood flow and interact with inflammatory cells and keratinocytes. NE acts in an ambiguous way depending on receptor type. Beta2-adrenoceptors could be activated near sympathetic endings; they suppress inflammation and re-epithelialization. Alpha1- and alpha2-adrenoceptors induce inflammation and activate keratinocytes. Sudomotor neurons secrete acetylcholine (ACh) and vasoactive intestinal peptide (VIP). Both induce vasodilatation, angiogenesis, inflammation, keratinocytes proliferation and migration. In healthy skin, all effects are important for successful healing. In treatment of diabetic ulcers, mediator balance could be shifted in different ways. Beta2-adrenoceptors blockade and nicotinic ACh receptors activation are the most promising directions in treatment of diabetic ulcers with neuropathy, but they require further research.

Topics: Acetylcholine; Diabetes Complications; Diabetes Mellitus; Hemodynamics; Humans; Inflammation; Neurons; Neuropeptide Y; Norepinephrine; Receptors, Adrenergic; Skin; Skin Ulcer; Sympathetic Nervous System; Vasoactive Intestinal Peptide; Vasoconstriction; Wound Healing

Topics: Animals; Benzoquinones; Biological Products; Biomimetics; Caffeic Acids; Curcumin; Cytokines; Exosomes; Humans; Inflammation; Inflammatory Bowel Diseases; Insecta; Macromolecular Substances; Nanomedicine; Oxidative Stress; Phenylethyl Alcohol; Phytochemicals; Plant Extracts; Polysaccharides; Quercetin; Resveratrol; Stilbenes; Transcription Factors; Translational Research, Biomedical; Vasoactive Intestinal Peptide; Zingiber officinale

The neuroendocrine and immune systems are coordinated to maintain the homeostasis of the organism, generating bidirectional communication through shared mediators and receptors. Vasoactive intestinal peptide (VIP) is the paradigm of an endogenous neuropeptide produced by neurons and endocrine and immune cells, involved in the control of both innate and adaptive immune responses. Exogenous administration of VIP exerts therapeutic effects in models of autoimmune/inflammatory diseases mediated by G-protein-coupled receptors (VPAC1 and VPAC2). Currently, there are no curative therapies for inflammatory and autoimmune diseases, and patients present complex diagnostic, therapeutic, and prognostic problems in daily clinical practice due to their heterogeneous nature. This review focuses on the biology of VIP and VIP receptor signaling, as well as its protective effects as an immunomodulatory factor. Recent progress in improving the stability, selectivity, and effectiveness of VIP/receptors analogues and new routes of administration are highlighted, as well as important advances in their use as biomarkers, contributing to their potential application in precision medicine. On the 50th anniversary of VIP's discovery, this review presents a spectrum of potential clinical benefits applied to inflammatory and autoimmune diseases.

Topics: Animals; Autoimmune Diseases; Diabetes Mellitus, Type 1; Humans; Inflammation; Inflammatory Bowel Diseases; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Rheumatic Diseases; Sjogren's Syndrome; Vasoactive Intestinal Peptide

A network of cell-cell communications through contact and soluble factors supports the maternal-placental interaction and provides a suitable environment for fetal growth. Trophoblast cells take center stage at these loops: they interact with maternal leukocytes to sustain the varying demands of gestation, and they synthesize hormones, cytokines among other factors that contribute to the maintenance of immune homeostasis. Here, we discuss vasoactive intestinal peptide (VIP) and its potential as a regulatory neuropeptide in pregnancy. VIP is synthesized by trophoblast cells; it regulates trophoblast cell function and interaction with the major immune cell populations present in the pregnant uterus. VIP activity produces an anti-inflammatory microenvironment by modulating the functional profile of monocytes, macrophages, and regulatory T cells. Trophoblast VIP inhibits neutrophil extracellular trap formation and accelerates neutrophil apoptosis, enabling their silent clearance by phagocytic cells. The effects of VIP on the trophoblast-immune interaction are consistent with its regulatory role throughout pregnancy for immune homeostasis maintenance. These observations may provide new clues for pharmacological targeting of pregnancy complications associated with exacerbated inflammation.

Topics: Apoptosis; Cell Communication; Extracellular Traps; Female; Homeostasis; Humans; Inflammation; Macrophages; Monocytes; Neutrophils; Pregnancy; T-Lymphocytes, Regulatory; Trophoblasts; Vasoactive Intestinal Peptide

The essential roles played by the immune system in the discrimination between self- versus non/altered-self and its integral role in promoting host defense against invading microbes and tumors have been extensively studied for many years. In these contexts, significant advances have been made in defining the molecular and cellular networks that orchestrate cell-cell communication to mediate host defense and pathogen expulsion. Notably, recent studies indicate that in addition to these classical immune functions, cells of the innate and adaptive immune system also sense complex tissue- and environment-derived signals, including those from the nervous system and the diet. In turn these responses regulate physiologic processes in multiple tissues throughout the body, including nervous system function, metabolic state, thermogenesis, and tissue repair. In this review we propose an integrated view of how the mammalian immune system senses and interacts with other complex organ systems to maintain tissue and whole-body homeostasis.

Topics: Adaptive Immunity; Animals; Cell Communication; Diet; Energy Metabolism; Homeostasis; Host-Pathogen Interactions; Humans; Immune System; Immunity, Innate; Inflammation; Neurons; Regeneration; Sympathetic Nervous System; Vasoactive Intestinal Peptide

To review and discuss the available international literature regarding the indirect and direct biochemical mechanisms that occur after exercise, which could positively, or negatively, influence oncogenic pathways.. The PubMed, MEDLINE, Embase and Cochrane libraries were searched for papers up to July 2016 addressing biochemical changes after exercise with a particular reference to cancer. The three authors independently assessed their appropriateness for inclusion in this review based on their scientific quality and relevance.. 168 papers were selected and categorised into indirect and direct biochemical pathways. The indirect effects included changes in vitamin D, weight reduction, sunlight exposure and improved mood. The direct effects included insulin-like growth factor, epigenetic effects on gene expression and DNA repair, vasoactive intestinal peptide, oxidative stress and antioxidant pathways, heat shock proteins, testosterone, irisin, immunity, chronic inflammation and prostaglandins, energy metabolism and insulin resistance.. Exercise is one of several lifestyle factors known to lower the risk of developing cancer and is associated with lower relapse rates and better survival. This review highlights the numerous biochemical processes, which explain these potential anticancer benefits.

Topics: Carcinogenesis; Energy Metabolism; Epigenesis, Genetic; Exercise; Fibronectins; Heat-Shock Proteins; Humans; Inflammation; Insulin Resistance; Life Style; Neoplasms; Oxidative Stress; Prostaglandins; Somatomedins; Testosterone; Vasoactive Intestinal Peptide

Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity.

Topics: Adrenomedullin; Animals; Calcitonin Gene-Related Peptide; Ghrelin; Humans; Inflammation; Inflammation Mediators; Leptin; Macrophage Activation; Microglia; Neuralgia; Neurodegenerative Diseases; Neuroglia; Neuropeptide Y; Neuropeptides; Pain; Pro-Opiomelanocortin; Tachykinins; Vasoactive Intestinal Peptide

Neuropeptides represent an important category of endogenous contributors to the establishment and maintenance of immune deviation in the immune-privileged organs such as the CNS and in the control of acute inflammation in the peripheral immune organs. Vasoactive intestinal peptide (VIP) is a major immunoregulatory neuropeptide widely distributed in the central and peripheral nervous system. In addition to neurones, VIP is synthesized by immune cells which also express VIP receptors. Here, we review the current information on VIP production and VIP-receptor-mediated effects in the immune system, the role of endogenous and exogenous VIP in inflammatory and autoimmune disorders and the present and future VIP therapeutic approaches.

Topics: Animals; Autoimmune Diseases; Humans; Inflammation; Neuropeptides; Receptors, Vasoactive Intestinal Peptide; T-Lymphocytes; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide/neurotransmitter, is widely distributed in both the central and peripheral nervous system. VIP is released by both neurons and immune cells. Various cell types, including immune cells, express VIP receptors. VIP has pleiotropic effects as a neurotransmitter, immune regulator, vasodilator and secretagogue. This review is focused on VIP production and effects on immune cells, VIP receptor signaling as related to immune functions, and the involvement of VIP in inflammatory and autoimmune disorders. The review addresses present clinical use of VIP and future therapeutic directions.

Topics: Animals; Autoimmunity; CD4-Positive T-Lymphocytes; Central Nervous System; Dendritic Cells; Humans; Inflammation; Macrophages; Mice; Neuroimmunomodulation; Peripheral Nervous System; Receptors, Vasoactive Intestinal Peptide; Signal Transduction; Vasoactive Intestinal Peptide

The vasoactive intestinal peptide (VIP) is a neuropeptide with wide distribution in both central and peripheral nervous systems, where it plays important regulatory role in many physiological processes. VIP displays a large biological functions including regulation of exocrine secretions, hormone release, fetal development, immune responses, etc. VIP appears to exert beneficial effect in neuro-degenerative and inflammatory diseases. The mechanism of action of VIP implicates two subtypes of receptors (VPAC1 and VPAC2), which are members of class B receptors belonging to the super-family of GPCR. This article reviews the current knowledge regarding the structure and molecular pharmacology of VPAC receptors. The structure-function relationship of VPAC1 receptor has been extensively studied, allowing to understand the molecular basis for receptor affinity, specificity, desensitization and coupling to adenylyl cyclase. Those studies have clearly demonstrated the crucial role of the N-terminal ectodomain (N-ted) of VPAC1 receptor in VIP recognition. By using different approaches including directed mutagenesis, photoaffinity labelling, NMR, molecular modelling and molecular dynamic simulation, it has been shown that the VIP molecule interacts with the N-ted of VPAC1 receptor, which is itself structured as a 'Sushi' domain. VPAC1 receptor also interacts with a few accessory proteins that play a role in cell signalling of receptors. Recent advances in the structural characterization of VPAC receptor and more generally of class B GPCRs will lead to the design of new molecules, which could have considerable interest for the treatment of inflammatory and neuro-degenerative diseases.

Topics: Animals; Drug Design; Humans; Inflammation; Models, Molecular; Molecular Dynamics Simulation; Neurodegenerative Diseases; Protein Conformation; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are members of a superfamily of structurally related peptide hormones that includes glucagon, glucagon-like peptides, secretin, gastric inhibitory peptide (GIP) and growth hormone-releasing hormone (GHRH). VIP and PACAP exert their actions through three GPCRs - PAC(1) , VPAC(1) and VPAC(2) - belonging to class B (also referred to as class II, or secretin receptor-like GPCRs). This family comprises receptors for all peptides structurally related to VIP and PACAP, and also receptors for parathyroid hormone, corticotropin-releasing factor, calcitonin and related peptides. PAC(1) receptors are selective for PACAP, whereas VPAC(1) and VPAC(2) respond to both VIP and PACAP with high affinity. VIP and PACAP play diverse and important roles in the CNS, with functions in the control of circadian rhythms, learning and memory, anxiety and responses to stress and brain injury. Recent genetic studies also implicate the VPAC(2) receptor in susceptibility to schizophrenia and the PAC(1) receptor in post-traumatic stress disorder. In the periphery, VIP and PACAP play important roles in the control of immunity and inflammation, the control of pancreatic insulin secretion, the release of catecholamines from the adrenal medulla and as co-transmitters in autonomic and sensory neurons. This article, written by members of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) subcommittee on receptors for VIP and PACAP, confirms the existing nomenclature for these receptors and reviews our current understanding of their structure, pharmacology and functions and their likely physiological roles in health and disease. More detailed information has been incorporated into newly revised pages in the IUPHAR database (http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=67).

Topics: Animals; Central Nervous System; Humans; Immunity; Inflammation; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide

Nuclear medicine techniques are becoming more important in imaging oncological and infectious diseases. For metabolic imaging of these diseases, antibody and peptide imaging are currently used. In recent years peptide imaging has become important, therefore the rationale for the use of peptide imaging is described in this article. Criteria for a successful peptide tracer are a high target specificity, a high binding affinity, a long metabolic stability and a high target-to-background ratio. Tracer internalization is also beneficial. For oncological imaging, many tracers are available, most originating from regulatory peptides, but penetrating peptides are also being developed. Peptides for imaging inflammatory and infectious diseases include regulatory peptides, antimicrobial peptides and others. In conclusion, for the imaging of oncological, imflammatory and infectious diseases, many promising peptides are being developed. The ideal peptide probe is characterized by rapid and specific target localization and binding with a high tumour-to-background ratio.

Topics: Antimicrobial Cationic Peptides; Bombesin; Cholecystokinin; Gastrin-Releasing Peptide; Glucagon-Like Peptide 1; Humans; Infections; Inflammation; Isotope Labeling; Neoplasms; Peptides; Radionuclide Imaging; Radiopharmaceuticals; Somatostatin; Vasoactive Intestinal Peptide

Gram negative sepsis remains a high cause of mortality and places a great burden on public health finance in both the developed and developing world. Treatment of sepsis, using antibiotics, is often ineffective since pathology associated with the disease occurs due to dysregulation of the immune system (failure to return to steady state conditions) which continues after the bacteria, which induced the immune response, have been cleared. Immune modulation is therefore a rational approach to the treatment of sepsis but to date no drug has been developed which is highly effective, cheap and completely safe to use. One potential therapeutic agent is VIP, which is a natural peptide and is highly homologous in all vertebrates. In this review we will discuss the effect of VIP on components of the immune system, relevant to gram negative sepsis, and present data from animal models. Furthermore we will hypothesise on how these studies could be improved in future and speculate on the possible different ways in which VIP could be used in clinical medicine.

Topics: Animals; Disease Models, Animal; Gram-Negative Bacterial Infections; Humans; Immune System; Inflammation; Lipopolysaccharides; Sepsis; Vasoactive Intestinal Peptide

Toll-like receptors (TLRs) are a family of key proteins that permit mammals to detect microbes and endogenous molecules, which are present in body fluids, cell membranes and cytoplasm. They confer mechanisms to the host for maintaining homeostasis, activating innate immunity and inducing signals that lead to the activation of adaptive immunity. TLR signalling induces the expression of pro-inflammatory and anti-viral genes through different and intricate pathways. However, persistent signalling can be dangerous and all members of the TLR family are involved in the pathogenesis of acute and chronic inflammation, autoimmunity, allergy, cancer and aging. The pharmaceutical industry has begun intensive work developing novel immunotherapeutic approaches based on both activation and inhibition of TLR triggering. Further, clinical trials are pending to evaluate TLR agonists as novel vaccine adjuvants and for the treatment of infectious diseases, allergic diseases and asthma. Since systemic, metabolic and neuroendocrine changes are elicited by inflammation, TLR activity is susceptible of regulation by hormones and neuroendocrine factors. Neuroendocrine mediators are important players in modulating different phases of TLR regulation contributing to the endogenous control of homeostasis through local, regional and systemic routes. Vasoactive intestinal peptide (VIP) is an important signal molecule of the neuroendocrine-immune network that has recently emerged as a potential candidate for the treatment of inflammatory and autoimmune disorders by controlling innate and adaptive immunity. This review shows current advances in the understanding of TLR modulation by VIP that could contribute to the use of this natural peptide as a therapeutic tool.

Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Drug Delivery Systems; Humans; Inflammation; Inflammation Mediators; Models, Biological; Peptides; Signal Transduction; Toll-Like Receptors; Vasoactive Intestinal Peptide

The vasoactive intestinal peptide (VIP) is a prominent 28 aminoacid neuropeptide with wide distribution in both central and peripheral nervous systems, where it plays important regulatory role in many physiological processes. VIP has a large spectrum of biological functions including exocrine secretions, hormone release, foetal development, immune response and also exerts beneficial effect in neuro-degenerative and inflammatory diseases. Few years ago, it has been shown that VIP can be a promising anti-inflammatory agent. VIP mechanisms of action implicate two sub-types of receptors (VPAC1 and VPAC2) which are members of class B receptors belonging to the super-family of G protein-coupled receptor (GPCR). Because, VPAC1 receptor plays an important role in the modulation of the ant-inflammatory response and represent an archetype of class B GPCR, we have extensively studied the structure-function relationship of this receptor, which allowed us to define the molecular basis of that receptor in term of affinity, specificity, desensitization and coupling to adenylyl cyclase. Those studies showed the crucial role of the N-terminal ectodomain (N-ted) of VPAC1 receptor in VIP binding. Using different techniques including photoaffinity labeling, NMR, molecular modeling and molecular dynamic simulation, it has been possible to define how VIP interacts with its receptor. We have shown that most of the VIP molecule, 1-28 (alpha-helix) sequence, tightly binds the N-ted part of the receptor which is himself structured as a <> domain. In contrast, the N-terminal part of the specific antagonist PG97-269 is in physical contact with the N-ted but in different region. These studies define the molecular mechanism implicated in the activation of class B VPAC1 receptor and should allow the development of new VIP pharmacology using rational synthesis of agonist molecules.

Topics: Animals; Binding Sites; Inflammation; Photoaffinity Labels; Protein Conformation; Receptors, Vasoactive Intestinal Polypeptide, Type I; Structure-Activity Relationship; Vasoactive Intestinal Peptide

Antigen presenting cells like dendritic cells (DC) are responsible for the initiation of adaptive immune responses via the T helper cells they activate. The type of T cell responses DC induce is dependent on the local immunological environment where antigen has been taken up. In the gut, resident DC are phenotypically and functionally shaped by epithelial and stromal cell derived signals, the cytokine microenvironment, and neuronal products. These factors can control the activation state of DC thereby inducing tolerance for food and commensal organisms or immunity against pathogenic microbes. The enteric nervous system (ENS) is increasingly recognized as an important regulatory factor in intestinal immune cell control. Neurotransmitters and neuropeptides like acetylcholine (ACh), norepinephrine (NE) and vasoactive intestinal peptide (VIP) are released by neurons of the ENS and can affect the function of DC and subsequent immune responses. The critical balance between tolerance and protective immunity is disrupted in inflammatory bowel disease, which results in an exaggerated immune response against commensal bacteria. In this review we discuss the effects of ACh, VIP, and NE on DC function. DC express various receptors for these neuron derived products and can alter DC co-stimulatory molecule expression, cytokine release and subsequent T cell activation in an anti-inflammatory fashion. Knowledge about these interactions will help find new drug targets and may facilitate the development of specific therapies for diseases like inflammatory bowel disease (IBD).

Topics: Acetylcholine; Animals; Autonomic Nervous System; Cell Differentiation; Dendritic Cells; Enteric Nervous System; Humans; Inflammation; Intestines; Neuroimmunomodulation; Norepinephrine; Parasympathetic Nervous System; Signal Transduction; Sympathetic Nervous System; T-Lymphocytes; Vasoactive Intestinal Peptide

An imbalance of pro-inflammatory and anti-inflammatory cytokines, autoreactive and inflammatory T helper 1 (Th1) cells, and regulatory T (Treg) cells results in the loss of immune tolerance and the subsequent appearance of inflammatory autoimmune diseases. On the other hand, hormones and neuropeptides are endogenous factors controlling the immune homeostasis that have been proposed as therapeutic agents in different autoimmune disorders. Among them, the vasoactive intestinal peptide (VIP) has been shown to downregulate the inflammatory response and to alter the Th1/Th2 balance in favor of anti-inflammatory Th2 immune responses. Recent studies have revealed a greater diversification of the T cell effector repertoire with the identification of Th17 cells. This subpopulation has been shown to be pathogenic in several autoimmune diseases previously attributed to the Th1 lineage. Arising new data and a critical revision of already published studies indicate that VIP is an immunomodulatory therapeutic agent targeting the Th17/Treg pathway.

Topics: Animals; Autoimmune Diseases; Humans; Inflammation; Interleukin-23; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells; Vasoactive Intestinal Peptide

Corticosteroids are the mainstay treatment for most severe inflammatory disorders. Due to the considerable toxicity associated with their long-term use, there is a great need for alternative treatments. Recently, two closely related neuropeptides with potent neuromodulatory activities, vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase activating peptide (PACAP) have emerged as candidate molecules for the treatment of such pathologies. These peptides act primarily on three high affinity receptor subtypes expressed on multiple immune cell types, and orchestrate a cytokine response that is primarily anti-inflammatory. In this regard, systemic treatment with these peptides has been shown to greatly reduce the clinical symptoms and alter the pathogenic and cytokine profiles in animal models of rheumatoid arthritis, Crohn's disease, septic shock, and multiple sclerosis. Likewise, VIP and PACAP receptor knockout and overexpressing mice show altered immune responses in different models. We review here data demonstrating the potential effectiveness of these peptides in immune disorders, discuss receptor pharmacology and signaling pathways, describe the development of receptor specific agonists and antagonists, and discuss pharmaceutical considerations relevant to the specific delivery of analogs to the appropriate targets.

Topics: Animals; Humans; Inflammation; Molecular Mimicry; Neuropeptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Vasoactive Intestinal Peptide; Structure-Activity Relationship; Vasoactive Intestinal Peptide

Our research about VIP/PACAP and the immune system goes back to 1990 when our group described the expression of VIP on lymphocytes for the first time. Since this year, using three models of disease, septic shock, rheumathoid arthritis, and Crohn's disease, we are trying to contribute with new pieces to the puzzle of immunity to approach the use of VIP/PACAP system as a therapeutic agent. In 1999 we established that the first step in the beneficial effect of the VIP/PACAP system exerts consists in its potent anti-inflammatory action. Thus, VIP and PACAP inhibit the expression and release of proinflammatory cytokines and chemokines, and enhance the production of the anti-inflammatory factors. These effects were reported both in vitro and in vivo, are mediated by the presence of PAC1, VPAC1, and VPAC2 receptors, in the three models of diseases used. The next step was that the system favors Th2 responses versus Th1 contributing to the remission of illness as rheumatoid arthritis or Crohn's disease by blocking the autoimmune component of these diseases. Because it appears that inflammatory processes requires more than blockade of a single mediator, new therapies blocking several components of both the infection- and the autoimmunity-induced inflammation cascades should be an interesting focus of attention. In this sense, at present we are trying to dissect new aspects of the potential therapeutic of the VIP/PACAP system in the control of CC and CXC chemokine and their receptors, coagulation factors, adhesion molecules, acute phase proteins, and osteoclastogenesis mediators as well as in the modulation of the expression of Toll-like receptors. Our more recent data open a hopeful door for the therapeutic use of VIP/PACAP in humans.

Topics: Animals; Humans; Immunotherapy; Inflammation; Pituitary Adenylate Cyclase-Activating Polypeptide; Signal Transduction; T-Lymphocytes, Helper-Inducer; Vasoactive Intestinal Peptide

The vasoactive intestinal peptide (VIP) is a neuropeptide belonging to the secretin/glucagon family of peptides, which exerts a wide spectrum of immunological functions controlling the homeostasis of immune system through different receptors expressed in various immunocompetent cells. In the last decade, VIP has emerged as a potent anti-inflammatory factor, which exerts its function by regulating the production of both anti- and pro-inflammatory mediators. In this sense, VIP has been proposed as a promising candidate, alternative to other existing treatments, for treating acute and chronic inflammatory and autoimmune diseases, such as septic shock, rheumatoid arthritis, multiple sclerosis and Crohn's disease. The present work reviews the involvement of the specific receptors and or different transduction pathways and transcription factors in the anti-inflammatory action of VIP, and their implication on its therapeutic effect on inflammatory/autoimmune disorders.

Topics: Animals; Humans; Inflammation; Signal Transduction; Vasoactive Intestinal Peptide

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

Complex circuits involving both local intrinsic neurones (i.e. enteric nervous system; ENS) and extrinsic neurones achieve nervous control of digestive functions. The ENS is comprised of many functionally different types of neurons: sensory neurons, interneurons and secreto-motor neurons. Each neuronal population is required to manifest local reflex behavior and is central to the regulation of both motor and secretory activities. It must be emphasized, however, that not only muscle and secretory cells but also other intestinal cells are targeted by enteric neurones, i.e. endocrine cells, interstitial cells of Cajal, immune cells, blood vessels and enteric glia. In addition to the ENS the gastrointestinal tract receives an extrinsic innervation by sympathetic, parasympathetic and sensory fibres. Neuronal projections from the intestine to prevertebral ganglia also exist. Taken together, the picture of a complex nervous regulation of digestive functions highly integrated with the central nervous system and the rest of the autonomic nervous system has emerged. The ENS is adaptive and plastic, but also vulnerable, system and ENS disturbances may be of pathogenic importance in functional bowel disease. In particular the interplay between the enteric neurones and the immune cells is suggested to be of crucial importance. The review discusses possible roles of the mediators vasoactive intestinal peptide (VIP) and prostanoids in ENS plasticity in response to injury and inflammation.

Topics: Animals; Cytokines; Digestive System; Enteric Nervous System; Humans; Inflammation; Neuronal Plasticity; Neurons; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP), a neuropeptide that is produced by lymphoid as well as neural cells, exerts a wide spectrum of immunological functions, controlling the homeostasis of the immune system through different receptors expressed in various immunocompetent cells. In the last decade, VIP has been clearly identified as a potent anti-inflammatory factor, which acts by regulating the production of both anti- and pro-inflammatory mediators. In this sense, VIP has been described to prevent death by septic shock, an acute inflammatory disease with a high mortality. In addition, VIP regulates the expression of co-stimulatory molecules, this being an action that may be related to modulating the shift toward Th1 and Th2 differentiation. We have recently reported that VIP prevents the deleterious effects of an experimental model of rheumatoid arthritis, by downregulating both inflammatory and autoimmune components of the disease. Therefore, VIP has been proposed as a promising candidate alternative treatment for acute and chronic inflammatory and autoimmune diseases such as septic shock, arthritis, multiple sclerosis, Crohn disease, or autoimmune diabetes.

Topics: Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Humans; Inflammation; Mice; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide

Vasoactive intestinal polypeptide (VIP) is one of the most abundant, biologically active peptides found in the human lung. VIP is a likely neurotransmitter or neuromodulator of the inhibitory non-adrenergic non-cholinergic airway nervous system and influences many aspects of pulmonary biology. In human airways VIP-immunoreactive nerve fibres are present in the tracheobronchial airway smooth muscle layer, the walls of pulmonary and bronchial vessels and around submucosal glands. Next to its prominent bronchodilatory effects, VIP potently relaxes pulmonary vessels. The precise role of VIP in the pathogenesis of asthma is still uncertain. Although a therapy using the strong bronchodilatory effects of VIP would offer potential benefits, the rapid inactivation of the peptide by airway peptidases has prevented effective VIP-based drugs so far and non-peptide VIP-agonists did not reach clinical use.

Topics: Airway Resistance; Asthma; Humans; Inflammation; Muscle, Smooth; Peptide Hydrolases; Receptors, Vasoactive Intestinal Peptide; Respiratory Physiological Phenomena; Respiratory System; Signal Transduction; Vasoactive Intestinal Peptide

Schistosomiasis is a parasitic disease in which focal inflammatory responses called granulomas develop in the liver and intestines. The inflammatory cells within these granulomas produce authentic vasoactive intestine peptide (VIP). VIP acts as an immune modulator. In the schistosome granuloma, VIP can suppress T cell proliferation and T lymphocyte IL-2 production. Also, it can enhance IL-5 production from granuloma T cells. The granuloma T cells bear authentic VIP receptors of both the VIPr1 and VIPr2 subclasses. It is probable that the expression of these receptors is subject to immunoregulation, which is the topic of current investigation. Moreover, differences in the structure of VIPr1 and VIPr2 suggest that each may have unique immunoregulatory functions in inflammation.

Topics: Animals; Granuloma; Inflammation; Mice; Schistosomiasis mansoni; Vasoactive Intestinal Peptide

Topics: Animals; Humans; Inflammation; Lung; Lung Injury; Myocardial Reperfusion Injury; Neurons; Nitric Oxide; Vasoactive Intestinal Peptide; Wounds and Injuries

A number of anatomical studies have demonstrated the presence of peptidergic nerve fibers infiltrating mucosal lymphoid tissues. The exact mechanisms of how neuropeptides are released to affect these lymphoid sites are unclear, but radiolabeled binding studies have shown that mucosal leukocytes bear a number of neuropeptide receptors on their cell surfaces capable of responding to neural signals. The presence of neuropeptide-containing fibers and the ability to receive neural signals suggest that mucosal lymphocytes can be influenced by neurogenic mediators. The objectives set forth in this review are to provide what is currently known about the ability of substance P and vasoactive intestinal peptide to promote mucosal IgA responses in the gastrointestinal tract via Th2 mechanisms and to discuss how these neuropeptides contribute to the exacerbation of the inflammatory diseases of the gastrointestinal tract. We describe how immune responses develop in the gastrointestinal immune system and emphasize how neuropeptides may influence the differentiation of lymphocytes in mucosal inductive tissues and their subsequent expression in mucosal effector sites. Finally, we discuss new techniques developed by the Mucosal Immunization Research Group that have enabled the study of mucosal immune responses.

Topics: Animals; Enteric Nervous System; Humans; Immunoglobulin A; Immunologic Memory; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Mice; Neuroimmunomodulation; Neuropeptides; Peyer's Patches; Rats; Receptors, Neuropeptide; Substance P; Th2 Cells; Vasoactive Intestinal Peptide

SP and NKA are potent endogenous bronchoconstrictors, whereas VIP is a potent endogenous bronchodilator. There is abundant evidence that these neuropeptides are released in the lung in a variety of conditions and that they have the capacity to modulate the bronchoactivity of the same stimuli that release them. On many occasions, their bronchoactive effects are masked by their degradation at or near the site of their release. However, when the microenvironment is modified to decrease their cleavage, they can express enhanced physiologic effects. Although it appears that the human asthmatic lung may be an environment in which the effects of neuropeptides can be amplified, the role of neuropeptides in the pathogenesis of airway obstruction remains speculative.

Topics: Amino Acid Sequence; Animals; Humans; Inflammation; Molecular Sequence Data; Neprilysin; Neurokinin A; Neuropeptides; Respiratory Physiological Phenomena; Respiratory System; Substance P; Vasoactive Intestinal Peptide

Topics: Animals; Calcitonin Gene-Related Peptide; Humans; Hypersensitivity, Immediate; Inflammation; Lung; Neurokinin A; Neuropeptides; Substance P; Vasoactive Intestinal Peptide

Topics: Animals; Bronchoconstriction; Humans; Inflammation; Lung; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide

Several peptides have been localised to pulmonary nerves and endocrine cells. The neuropeptides vasoactive intestinal polypeptide (VIP) and substance P have potent effects on the airway smooth muscle, bronchial glands and blood vessels. There is increasing evidence that VIP and substance P are neurotransmitters of the non-adrenergic, non-cholinergic nervous (NANC) system. Non-adrenergic inhibitory nerves are the predominant inhibitory nervous system of the human airways. The presence of VIP in the innervation of the airways and the demonstration that it can mimick the effect of NANC nerve stimulation supports the hypothesis that it could be a mediator of the NANC system in the lungs. Sensory nerve fibers containing substance P can contribute to the smooth muscle contraction and mucosal oedema seen in asthma, by local axon reflexes that are initiated by noxious stimuli, such as for example cigarette smoke. A rat model for study of the bronchial reaction to substance P and related tachykinins, is described. In addition to a direct effect on airway smooth muscle, a large part of the broncho-constrictory actions of tachykinins in the rat is mediated by interaction with cholinergic nerves.

Topics: Airway Resistance; Animals; Asthma; Bronchi; Humans; Inflammation; Kinins; Lung; Nerve Tissue Proteins; Substance P; Vasoactive Intestinal Peptide; Vasodilation

Autonomic nerves control many aspects of airway function, including smooth muscle tone, epithelial cell function, mucus secretion, bronchial flow and permeability, and inflammatory mediator release. There is considerable evidence that there may be abnormalities of autonomic function in asthma, perhaps as a result of airway inflammation. Inflammatory mediators might stimulate bronchial afferent receptors (irritant receptors and C-fibre endings) to produce reflex cholinergic bronchoconstriction. Anticholinergic drugs have not proved to be very effective in controlling clinical asthma, however, suggesting that cholinergic reflex mechanisms may not play a major role. Adrenergic abnormalities have been described in asthma. There is no direct sympathetic neural control of airway smooth muscle, suggesting that circulating catecholamines may regulate airway tone, and counteract the effect of inflammatory mediators in asthma. Surprisingly, the concentration of adrenaline in plasma does not rise in asthmatic subjects with induced bronchoconstriction, or even during an acute asthma attack. The function of beta-adrenoceptors in asthma is uncertain, but there is some evidence that beta-receptor function may be impaired, possibly as a result of inflammatory mediator release. alpha-Adrenoceptor function may be enhanced in asthma; inflammatory mediators may 'turn on' bronchoconstrictor alpha-adrenergic responses in airway smooth muscle, and alpha-agonists may have a bronchoconstrictor effect in asthmatic subjects. But specific alpha-blockers have little effect on airway function, and the role of alpha-receptors in asthma is questionable. Non-adrenergic, non-cholinergic nerves are the only neural bronchodilator mechanism in human airways. The neurotransmitter has not yet been identified but vasoactive intestinal peptide (VIP) is a possible candidate.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Autonomic Nervous System; Axons; Catecholamines; Cholinergic Fibers; Ganglia; Humans; Inflammation; Neurons, Afferent; Neurotransmitter Agents; Receptors, Adrenergic, beta; Reflex; Respiratory Tract Infections; Vasoactive Intestinal Peptide

Polypeptides are endogenous agents, involved in the regulation of many physiologic functions and the pathogenesis of several diseases. Polypeptide antagonists form a group of new chemical entities which may provide valid therapeutic agents. Some polypeptides (angiotensin, kinins) are released through the action of proteolytic enzymes (renin, kallikreins) and act as hormones or autacoids; others (substance P, neurotensin) are synthetized by nervous cells to serve as neurotransmitters or neuromodulators. The main homeostatic role of the renin-angiotensin system is to uphold high systemic arterial blood pressure. Overproduction of renin and insufficient checking of renin secretion are among the most common causes of arterial hypertension. Several forms of arterial hypertension (neurovascular, idiopathic) benefit from a reduction in renin-angiotensin system activity. This is achieved either through decreasing renin secretion, by inhibiting conversion of angiotensin I into angiotensin II, or through blocking the peripheral actions (at the receptor sites) of angiotensin II. Renin secretion is very significantly reduced by beta-blocking agents (propranolol); conversion of angiotensin I into angiotensin II is inhibited by teprotide, captopril and their derivatives; peripheral actions of angiotensin II are blocked by saralasin. Bradykinin and related agents produce vasodilation, increase vascular permeability and stimulate pain fibers. Kinins thus reproduce the cardinal features of inflammation and are held to be mediators of the inflammatory reaction. The substance P neuropeptide is found in the brain and bowel; it may act as a transmitter of the sensation of pain at the spinal cord and central nervous system sites. Among other effects outside of the brain, substance P is a potent vasodilator and inhibits renin secretion. Neurotensin is a neuropeptide which produces hypothermia, muscular relaxation and analgesia. Outside of the brain, this peptide is involved in the regulation of gastric secretion, intestinal motility and insulin and glucagon secretion. The vasoactive intestinal peptide, found in certain cholinergic nerve endings, is a large peptide which inhibits gastric secretion, intestinal motility and vascular tone.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Captopril; Humans; Hypertension; Inflammation; Kallikreins; Kinins; Neurotensin; Peptides; Renin-Angiotensin System; Substance P; Vasoactive Intestinal Peptide

Topics: Anaphylaxis; Animals; Arachidonic Acid; Arachidonic Acids; Autacoids; Chemical Phenomena; Chemistry; Chemotactic Factors; Chemotactic Factors, Eosinophil; Histamine; Humans; Hydrolases; Inflammation; Leukocytes; Leukotriene B4; Mast Cells; Platelet Activating Factor; Prostaglandins; Serotonin; SRS-A; Structure-Activity Relationship; Thromboxanes; Vasoactive Intestinal Peptide

Chronic obstructive pulmonary disease (COPD) as an inflammatory respiratory system disease is caused by exposure to cigarette smoke and tobacco in long-term. Some anti-inflammatory peptides can control inflammation in COPD. N-acetyl-seryl-aspartyl-proline (Ac-SDKP) and vasoactive intestinal peptide (VIP) as peptide have anti-inflammatory effect, and, in this study, the effect of Ac-SDKP and VIP on COPD inflammation was studied. After producing cigarette smoke-induced COPD mice model, which were treated with VIP and Ac-SDKP, the levels of antioxidant-related factors (malondialdehyde (MDA) and superoxide dismutase (SOD)), fibrotic factors (hydroxyproline (HP) and TGF-β), pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), and inflammation in histopathological examination were studied. MDA, Remodeling factors, pro-inflammatory cytokines, and inflammation in lung tissue were controlled by VIP and Ac-SDKP treatment. These treatments could enhance SOD. VIP and Ac-SDKP as immuno-regulatory factors had benefit effect in treatment of COPD. The anti-inflammatory, anti-fibrosis, and anti-oxidant properties of VIP and Ac-SDKP may be effective therapy in COPD.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Fibrosis; Inflammation; Mice; Oligopeptides; Pulmonary Disease, Chronic Obstructive; Superoxide Dismutase; Vasoactive Intestinal Peptide

Deviated nasal septum (DNS) is suggested to be associated with nonspecific inflammation of the nasal mucosa. The authors hypothesized septoplasty may reduce nasal mucosal inflammation, therefore the authors aimed to measure various inflammatory biomarkers in the nasal secretion following septoplasty. Prospectively, 17 patients undergoing elective septoplasty were included. Symptomatic changes after septoplasty were evaluated with Sino-nasal Outcome Test (SNOT-22) and Nasal obstruction symptom evaluation (NOSE) scores. Using acoustic rhinometry, changes of the nasal airway volume were measured. Nasal secretion was collected within 2 weeks and 3 months before and after septoplasty, respectively. The inflammatory biomarker high-mobility group box 1 (HMGB1) and vasoactive intestinal peptide (VIP), and inflammatory cytokines including tumor necrosis factor α (TNF α), interferon γ (IFN-γ), interleukin-4 (IL-4), eotaxin-1, and regulated upon activation, normal T cell expressed and presumably secreted (RANTES) were quantified in the nasal secretion by enzyme-linked immunosorbent assays or multiplex bead array assays. The patients' mean age was 30.5 ± 6.8 (ranging from 19 to 43), consisting of 15 male and 2 female patients. The median SNOT-22 and NOSE scores changed from 54 to 14 and 78 to 15, respectively, both showing a significant decrease. In acoustic rhinometry, nasal cavity volume of convex side significantly increased after septoplasty, whereas significant discrepancy of nasal airway volume between concave and convex sides became insignificant. No significant difference was noted both before and after septoplasty between the concave and convex sides in all seven biomarkers. The HMGB1, RANTES, IL-4, and TNF-α concentrations following septoplasty showed significant decrease in 34 nasal cavities of 17 patients (all p < 0.05). However, when the 17 concave and 17 convex sides were analyzed separately, the significant reduction in four biomarkers were only significant in the concave sides (all p < 0.05), but not significantly reduced in convex sides. Septoplasty may have benefited not only in normalizing the nasal airflow and symptom improvement, but also in nonspecific inflammation attenuation in the nasal airway.

Topics: Adult; Biomarkers; Chemokine CCL11; Chemokine CCL5; Female; HMGB1 Protein; Humans; Inflammation; Interferon-gamma; Interleukin-4; Male; Nasal Mucosa; Nasal Obstruction; Nasal Septum; Treatment Outcome; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide; Young Adult

Pterygium, a disease of the ocular surface, is characterized by the proliferation and invasion of fibrovascular tissue. Chronic inflammation contributes to pterygium occurrence. Sensory neuropeptides of TRPV1-positive nerve fibers are involved in inflammation and corneal wound healing. The possible association between TRPV1 in nerve fibers and neuropeptides such as Substance P (SP) and Vasoactive Intestinal Peptide (VIP) in the recurrence of pterygium has not been examined before. The pterygia from 64 patients were used to determine changes in SP and VIP levels using 10 min acetic-acid extraction that yielded mainly neuronal peptides. There was a sufficient amount of pterygium tissues from the 35 patients for further immunohistochemical analysis of TRPV1 and S100, which is a glial marker to visualize nerve fibers. SP and VIP levels increased markedly in cases with primary and secondary recurrences, and there was a close correlation between SP and VIP levels. TRPV1 expression increased in the epithelium, while stromal expression decreased in recurrences. Nerve fibers were demonstrated mainly in the stroma, and serial sections confirmed the localization of TRPV1 with the nerve fibers. These results together with previous findings demonstrated that the increased epithelial expression of TRPV1 in recurrent pterygia might be involved in the pathogenesis, and the inhibition of epithelial TRPV1 activity may prevent recurrence.

Topics: Humans; Inflammation; Neuropeptides; Pterygium; Substance P; TRPV Cation Channels; Vasoactive Intestinal Peptide

Type 1 diabetes (T1DM) is an autoimmune condition in which the immune system attacks and destroys insulin-producing beta cells in the pancreas leading to hyperglycemia. Vasoactive intestinal peptide (VIP) manifests insulinotropic and anti-inflammatory properties, which are useful for the treatment of diabetes. Because of its limited half-life due to DPP-4-mediated degradation, constant infusions or multiple injections are needed to observe any therapeutic benefit. Since gene therapy has the potential to treat genetic diseases, an HIV-based lentiviral vector carrying VIP gene (LentiVIP) was generated to provide a stable VIP gene expression in vivo. The therapeutic efficacy of LentiVIP was tested in a multiple low-dose STZ-induced animal model of T1DM. LentiVIP delivery into diabetic animals reduced hyperglycemia, improved glucose tolerance, and prevented weight loss. Also, a decrease in serum CRP levels, and serum oxidant capacity, but an increase in antioxidant capacity were observed in LentiVIP-treated animals. Restoration of islet cell mass was correlated with an increase in pancreatic beta-cell proliferation. These beneficial results suggest the therapeutic effect of LentiVIP is due to the repression of diabetes-induced inflammation, its insulinotropic properties, and VIP-induced beta-cell proliferation.

Topics: Animals; Cell Proliferation; Diabetes Mellitus, Type 1; Genetic Therapy; Inflammation; Insulin; Vasoactive Intestinal Peptide

Systemic inflammation has been shown to play a pivotal role in the pathogenesis of moyamoya disease (MMD). Brain-gut peptides exhibit regulatory effects in the secretion of proinflammatory cytokines. To investigate the association between brain-gut peptides and inflammation in the occurrence of MMD, 41 patients with MMD, as well as 74 age- and sex-matched healthy individuals were enrolled. The levels of four brain-gut peptides (vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK), somatostatin (SST), substance P (SP)) and three proinflammatory cytokines (interleukin-1

Topics: Adult; Biomarkers; Brain; Case-Control Studies; Cytokines; Female; Gastrointestinal Microbiome; Humans; Inflammation; Intestines; Male; Middle Aged; Moyamoya Disease; Peptides; Regression Analysis; ROC Curve; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide

Neuropeptides synthetised in the enteric nervous system can change the function of the immunocells and play a role in inflammatory processes. In our review the effects of inflammation on the neuropeptide content of nerves and immune cells were compared. Inflamed tissue samples (human gastritis and animal models with experimental colitis and streptozotocin-induced diabetes mellitus) were examined. The number and contacts of neuropeptide-containing nerves and immune cells were studied using immunohistochemistry, confocal laser microscopy and electronmicroscopy. In inflammation, the number of substance P, vasoactive intestinal polypeptide and neuropeptide Y nerve fibres was increased significantly in parallel with the strongly increased number of immunocompetent cells (p<0.001). In inflammatory diseases, a large number of lymphocytes and mast cells were also positive for these neuropeptides. Very close morphological relationship between substance P and neuropeptide Y immunoreactive nerve fibres and immunocells could be demonstrated only in inflamed mucosa. Some of the substance P immunoreactive immunocells were also immunoreactive for tumor necrosis factor alpha and nuclear factor kappa B in the case of inflammation. The increased number of tumor necrosis factor alpha and nuclear factor kappa B immunoreactive immune cells correlated with the increased number of substance P-containing nerve fibres. Substance P, vasoactive intestinal polypeptide and neuropeptide Y released from nerve fibres and immunocells can play a role in inflammation. Our results suggest that using substance P antagonists or vasoactive intestinal polypeptide and neuropeptide Y peptides might be a novel therapeutic concept in the management of inflammation. Orv Hetil. 2020; 161(35): 1436-1440.

Topics: Animals; Immunohistochemistry; Inflammation; Nerve Fibers; Neuropeptide Y; Substance P; Vasoactive Intestinal Peptide

Topics: Angiotensin-Converting Enzyme 2; Arthritis, Rheumatoid; Autoimmune Diseases; Drug Combinations; Gastrointestinal Neoplasms; Humans; Inflammation; Inflammatory Bowel Diseases; Neurodegenerative Diseases; Phentolamine; Receptors, G-Protein-Coupled; Vasoactive Intestinal Peptide

We aimed to explore the effects of neuropeptides ghrelin, obestatin, and vasoactive intestinal peptide (VIP) on seizures and plasma concentrations of neuroinflammation biomarkers including calcitonin gene-related peptide (CGRP), substance-P (SP), and interleukin-1 beta (IL-1β) in pentylenetetrazol-induced seizures in rats.. Ghrelin (80 µg/kg), obestatin (1 µg/kg), VIP (25 ng/kg) or saline were administered to rats intraperitoneally 30 min before pentylenetetrazole (PTZ, 50 mg/kg) injections. Stages of epileptic seizures were evaluated by Racine's scale, and plasma CGRP, SP, and IL-1β concentrations were measured using ELISA.. Both obestatin and VIP shortened onset-time of generalized tonic-clonic seizure, respectively, moreover VIP also shortened the onset-time of first myoclonic-jerk induced by PTZ. While PTZ increased plasma CGRP, SP and IL-1β concentrations, ghrelin reduced the increases evoked by PTZ. While VIP further increased PTZ-evoked CGRP levels, it diminished IL-1β concentrations. However, obestatin did not change CGRP, SP, and IL-1β concentrations.. Our results suggest that ghrelin acts as an anticonvulsant, obestatin acts as a proconvulsant, and VIP has dual action on epilepsy. Receptors of those neuropeptides may be promising targets for epilepsy treatment.

Topics: Animals; Biomarkers; Calcitonin Gene-Related Peptide; Convulsants; Disease Models, Animal; Ghrelin; Inflammation; Interleukin-1beta; Male; Myoclonus; Neuropeptides; Pentylenetetrazole; Peptide Hormones; Random Allocation; Rats, Wistar; Seizures; Substance P; Time Factors; Vasoactive Intestinal Peptide

Vulvodynia is a prevalent chronic pain disorder associated with high medical costs and often ineffective treatments. The major pathological feature is proliferation of vaginal nerve fibers. This study aimed to develop a highly reproducible animal model to study neuroproliferation in the vagina and aid the identification of appropriately targeted treatments for conditions such as vulvodynia. Mild chronic inflammation was induced using microinjection of complete Freund's adjuvant in the distal vagina of C57Bl/6 mice. Control mice received saline. Inflammation and innervation density were assessed at 7 and 28 days after a single administration or 14 days following repeated administration of complete Freund's adjuvant or saline. Histochemistry and blinded-analysis of images were used to assess vaginal morphology (H & E) and abundance of macrophages (CD68-labeling), mast cells (toluidine blue staining, mast cell tryptase-immunoreactivity), blood vessels (αSMA-immunoreactivity) and nerve fibers immunoreactive for the pan-neuronal marker PGP9.5. Subpopulations of nerve fibers were identified using immunoreactivity for calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY). Single administration of complete Freund's adjuvant resulted in vaginal swelling, macrophage infiltration, vascular proliferation and increased abundance of nerve fibers immunoreactive for CGRP, SP, VIP and/or PGP9.5 but not NPY, evident at seven days. Inflammation further increased following repeated administration of complete Freund's adjuvant but nerve fiber proliferation did not. Nerve fiber proliferation continued to be evident at 28 days. The inter-individual differences within each treatment group were small, indicating that this model may be useful to study mechanisms underlying vaginal nerve fiber proliferation associated with inflammation.

Topics: Animals; Calcitonin Gene-Related Peptide; Edema; Female; Freund's Adjuvant; Inflammation; Mice, Inbred C57BL; Neovascularization, Pathologic; Nerve Fibers; Substance P; Time Factors; Vagina; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is one of the most abundant neuropeptides in the lungs with various biological characters. We have reported that VIP inhibited the expressions of TREM-1 and IL-17A, which are involved in the initiation and amplification of inflammation in acute lung injury (ALI). However, the overall effect of VIP on ALI remains unknown. The aim of this study is to investigate the therapeutic effect of VIP mediated by lentivirus (Lenti-VIP) on lipopolysaccharide (LPS)-induced murine ALI. We found that the expression of intrapulmonary VIP peaked at day7 after the intratracheal injection of Lenti-VIP. Lenti-VIP increased the respiratory rate, lung compliance, and tidal volume, while decreased airway resistance in ALI mice, detected by Buxco system. Lenti-VIP significantly reduced inflammatory cell infiltration and maintained the integrity of the alveolar septa. Lenti-VIP also remarkably decreased the total protein level, the number of neutrophil and lactate dehydrogenase activity in the bronchoalveolar lavage fluid of LPS-induced ALI mice. In addition, Lenti-VIP down-regulated pro-inflammatory tumor necrosis factor (TNF)-α mRNA and protein expression, while up-regulated anti-inflammatory interleukin-10 mRNA and protein expression in lungs of ALI mice. Furthermore, we observed that VIP reduced the TNF-α expression in murine macrophages under LPS stimulation through protein kinase C and protein kinase A pathways. Together, our findings show that in vivo administration of lentivirus expressing VIP exerts a potent therapeutic effect on LPS-induced ALI in mice via inhibiting inflammation.

Topics: Acute Lung Injury; Animals; Cytoprotection; Disease Models, Animal; Down-Regulation; Genetic Therapy; Genetic Vectors; Inflammation; Lentivirus; Lipopolysaccharides; Macrophages, Alveolar; Male; Mice; Transfection; Vasoactive Intestinal Peptide

Topics: Animals; Cell Line; Cell Survival; Cytokines; Dose-Response Relationship, Drug; Inflammation; Lipopolysaccharides; MicroRNAs; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Regression Analysis; Schwann Cells; Transcriptome; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is a neuropeptide that exerts various vascular and cardioprotective functions and regulates immune function and inflammatory response at multiple levels. However, its role in inflammatory cardiovascular disorders is largely unknown. Myocarditis and atherosclerosis are two inflammatory and autoimmune cardiovascular diseases that cause important adverse circulatory events. In this study, we investigate the therapeutic effects of VIP in various well-established preclinical models of experimental autoimmune myocarditis and atherosclerosis. Intraperitoneal injection of VIP during the effector phase of experimental autoimmune myocarditis in susceptible BALB/c mice significantly reduced its prevalence, ameliorated signs of heart hypertrophy and injury, attenuated myocardial inflammatory infiltration, and avoided subsequent profibrotic cardiac remodeling. This effect was accompanied by a reduction of Th17-driven cardiomyogenic responses in peripheral lymphoid organs and in the levels of myocardial autoantibodies. In contrast, acute and chronic atherosclerosis was induced in apolipoprotein E-deficient mice fed a hyperlipidemic diet and subjected to partial carotid ligation. Systemic VIP treatment reduced the number and size of atherosclerotic plaques in carotid, aorta, and sinus in hypercholesterolemic mice. VIP reduced Th1-driven inflammatory responses and increased regulatory T cells in atherosclerotic arteries and their draining lymph nodes. VIP also regulated cholesterol efflux in macrophages and reduced the formation of foam cells and their presence in atherosclerotic plaques. Finally, VIP inhibited proliferation and migration of smooth muscle cells and neointima formation in a mouse model of complete carotid ligation. These findings encourage further studies aimed to assess whether VIP can be used as a pharmaceutical agent to treat heart inflammation and atherosclerosis.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Autoantibodies; Autoimmune Diseases; Autoimmunity; Disease Models, Animal; Female; Inflammation; Lymph Nodes; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Muscle, Smooth; Myocarditis; Myocardium; Neuropeptides; T-Lymphocytes, Regulatory; Th17 Cells; Vasoactive Intestinal Peptide

Chronic pelvic pain (CPP) causes compromised the quality of life in women with endometriosis and is often attributed to local inflammation and ingrowth of nerve fibers. In this pilot study, we aimed to investigate whether the inflammation-related vasoactive intestinal peptide (VIP) and interleukin (IL)-6 were increased in affected patients.. Endometrial and endometriotic tissue biopsy specimens, and serum and peritoneal fluid (PF) samples, were obtained from 85 endometriosis patients and 53 controls. VIP and IL-6 analysis and measurement of microvessel density in tissue were performed using immunohistochemistry, Western blotting, RT-qPCR, and ELISA.. Compared with controls, VIP transcript and protein levels were increased in endometrium from endometriosis patients and further elevated in patients with CPP. In addition, microvessel density, a measurement of angiogenic activity, was increased in the endometrium and in endometriosis lesions in the same subset of patients. Serum and PF levels of VIP and IL-6 were higher in women with endometriosis and CPP compared with endometriosis patients who reported no chronic pain.. Vasoactive intestinal peptide is upregulated in endometriosis patients reporting chronic pain. Increased microvessel density in tissue and peritoneal fluid concentrations of IL-6 indicate an elevated inflammation in the pelvic microenvironment of these patients.

Topics: Adult; Ascitic Fluid; Chronic Disease; Endometriosis; Endometrium; Female; Humans; Inflammation; Interleukin-6; Microvessels; Pelvic Pain; Pilot Projects; Quality of Life; Vasoactive Intestinal Peptide

The enteric nervous system (ENS), situated in the wall of the gastrointestinal tract, regulates the majority of intestinal activities in physiological conditions and during pathological processes. Enteric neurons are diversified in terms of active substance expression. One of the most important neuropeptides within the ENS is vasoactive intestinal polypeptide (VIP). It seems to be one among the important inhibitory peptides in addition to neuropeptide Y (NPY), nitric oxide (NO), and adenosine triphosphate (ATP) of the intestinal motility and secretion, however, many issues connected with distribution and roles of VIP in the large intestine, especially during pathological states, still remain unknown.. Changes in the VIP-like immunoreactivity of the enteric nervous structures under experimental pathological states, including chemically induced inflammation and nerve damage was examined using the double immunofluorescence technique with commercial antibodies.. Generally, both pathological factors studied caused an increase in the number of VIP-like immunoreactive (VIP-LI) neurons and nerve fibers, but the intensity of fluctuations depended on both the acting factor and the part of the ENS studied.. The obtained results suggest that VIP participates in pathological processes concerning the digestive tract, and its exact functions probably depend on the type of damaging factor acting on the intestine.

Topics: Animals; Axotomy; Colon, Descending; Enteric Nervous System; Female; Inflammation; Neurons; Sus scrofa; Vasoactive Intestinal Peptide

It is suggested that different neuropeptides are actively involved in the pathogenesis of Helicobacter pylori (H. pylori)-induced gastritis acting as important effectors of the neuroimmune complex interactions, but the available data is limited and contradictory. The aim of this study was to determine whether the chronic infection generates changes in substance P (SP) and vasoactive intestinal peptide (VIP) gastric level and to evaluate the dependence of these potential effects on the degree of bacterial colonization or the severity of the inflammatory infiltrate. Therefore, immunohistochemical tests were performed to examine SP and VIP expression in mucosal nerve endings and myenteric neurons. Both SP and VIP levels were significantly higher in gastric samples of patients infected with H. pylori compared to uninfected individuals, confirming that these neuropeptides are neuroimmune modulators involved in the pathogenesis of H. pylori infection. Although their expression did not correlate with the intensity of mucosal inflammation nor with the bacterial density, we observed a strong association between SP neuronal level and the degree of myenteric ganglionitis, which in turn correlated with the severity of mucosal T-cell infiltration. These findings suggest that the mechanisms of neuroimmune cross-talk depend on some other factors that remain to be determined.

Topics: Adult; Cohort Studies; Enteric Nervous System; Female; Gastric Mucosa; Helicobacter Infections; Humans; Inflammation; Male; Retrospective Studies; Substance P; Vasoactive Intestinal Peptide

This study tested the hypothesis that vasoactive intestinal peptide (VIP) is able to modify the macrophage inflammatory profile, thus supporting its therapeutic role in autoimmune diseases. Macrophages are innate immune cells that display a variety of functions and inflammatory profiles in response to the environment that critically controls their polarization. Deregulation between the pro- and anti-inflammatory phenotypes has been involved in different pathologies. Rheumatoid arthritis (RA) is an autoimmune disease, in which macrophages are considered central effectors of synovial inflammation, displaying a proinflammatory profile. VIP is a pleiotropic neuropeptide with proven anti-inflammatory actions. As modulation of the macrophage phenotype has been implicated in the resolution of inflammatory diseases, we evaluated whether VIP is able to modulate human macrophage polarization. In vitro-polarized macrophages by GM-CSF (GM-MØ), with a proinflammatory profile, expressed higher levels of VIP receptors, vasoactive intestinal polypeptide receptors 1 and 2 (VPAC1 and VPAC2, respectively), than macrophages polarized by M-CSF (M-MØ) with anti-inflammatory activities. RA synovial macrophages, according to their GM-CSF-like polarization state, expressed both VPAC1 and VPAC2. In vitro-generated GM-MØ exposed to VIP exhibited an up-regulation of M-MØ gene marker expression, whereas their proinflammatory cytokine profile was reduced in favor of an anti-inflammatory function. Likewise, in GM-MØ, generated in the presence of VIP, VIP somehow changes the macrophages physiology profile to a less-damaging phenotype. Therefore, these results add new value to VIP as an immunomodulatory agent on inflammatory diseases.

Topics: Arthritis, Rheumatoid; Cells, Cultured; Cyclic AMP; Cytokines; Gene Expression Regulation; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunophenotyping; Inflammation; Macrophage Activation; Macrophage Colony-Stimulating Factor; Macrophages; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; RNA, Messenger; Synovial Fluid; Up-Regulation; Vasoactive Intestinal Peptide

Interleukin (IL)-17A is a pro-inflammatory cytokine that markedly enhances inflammatory responses in the lungs by recruiting neutrophils and interacting with other pro-inflammatory mediators. Reducing the expression of IL-17A could attenuate inflammation in the lungs. However, whether VIP exerts its anti-inflammatory effects by regulating the expression of IL-17A has remained unclear. Here, we show that there is a remarkable increase of IL-17A in bronchoalveolar lavage fluid (BALF) and lung tissue of mice with acute lung injury (ALI). Moreover, lipopolysaccharides (LPS) stimulated elevated expression of IL-17A, which was evident by the enhanced levels of mRNA and protein observed. Furthermore, we also found that VIP inhibited LPS-mediated IL-17A expression in a time- and dose-dependent manner in an in vitro model of ALI and that this process might be mediated via the phosphokinase A (PKA) and phosphokinase C (PKC) pathways. Taken together, our results demonstrated that VIP might be an effective protector during ALI by suppressing IL-17A expression.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Inflammation; Inflammation Mediators; Interleukin-17; Macrophages; Male; Mice; Protein Kinase C; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Vasoactive Intestinal Peptide

Arterial hypertension is associated with serious dysfunction of the cardiovascular system and digestive system. Given the relevant role of vasoactive intestinal peptide (VIP) in the regulation of digestion process, control of blood pressure and heart rate as well as cardio- and gastro-protective character of the peptide, it appeared worthwhile to undertake the research aimed at immunohistochemical identification and evaluation of VIP-positive structures in the pylorus and heart of hypertensive rats. Up to now, this issue has not been investigated. The experimental model of hypertension in rats according to Goldblatt (two-kidney one clip model of hypertension) was used in the study. The experimental material (pylorus and heart) was collected in the sixth week of the study. VIP-containing structures were evaluated using immunohistochemical and morphometric methods. The analysis of the results showed a significant increase in the number of immunoreactive VIP structures and in the intensity of immunohistochemical staining in the stomach and in the heart of hypertensive rats. Our findings indicate that VIP is an important regulator of cardiovascular and digestive system in physiological and pathological conditions. However, to better understand the exact role of VIP in hypertension further studies need to be carried out.

Topics: Animals; Blood Pressure; Body Weight; Disease Models, Animal; Gastric Mucosa; Gene Expression Regulation; Heart Rate; Hypertension, Renovascular; Immunohistochemistry; Inflammation; Male; Myocardium; Rats; Rats, Wistar; Tissue Distribution; Vasoactive Intestinal Peptide

We compared the effect of VIP on human blood monocytes infected with Salmonella typhimurium 4/74 or stimulated with LPS. VIP (10(-7)M) increased monocyte viability by 24% and 9% when cultured for 24h with 4/74 or Salmonella LPS (100ng/ml), respectively. Significantly increased (P<0.05) numbers of 4/74 were also recovered from monocytes co-cultured with VIP after 6h post-infection (pi) and this remained high after 24h pi. Both 4/74 and LPS increased (P<0.05) the concentration of TNF-α, IL-1β and IL-6 measured in monocyte supernatants. However, LPS induced this effect more rapidly while, with the exception of IL-6, 4/74 induced higher concentrations (P<0.05). VIP significantly decreased (P<0.05) TNF-α and IL-1β production by 4/74-infected monocytes after 6 pi, but only after 24h in LPS-cultured monocytes. This trend was reversed for IL-6 production. However, TNF-α and IL-1β production by 4/74-infected monocytes, cultured with VIP, still remained higher (P<0.05) than concentrations measured in supernatants cultured only with LPS. VIP also increased (P<0.05) production of anti-inflammatory IL-10 in both 4/74 and LPS cultures after 24h. We also show a differential effect of VIP on the expression of TNFα and IL-6 receptors, since VIP was only able to decreased expression in LPS-stimulated monocytes but not in 4/74-infected monocytes. In conclusion, we show a differential effect of VIP on human monocytes infected with virulent Salmonella or stimulated with LPS. Our study suggests that the use of VIP in bacteraemia and/or sepsis may be limited to an adjunctive therapy to antibiotic treatment.

Topics: Gene Expression Regulation; Humans; Inflammation; Lipopolysaccharides; Monocytes; Monokines; Receptors, Interleukin-6; Receptors, Tumor Necrosis Factor; Salmonella Infections; Salmonella typhimurium; Vasoactive Intestinal Peptide

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

Multiple sclerosis (MS) is a severe debilitating disorder characterized by progressive demyelination and axonal damage of the central nervous system (CNS). Current therapies for MS inhibit the immune response and demonstrate reasonable benefits if applied during the early phase of relapsing–remitting MS (RRMS) while there are no treatments for patients that progress neither to the chronic phase nor for the primary progressive form of the disease. In this manuscript, we have studied the therapeutic efficacy of a cell and gene therapy strategy for the treatment of a mouse model of chronic MS [myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE)]. We used allogenic mesenchymal stem cells (MSCs) asa therapeutic tool and also as vehicle to deliver fully processed 3.3-kDa vasoactive intestinal peptide (VIP) to the peripheral immune organs and to the inflamed CNS. Intraperitoneal administrations of MSCs expressing VIP stopped progression and reduced symptoms when administered at peak of disease. The improvement in clinical score correlated with diminished peripheral T-cell responses against MOG as well as lower inflammation,lower demyelination, and higher neuronal integrity in the CNS. Interestingly, neither lentiviral vectors expressing VIP nor unmodified MSCs were therapeutic when administer at the peak of disease. The increased therapeutic effect of MSCs expressing VIP over unmodified MSCs requires the immunoregulatory and neuroprotective roles of both VIP and MSCs and the ability of the MSCs to migrate to peripheral lymph organs and the inflamed CNS.

Topics: Adipose Tissue; Animals; Central Nervous System; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Forkhead Transcription Factors; Immunophenotyping; Inflammation; Infusions, Parenteral; Lentivirus; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; T-Lymphocytes; Transplantation, Homologous; Vasoactive Intestinal Peptide

Despite advances in rheumatoid arthritis (RA) treatment, efficacious and safe disease-modifying therapy still represents an unmet medical need. Here, we describe an innovative strategy to treat RA by targeting low doses of vasoactive intestinal peptide (VIP) self-associated with sterically stabilized micelles (SSMs). This spontaneous interaction of VIP with SSM protects the peptide from degradation or inactivation in biological fluids and prolongs circulation half-life. Treatment with targeted low doses of nanosized SSM-VIP but not free VIP in buffer significantly reduced the incidence and severity of arthritis in an experimental model, completely abrogating joint swelling and destruction of cartilage and bone. In addition, SSM associated VIP, unlike free VIP, had no side-effects on the systemic functions due to selective targeting to inflamed joints. Finally, low doses of VIP in SSM successfully downregulated both inflammatory and autoimmune components of RA. Collectively, our data clearly indicate that VIP-SSM should be developed to be used as a novel nanomedicine for the treatment of RA.

Topics: Animals; Arthritis, Rheumatoid; Inflammation; Male; Mice; Micelles; Nanomedicine; Phospholipids; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is a pleiotropic neuropeptide with immunomodulatory properties. The administration of this peptide has been shown to have beneficial effects in murine models of inflammatory diseases including septic shock, rheumatoid arthritis, multiple sclerosis (MS) and Crohn's disease. However, the role of the endogenous peptide in inflammatory disease remains obscure because VIP-deficient mice were recently found to exhibit profound resistance in a model of MS. In the present study, we analyzed the response of female VIP deficient (KO) mice to intraperitoneal lipopolysaccharide (LPS) administration. We observed significant resistance to LPS in VIP KO mice, as evidenced by lower mortality and reduced tissue damage. The increased survival was associated with decreased levels of proinflammatory cytokines (TNFα, IL-6 and IL-12) in sera and peritoneal suspensions of these mice. Moreover, the expression of TNFα and IL-6 mRNA was reduced in peritoneal cells, spleens and lungs from LPS-treated VIP KO vs. WT mice, suggesting that the resistance might be mediated by an intrinsic defect in the responsiveness of immune cells to endotoxin. In agreement with this hypothesis, peritoneal cells isolated from VIP KO naive mice produced lower levels of proinflammatory cytokines in response to LPS in vitro. Finally, decreased NF-κB pathway activity in peritoneal cells was observed both in vivo and in vitro, as determined by assay of phosphorylated I-κB. The results demonstrate that female VIP KO mice exhibit resistance to LPS-induced shock, explainable in part by the presence of an intrinsic defect in the responsiveness of inflammatory cells to endotoxin.

Topics: Animals; Endotoxemia; Endotoxins; Female; Inflammation; Inflammation Mediators; Interleukin-12; Interleukin-6; Lipopolysaccharides; Lung; Mice; Mice, Inbred C57BL; Neuropeptides; NF-kappa B; RNA, Messenger; Spleen; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide

Vasoactive intestinal polypeptide (VIP) is a neuropeptide from secretin/glukagon family. Recently, the importance of VIP is becoming more evident, and it is thought that VIP is playing an important regulatory role between neuroendocrine-immune-gastrointestinal systems. In this study, we have tried to evaluate the potential role of VIP in patients with ankylosing spondylitis (AS). In this study, 40 patients (30 male and 10 female) with AS and 40 healthy controls were included. X-ray examinations and scoring of sacroiliac joints of the patients with AS were done according to 1984 Modified New York Criteria for AS. All patients have been assessed with Bath Ankylosing Spondylitis Disease Activity Index. Platelet counts were significantly higher in study group (P < 0.05) in contrast to levels of the hemoglobin. The mean VIP levels were 4.2 ± 1.8 (pg/mL) for study group and 2.8 ± 0.8 (pg/mL) for controls. These results were statistically significant (P < 0.05). There was not any correlation between plasma VIP levels with CRP, ESR, Hb, BASDAI results and radiological scoring of the patients (P > 0.05) in contrast to our expectations. However, platelet counts and VIP levels were correlated significantly (P = 0.03). Our data demonstrate that VIP tended to be high in patients with AS when compared with healthy subjects and correlated with platelet counts significantly, for the first time at the literature. According to this study, VIP may have potential role in the pathogenesis of AS, and it is a potential candidate for many kinds of therapies.

Topics: Adult; Biomarkers; Blood Sedimentation; C-Reactive Protein; Female; Hemoglobins; Humans; Inflammation; Male; Platelet Count; Radiography; Sacroiliac Joint; Spondylitis, Ankylosing; Vasoactive Intestinal Peptide; Young Adult

Vasoactive intestinal peptide (VIP) is one of the most plentiful neuropeptides in the lung and it has anti-inflammatory effects in the respiratory system. Triggering receptors expressed on myeloid cells-1 (TREM-1) and triggering receptors expressed on myeloid cells-2 (TREM-2) regulate immune responses to lipopolysaccharide (LPS). In the present study, we tested the expressions of TREM-1 and TREM-2 in various pulmonary cell lines and/or tissue using an animal model of LPS-induced acute lung injury (ALI), and determined the effects of VIP on expression of the TREM-1 and TREM-2 in lung tissues and cells from ALI mice. We found 1) expression of the TREM-1 mRNA from lung tissues of ALI was significantly increased, whereas the expression of TREM-2 mRNA was decreased in these tissues; 2) TREM-1 mRNA was only expressed in macrophages, while TREM-2 mRNA was detected in HBECs, lung fibroblasts, lung adenocarcinoma cells and macrophages; 3) the ratio of TREM-1 mRNA to TREM-2 mRNA was increased in LPS-induced lung tissues and macrophages; 4) VIP inhibited expression of the TREM-1 mRNA in a time- and dose-dependent manner in lung cells from LPS-induced ALI mice; however, it increased expression of the TREM-2 mRNA. As a result of these effects, VIP normalized the ratio of TREM-1 to TREM-2 mRNA in these cells. Our results suggest that VIP might exert its anti-inflammatory effect through a mechanism involved in regulation of expression of the TREM-1 and TREM-2 in LPS-induced ALI.

Topics: Acute Lung Injury; Adenocarcinoma; Adenocarcinoma of Lung; Animals; Anti-Inflammatory Agents; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Inflammation; Lipopolysaccharides; Lung; Lung Neoplasms; Male; Membrane Glycoproteins; Mice; Myeloid Cells; Neoplasms; Neuroprotective Agents; Receptors, Immunologic; RNA, Messenger; Triggering Receptor Expressed on Myeloid Cells-1; Vasoactive Intestinal Peptide

Growing evidence is showing a role of neurogenic inflammation in allergic reactions, with sensory and autonomic nerve fibers releasing neuromediators, which may actively participate in the allergic inflammatory cascade. Although the cornea is the most densely innervated tissue of the human body, little is known on the role of neuromediators at the ocular surface. In this study, we aimed at evaluating the role of substance P (SP), calcitonine gene related peptide (CGRP), neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) in allergic reactions of the ocular surface.. Fifteen patients with allergic conjunctivitis (6 female, 9 male, mean age 30±8 years) in non-active phase, and 10 age-matched healthy subjects were included in this study. The conjunctival provocation test (CPT) with allergen was performed in all allergic patients and in 5 healthy subjects. Tear samples were collected and the tear content of VIP, NPY, CGRP, and SP was measured by ELISA at baseline and after CPT. The Mann-Whitney U-test and Wilcoxon test were used to compare neuromediator tear levels.. No significant differences in neuropeptide tear levels were observed between healthy and allergic patients in non-active phase. CPT induced conjunctival hyperemia and itching in all allergic patients, while no reaction was observed in the control eyes and in healthy subjects. In allergic patients SP, CGRP, and VIP, but not NPY, were significantly higher after CPT as compared to baseline (SP: 3.9±1.3 ng/ml versus 5.8±1.1 ng/ml, p=0.011; CGRP: 5.5±2.3 ng/ml versus 7.3±2.7 ng/ml; p=0.002; VIP: 4±0.9 ng/ml versus 5.1±1.5 ng/ml, p=0.007). No significant changes were observed in the control eyes of allergic patients challenged with diluent and in healthy subjects after allergen provocation.. Locally-released neuromediators may participate in modulating the allergic response of the ocular surface.

Topics: Adult; Allergens; Animals; Bronchial Provocation Tests; Calcitonin Gene-Related Peptide; Conjunctivitis, Allergic; Enzyme-Linked Immunosorbent Assay; Eye; Female; Humans; Inflammation; Male; Neuropeptide Y; Neuropeptides; Pyroglyphidae; Tears; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) has been considered as a promising drug candidate for asthma and COPD because of its potent immunomodulating and anti-inflammatory activities. Recently, our group developed a new VIP derivative, [R(15, 20, 21), L(17), A(24,25), des-N(28)]-VIP-GRR (IK312548), with improved chemical and metabolic stability. In the present study, a dry powder inhaler system of IK312548 was designed for inhalation therapy with minimal systemic side effects, the physicochemical properties of which were also evaluated with a focus on morphology, particle size distribution, inhalation performance, and peptide stability. Laser diffraction and cascade impactor analysis suggested high dispersion and deposition in the respiratory organs with a fine particle fraction of 31.2%. According to UPLC/ESI-MS and circular dichroic spectral analyses, no significant changes in the purity and structure of VIP derivative were observed during preparation of respirable formulation. Anti-inflammatory properties of IK312548 respirable powder (RP) were characterized in antigen-sensitized asthma/COPD-model rats. There were marked inflammatory cells infiltrated into the lung tissues of experimental asthma/COPD-model rats; however, intratracheal administration of IK312548-RP led to significant reductions of recruited inflammatory cells in lung tissues and BALF by 72 and 78%, respectively. Thus, respirable powder formulation of IK312548 might be a promising medication for asthma, COPD, and other airway inflammatory diseases.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents; Asthma; Disease Models, Animal; Drug Stability; Dry Powder Inhalers; Inflammation; Lung; Male; Particle Size; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Tissue Distribution; Vasoactive Intestinal Peptide

Cigarette smoke (CS) has been identified as a predominant causative factor for chronic obstructive pulmonary disease (COPD), so CS-exposed rodent model of COPD has drawn considerable interest and attention for fundamental study and drug discovery. In the present study, using experimental COPD model rats, the therapeutic potential of a newly prepared respirable powder (RP) formulation of a long-acting VIP derivative, [Arg(15,20,21), Leu(17)]-VIP-GRR (IK312532), was assessed with a focus on pro-inflammatory biomarkers, morphological and histochemical changes, and infiltrated cells in the respiratory system. CS exposure of rats for 11 days led to the marked infiltration of inflammatory cells, except for eosinophils, in bronchiolar epithelium, followed by goblet cell metaplasia and hyperplasia. However, inhalation of IK312532-RP (50μg/rat) in the CS-exposed rats resulted in 74 and 71% reductions of granulocyte recruitment in bronchoalveolar lavage fluids and lung tissues, respectively, with 68% decrease of goblet cells. Biomarker study demonstrated that the inhaled IK312532-RP could suppress the CS-evoked increase of myeloperoxidase in both plasma and lung by 87 and 70%, respectively, possibly leading to potent suppression of neutrophilic inflammatory symptoms. The results from TUNEL staining were indicative of apoptotic damage in respiratory tissues of the CS-exposed rats, and there appeared to be marked decrease of TUNEL-positive cells in the CS-exposed rat with inhaled IK312532-RP. The present findings suggest that an inhalable formulation of IK312532 might be efficacious as a therapy for COPD or other airway inflammatory diseases because of its potent immunomodulating activities.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents; Biomarkers; Eosinophil Peroxidase; Inflammation; Lung Diseases; Male; Neutrophils; Nicotiana; Peroxidase; Powders; Rats; Rats, Sprague-Dawley; Respiratory Mucosa; Smoke; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide widely expressed in the body and binding three types of receptors: VPAC(1)-R, VPAC(2)-R and PAC(1)-R. Based on beneficial effects of VIP and VPAC(1)-R agonists in mouse models of several chronic inflammatory disorders, we hypothesized that activation of VIP receptors would prevent atherosclerosis development in apolipoprotein E-deficient mice.. Contrary to our hypothesis, administration of a VPAC(1)-R agonist, (Ala(11,22,28))-VIP aggravated atherosclerotic lesion development in the aortic root of these mice compared to control mice. This was accompanied by a significant increase in the expression of MHC class II protein I-A(b), and suggests enhanced inflammatory activity in the vessel wall. The amount of macrophage-specific CD68 staining as well as serum cholesterol and triglyceride levels did not change as a result of the (Ala(11,22,28))-VIP treatment, i.e. the treatment resulted in significant changes in lipid accumulation in the lesions without changing the number of macrophages or systemic lipid levels. Interestingly, administration of VIP did not alter the course of the disease.. Despite beneficial effects in murine models of several inflammatory disorders, VPAC(1)-R activation aggravates atherosclerotic lesion formation in apolipoprotein E-deficient mice through enhanced inflammatory activity in the vessel wall.

Topics: Animals; Apolipoproteins E; Atherosclerosis; B-Lymphocytes; Cytokines; Disease Models, Animal; Hypercholesterolemia; Inflammation; Mice; Mice, Knockout; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Spleen; T-Lymphocytes; Vasoactive Intestinal Peptide

The neuropeptide vasoactive intestinal peptide (VIP) has been shown to inhibit macrophage proinflammatory actions, promote a positive Th2/Th1 balance, and stimulate regulatory T-cell production. The fact that this peptide is highly efficacious in animal models of inflammatory diseases such as collagen-induced arthritis and experimental autoimmune encephalomyelitis (EAE) suggests that the endogenous peptide might normally provide protection against such pathologies. We thus studied the response of VIP-deficient (i.e., VIP KO) mice to myelin oligodendrocyte protein-induced EAE. Surprisingly, VIP KO mice were almost completely resistant to EAE, with delayed onset and mild or absent clinical profile. Despite this, flow cytometric analyses and antigen-rechallenge experiments indicated that myelin oligodendrocyte protein-treated VIP KO mice exhibited robust Th1/Th17 cell inductions and antigen-specific proliferation and cytokine responses. Moreover, adoptive transfer of lymphocytes from immunized VIP KO mice to WT recipients resulted in full-blown EAE, supporting their encephalitogenic potential. In contrast, transfer of encephalitogenic WT cells to VIP KO hosts did not produce EAE, suggesting that loss of VIP specifically affected the effector phase of the disease. Histological analyses indicated that CD4 T cells entered the meningeal and perivascular areas of VIP-deficient mice, but that parenchymal infiltration was strongly impaired. Finally, VIP pretreatment of VIP KO mice before immunization was able to restore their sensitivity to EAE. These results indicate that VIP plays an unanticipated permissive and/or proinflammatory role in the propagation of the inflammatory response in the CNS, a finding with potential therapeutic relevance in autoimmune neuroinflammatory diseases such as multiple sclerosis.

Topics: Animals; Autoimmune Diseases; Cell Movement; Central Nervous System; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Inflammation; Lymphocyte Activation; Mice; Mice, Knockout; Myelin-Associated Glycoprotein; T-Lymphocytes; Th1 Cells; Th17 Cells; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is a neuropeptide with potent bronchodilator, immunomodulator, and anti-inflammatory properties, and thus has biological properties capable of counteracting all major features of the asthmatic response. However, the effect of VIP on bronchial mucin secretion remains unclear. In order to observe the influence of VIP on bronchial mucin, the present study was designed to observe the correlation between VIP and total bronchial mucin changes under different time of ozone stress in rat lung. Sixty-four Sprague-Dawley rats were used in the experiment. Under different time of ozone stress, VIP content in lung homogenate was analyzed by radioimmunoassay, and changes in total bronchial mucin in the lung were analyzed by calculating the goblet cell hyperplasia ratio and the epithelial cell mucus occupying ratio from the periodic acid-Schiff reaction (PAS) staining. The results showed that, at early stage of respiratory tract injury, VIP did not change significantly, while the total bronchial mucin secretion increased; with the development of damage, the secretion of VIP increased by compensation, followed by a decrease in total bronchial mucin; with further injury, the numbers of pulmonary endocrine VIP positive nerve fibers and endocrine cells decreased, but bronchial mucin volume gradually increased. It is concluded that the secretion of VIP is negatively correlated with the secretion of bronchial mucin during the development of inflammation.

Topics: Animals; Inflammation; Lung; Mucins; Ozone; Rats, Sprague-Dawley; Vasoactive Intestinal Peptide

Prostaglandin E2 (PGE2) is a potent lipid mediator produced by the inducible form of the enzyme cyclooxygenase (COX-2) in inflammatory cells. PGE2 and COX-2 are critical mediators in the pathogenesis of several inflammatory and degenerative diseases, and have therefore emerged as therapeutic targets for the treatment of such disorders. Vasoactive intestinal peptide (VIP) is a well-known anti-inflammatory neuropeptide that protects against several immune disorders by regulating a wide panel of inflammatory mediators. In this work we show the inhibitory effect of VIP on COX-2 expression and subsequent production of PGE2 by macrophages, dendritic cells, and microglia activated with different inflammatory stimuli. This inhibitory effect is exerted at the transcriptional level and mediated through the VIP receptor VPAC1. VIP downregulates NFkappaB-dependent gene activation of the COX-2 promoter. These findings demonstrate a novel property of VIP that might contribute to their anti-inflammatory effects in vivo, i.e., the inhibition of the inducible COX-2/PGE2 system.

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dendritic Cells; Dinoprostone; Down-Regulation; Drug Synergism; Gene Expression; Gene Expression Regulation; Inflammation; Interferon-gamma; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred BALB C; Microglia; NF-kappa B; Promoter Regions, Genetic; Receptors, Vasoactive Intestinal Polypeptide, Type I; Transcriptional Activation; Vasoactive Intestinal Peptide

The pathogenesis of idiopathic pulmonary arterial hypertension (PAH) remains poorly understood. The present authors recently reported that mice with vasoactive intestinal peptide (VIP) gene disruption show a spontaneous phenotype of PAH, with pulmonary vascular remodelling and lung inflammation. To explore the underlying molecular mechanisms in this model, it was examined whether absence of the VIP gene might alter the expression of additional genes involved in the pathogenesis of PAH, as single-gene deletions, in the absence of hypoxia, rarely result in significant pulmonary vascular remodelling. Lung tissue from mice with targeted disruption of the vasoactive intestinal peptide gene (VIP(-/-) mice) and from control mice was subjected to whole-genome gene microarray analysis, and the results validated with quantitative, real-time PCR. Lungs from VIP(-/-) mice showed a wide range of significant gene expression alterations, including overexpression of genes that promote pulmonary vascular smooth muscle cell proliferation, underexpression of antiproliferative genes and upregulation of pro-inflammatory genes. In conclusion, vasoactive intestinal peptide is a pivotal modulator of genes controlling the pulmonary vasculature, its deficiency alone resulting in gene expression alterations that can readily explain both the vascular remodelling and associated inflammatory response in pulmonary arterial hypertension. The present findings shed more light on the molecular mechanisms of pulmonary arterial hypertension, and could lead to better understanding of the pathogenesis of human pulmonary arterial hypertension, and hence to improved therapy.

Topics: Animals; Gene Deletion; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligonucleotide Array Sequence Analysis; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) has been shown to exert potent immunomodulatory activity, and the use of lentiviral vectors has been found to be an effective means of gene delivery. The present study was therefore undertaken to investigate the feasibility and efficiency of gene therapy using lentiviral vectors expressing VIP (LentiVIP) for the treatment of rheumatoid arthritis (RA).. We evaluated the therapeutic potential of the gene therapy strategy in the collagen-induced arthritis (CIA) mouse model, administering the vectors at different phases of the disease. The inflammatory response was determined by measuring the levels of various inflammatory cytokines and chemokines in the joints and serum. The Th1-mediated response was evaluated by determining the proliferative response and cytokine profile of T cells stimulated with autoantigen.. A single intraperitoneal injection of LentiVIP was highly effective in treating CIA. Mice with established, severe arthritis showed complete regression of the disease. The therapeutic effect of LentiVIP was associated with widespread biodistribution of the vector and increased VIP levels, especially in joints and lymphoid organs, and was mediated through a striking reduction of the 2 deleterious components of the disease, i.e., the autoimmune response (self-reactive Th1 cell activity and autoantibody production) and the inflammatory response. LentiVIP treatment also induced the generation and/or activation of CD4+,CD25+,FoxP3+ Treg cells in arthritic mice.. Our findings show that in vivo administration of lentiviral vector expressing VIP produces one of the most potent therapeutic effects described so far in any animal model of RA. We propose that VIP gene transfer should be further investigated as a potential novel, effective treatment of RA and other chronic autoimmune disorders.

Topics: Animals; Arthritis, Experimental; DNA, Complementary; Genetic Therapy; Genetic Vectors; Inflammation; Lentivirus; Mice; T-Lymphocytes, Regulatory; Th1 Cells; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) was administered in a model of zymosan-induced generalized inflammation (ZIGI). Its beneficial action was associated with reduced TNF-alpha and increased IL-10 production, lowered levels of creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin in circulation. VIP diminished the level of RANTES and MIP-1alpha in peritoneal exudate and circulation. The neuropeptide inhibited NO release from stimulated peritoneal macrophages. Decreased spleen, liver and kidney enlargement and less pathological changes in liver were observed. The effect of VIP was attenuated by pretreatment with VIP antagonist (anti-VIP) before the induction of shock.

Topics: Animals; Cytokines; Inflammation; Inflammation Mediators; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Organ Size; Vasoactive Intestinal Peptide; Zymosan

Several reports have highlighted the potential roles for the VIP-related neuropeptides in regeneration/neuroprotection after brain or nerve injuries. We previously reported that peripheral inflammation worsened ibotenate-induced cystic white matter lesions. Because VIP is also known as an immunomodulator, we wonder if VIP could also limit the deleterious effects of local inflammation. Therefore, we first tested the effects of peripheral IL-1beta on VIP and PACAP central production. Second, we observed that cox-2 activation by IL-1beta was essential to generate changes in ligand/receptor gene expression. We further tested whether the intraperitoneal injection of IL-1beta, known to aggravate the ibotenate-induced lesions, could modify the expression pattern of VIP-related genes. Finally, we concluded using histological analysis that VIP[ala(11,22,28)], a synthetic VPAC(1) agonist completely reversed the aggravating effects of IL-1beta on ibotenate-induced lesions of the periventricular white matter. Conversely, VIP-neurotensin hybrid, a nonselective VIP receptor antagonist, worsened the lesions. All together, our results suggest that an activation of VIP/VPAC(1) signaling cascade in the vicinity of the injury site could circumvent the synergizing degenerative effects of ibotenate and pro-inflammatory cytokines. Therefore, development of therapeutic tools inducing/sustaining the activation of VIP/VPAC(1) signaling cascade may lead to future preventive treatments for inflammatory conditions during pregnancy.

Topics: Animals; Animals, Newborn; Brain; Female; Gene Expression; Ibotenic Acid; Inflammation; Interleukin-1beta; Male; Peptide Fragments; Pregnancy; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Vasoactive Intestinal Polypeptide, Type I; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Vasoactive Intestinal Peptide

The neuropeptide vasoactive intestinal peptide (VIP) is involved in the neuroimmunomodulation of the intestine. In the present study, specimens from the sigmoid colon of ulcerative colitis (UC) and non-UC patients were examined for immunohistochemistry and in vitro receptor autoradiography. Marked occurrence of VIP binding was observed in the mucosa. However, there were very low levels of binding in areas showing pronounced inflammation/derangement. The study shows that marked derangement of the mucosa leads to a distinct decrease in VIP binding. Thus, it is possible that a decrease in trophic and anti-inflammatory VIP effects occurs in areas exhibiting a very marked inflammation.

Topics: Adult; Aged; Aged, 80 and over; Autoradiography; Biomarkers; Colitis, Ulcerative; Female; Gastric Mucosa; Humans; Immunohistochemistry; Inflammation; Intestinal Mucosa; Male; Middle Aged; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide

A complex network of regulatory neuropeptides controls airway inflammation reaction, in which airway epithelial cells adhering to and activating leukocytes is a critical step. To study the effect of intrapulmonary regulatory peptides on adhesion of polymorphonuclear leukocytes (PMNs) to bronchial epithelial cells (BECs) and its mechanism, several regulatory peptides including vasoactive intestinal peptide (VIP), epidermal growth factor (EGF), endothelin-1 (ET-1) and calcitonin gene-related peptide (CGRP), were investigated. The results demonstrated that VIP and EGF showed inhibitory effects both on the secretion of IL-1, IL-8 and the adhesion of PMNs to BECs, whereas ET-1 and CGRP had the opposite effect. Anti-intercellular adhesion molecule-1 (ICAM-1) antibody could block the adhesion of PMNs to ozone-stressed BECs. Using immunocytochemistry and reverse transcription-polymerase chain reaction (RT-PCR), it was shown that VIP and EGF down-regulated the expression of ICAM-1 in BECs, while ET-1 and CGRP up-regulated ICAM-1 expression. NF-kappaB inhibitor MG132 blocked ICAM-1 expression induced by ET-1 and CGRP. Furthermore, in electric mobility shift assay (EMSA), VIP and EGF restrained the binding activity of NF-kappaB to the NF-kappaB binding site within the ICAM-1 promoter in ozone-stressed BECs, while CGRP and ET-1 promoted this binding activity. IkappaB degradation was consistent with NF-kappaB activation. These observations indicate that VIP and EGF inhibit inflammation, while ET-1 and CGRP enhance the inflammation reaction.

Topics: Animals; Base Sequence; Bronchi; Calcitonin Gene-Related Peptide; Cell Adhesion; Cells, Cultured; Endothelin-1; Epidermal Growth Factor; Epithelial Cells; I-kappa B Kinase; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1; Interleukin-8; Interleukins; Neutrophils; NF-kappa B; Peptides; Rabbits; Time Factors; Vasoactive Intestinal Peptide

Multiple sclerosis (MS) is a disabling inflammatory, autoimmune demyelinating disease of the central nervous system. Despite intensive investigation, the mechanisms of disease pathogenesis remain unclear, and curative therapies are unavailable for MS. The current study describes a possible new strategy for the treatment of MS, based on the administration of the vasoactive intestinal peptide (VIP), a well-known immunosuppressive neuropeptide. Treatment with VIP significantly reduced incidence and severity of experimental autoimmune encephalomyelitis (EAE), in a MS-related rodent model system. VIP suppressed EAE neuropathology by reducing central nervous system inflammation, including the regulation of a wide spectrum of inflammatory mediators, and by selectively blocking encephalitogenic T-cell reactivity. Importantly, VIP treatment was therapeutically effective in established EAE and prevented the recurrence of the disease. Consequently, VIP represents a novel multistep therapeutic approach for the future treatment of human MS.

Topics: Animals; Autoimmunity; Encephalomyelitis, Autoimmune, Experimental; Female; Inflammation; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Spinal Cord; Th1 Cells; Vasoactive Intestinal Peptide

Multiple sclerosis (MS) is a disabling inflammatory, autoimmune demyelinating disease of the central nervous system (CNS). Despite intensive investigation, the mechanisms of disease pathogenesis remain unclear, and curative therapies are unavailable for MS. The current study describes a new possible strategy for the treatment of MS, based on the administration of the vasoactive intestinal peptide (VIP). Treatment with VIP significantly reduced incidence and severity of experimental autoimmune encephalomyelitis (EAE), an MS-related rodent model. VIP suppressed EAE neuropathology by reducing CNS inflammation and by selective blocking encephalitogenic T-cell reactivity, emerging as an attractive candidate for the treatment of human MS.

Topics: Animals; Autoimmunity; Disease Models, Animal; Down-Regulation; Humans; Inflammation; Mice; Multiple Sclerosis; Vasoactive Intestinal Peptide

Neuropeptides released from the cutaneous sensory nerve endings have neurotransmitter and immunoregulatory roles; they exert mitogenic actions and can influence the functions of different cell types in the skin. The aims of this study were a systematic investigation of the effects of the neuropeptides substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) and galanin (GAL) on the inflammatory cytokine production (IL-1alpha, IL-8 and TNF-alpha) of the keratinocytes, and a study of their role in the production and secretion of nerve growth factor (NGF) and its precursor molecule (proNGF). Cultures of normal human keratinocytes were treated with 10(-8)M SP, CGRP, VIP or GAL for 30 min. After different time intervals, cells were harvested for total RNA isolation; in addition, cell lysates and supernatants were collected. The effects of the neuropeptides on the mRNA expressions of the different cytokines and NGF were investigated by Q-RT-PCR and the protein levels were studied by means of ELISA assays and Western blotting. Each of the four neuropeptides induced increases in the expressions of IL-1alpha, IL-8 and TNF-alpha mRNA. Increases appeared in the amount of the IL-1alpha protein in the supernatants of neuropeptide-treated cells, and the IL-8 secretion was mildly elevated, while secretion of TNF-alpha remained undetectable. The four neuropeptides increased the NGF mRNA expression to different extents. In the cell lysates of the keratinocytes, only proNGF could be detected, its concentration in the neuropeptide-treated cells being approximately twice that in the time-matched controls. Both control cultures and neuropeptide-treated cultures were found to secrete proNGF and mature NGF, but neuropeptide-treated cell cultures produced markedly higher (3-7-fold) amounts of NGF-like immunoreactive materials. The results demonstrated that neuropeptides released from cutaneous nerves after an injurious stimulus are able to induce an upregulation of IL-1alpha and IL-8 production; they are additionally able to influence the expressions of proNGF/NGF and their secretion from the keratinocytes. These findings may contribute toward an understanding of the neural influence on skin health and disease.

Topics: Calcitonin Gene-Related Peptide; Cells, Cultured; Cytokines; Female; Galanin; Humans; Inflammation; Keratinocytes; Nerve Growth Factor; Protein Precursors; RNA, Messenger; Substance P; Vasoactive Intestinal Peptide

Intestinal inflammation causes hyporesponsiveness of the inflamed tissue to secretagogues but little is known about the behaviour of the areas proximal to the site of inflammation. We studied the responses of the proximal segment of the colon to carbachol, histamine, isobutylmethylxanthine (IBMX) and vasoactive intestinal peptide (VIP) in rats with trinitrobenzenesulphonic acid (TNBS)-induced, chronic inflammation of the distal colon. Macroscopic and biochemical analysis ruled out the presence of inflammation in the proximal colon. When mounted in Ussing chambers under voltage-clamp conditions, basal transport and conductance were not affected. However, the maximum response in the concentration/response curves (short-circuit current) for carbachol and histamine was reduced in TNBS-treated rats, without changes in the EC(50). This effect corresponded to reduced chloride secretion, as demonstrated by ion substitution experiments. The responses to IBMX and VIP were virtually unaffected. The inhibitory effect was abolished by pretreatment with the neural blockers tetrodotoxin and lidocaine but not indomethacin, suggesting that the enteric nervous system is responsible for the inhibition. In conclusion, chronic distal inflammation of the distal colon results in inhibition of calcium-dependent secretion in the proximal colon via a reduction of the contribution of the enteric nervous system.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Carbachol; Cholinergic Agonists; Colon; Colonic Diseases; Female; Glutathione; Histamine; Inflammation; Patch-Clamp Techniques; Peroxidase; Phosphodiesterase Inhibitors; Rats; Rats, Wistar; Vasoactive Intestinal Peptide

Toll-like receptor 2 (TLR2) and -4 mediate signals from a great variety of bacterial gut products, giving the host a panel of microbe-recognizing receptors. Under homeostatic conditions, TLRs act as protective receptors of the intestinal epithelium. When homeostasis is disrupted in diseases such as inflammatory bowel disease, TLR2 and -4 are deregulated. Our study demonstrates, by using a trinitrobenzene sulfonic acid-induced colitis model of Crohn's disease, the constitutive expression and the up-regulation of TLR2 and -4 at messenger and protein levels in colon extracts, as well as in macrophages, dendritic cells, and lymphocytes from mesenteric lymphoid nodes. Vasoactive intestinal peptide (VIP) treatment induced a decrease of TLR2 and -4 expressions approaching ethanol control levels. Our results suggest that VIP modulation of TLR2 and -4 could be explained by two possible mechanisms. The first one would be the secondary reduction of TLR2 and -4 caused by the VIP-mediated decrease of inflammatory mediators such as interleukin-1beta and interferon-gamma, which synergize with bacterial products, contributing to the amplification of TLR presence in the intestine. The other possible mechanism would involve a VIP-mediated decrease of nuclear factor-kappaB, which would cause a direct down-regulation of TLR expression. In summary, the resultant physiological effect is the decrease of TLR2 and -4 expressions to homeostatic levels. Our study describes for the first time the role of a peptide present in the gut microenvironment as an effective modulator of the initial steps of acute inflammation, acting at local and systemic levels and leading to the restoration of the homeostasis lost after an established inflammatory/autoimmune disease.

Topics: Animals; Autoimmune Diseases; Gene Expression Regulation; Homeostasis; Inflammation; Inflammatory Bowel Diseases; Injections, Intraperitoneal; Interferon-gamma; Interleukin-1; Intestinal Mucosa; Intestines; Male; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Neuroprotective Agents; Receptors, Cell Surface; Recovery of Function; Toll-Like Receptor 2; Toll-Like Receptors; Trinitrobenzenesulfonic Acid; Vasoactive Intestinal Peptide

Crohn's disease (CD) is a chronic inflammatory pathology of the intestine, characterized by diarrhea and weight loss. A healing effect of vasoactive intestinal peptide (VIP) in the murine model of CD based on 2,4,6-trinitrobencene sulfonic acid (TNBS) administration has been previously shown. The aim of this work was to analyze the expression of several mediators related to the inflammatory cascade in colitic and VIP-treated animals. With this aim, mice received either only TNBS or TNBS and VIP treatment on alternate days. cDNA microarray analysis and real-time polymerase chain reaction were performed on total mRNA from colon to study the expression of a battery of proinflammatory molecules such as the enzyme COX-2, the chemokines CX3CL1, CXCL12, CXCL13, CXCL14, CCR5, and CXCR2, and the cytokines interleukin (IL)-1beta, IL-12, IL-18, IL-10, interferon-gamma, and IL-4. TNBS administration induced the expression of all the proinflammatory mediators studied, whereas VIP treatment reduced their levels, increasing the anti-inflammatory IL-10 and the TH2 cytokine IL-4, explaining its beneficial action through inhibition of the inflammatory/TH1 response. These data describe not only the relation of several proinflammatory mediators to the development of TNBS colitis, reporting their time-course, but also show the beneficial action of VIP in this model through complete blockage of the inflammatory cascade and recovery of the colon homeostasis, providing a potential new alternative for CD therapy.

Topics: Analysis of Variance; Animals; Chemokines; Crohn Disease; Cytokines; Gastrointestinal Agents; Humans; Inflammation; Inflammation Mediators; Male; Mice; Mice, Inbred BALB C; Oligonucleotide Array Sequence Analysis; Receptors, Immunologic; Trinitrobenzenesulfonic Acid; Vasoactive Intestinal Peptide

Bacillary dysentery arises when Shigella invades the colonic and rectal mucosae of the human gut and elicits a strong inflammatory response, which may lead to life-threatening complications. Hence, downregulation of the host inflammatory response is an appealing therapeutical alternative. The gastrointestinal tract is densely innervated, and nerve endings are often found in the vicinity of leukocytes. We have assessed the impact of experimental Shigella infection on levels of neuropeptides in the intestinal mucosa of rabbits. Ligated small intestinal loops were created in rabbits, and either live, pathogenic Shigella flexneri, a nonpathogenic mutant of Shigella, or NaCl was injected into the loops. Infection was allowed to proceed for 8 or 16 h, after which the rabbits were sacrificed and intestinal biopsies collected. Tissue destruction, fluid secretion and degree of bacterial invasion were monitored. Intestinal biopsies were homogenized, and levels of the neuropeptides calcitonin gene-related peptide, substance P, peptide YY (PYY), vasoactive intestinal peptide, somatostatin, galanin, motilin and neurotensin were measured by radioimmunoassay. Loops exposed to invasive Shigella had 5.7 times lower levels of PYY (P = 0.0095) than loops exposed to NaCl, after 16 h of infection. The levels of the other neuropeptides tested were unchanged. Inhibition of nicotinic cholinergic neurotransmission partly protected the intestinal mucosa from destruction elicited by invasive Shigella. These findings indicate that a tissue-invasive bacterium such as Shigella, which is strictly localized to the intestinal mucosa, activates intramural nerve reflexes that presumably involve a nicotinic synapse as well as the neuropeptide PYY.

Topics: Animals; Calcitonin Gene-Related Peptide; Dysentery, Bacillary; Galanin; Hexamethonium; Inflammation; Intestinal Mucosa; Intestine, Small; Motilin; Neuropeptides; Neurotensin; Nicotinic Antagonists; Peptide YY; Rabbits; Shigella flexneri; Somatostatin; Substance P; Vasoactive Intestinal Peptide

The general pattern of local inflammation in the rat is developed in the pad of the paw. In otorhinolaryngology a model of local inflammation can be reached in the rat ear by means of the production of an auricular chondritis. For that, we have protocolized the methodology. The induction of inflammation is carried out by the substance vegetable carrageenan. It has been verified by histological studies the inflammation generated, as well as studying the action of antiinflammatory, proinflammatory and inflammatory compounds. The inflammation has been measured by nonius and by determination of the activity of the myeloperoxidase enzyme. After these studies we can validate the auricular chondritis in rat as an experimental model of local inflammation in otorhinolaryngology.

Topics: Animals; Cartilage; Disease Models, Animal; Ear Diseases; Ear, External; Female; Inflammation; Rats; Rats, Wistar; Vasoactive Intestinal Peptide

Neuroimmunomodulation has experienced an explosive growth not only in basic research, but expanding to the point that prospective clinical research could be now a reality. A crucial factor for the functioning of this intimate bidirectional network was the demonstration that the immune and neuroendocrine systems speak a mutual biochemical language. This implies 1) production of neuroendocrine hormones and neuropeptides by immune cells and of cytokines by neuroendocrine cells; 2) evidence for shared receptors on cells of the immune and neuroendocrine systems; 3) effect of neuroendocrine mediators on immune functions; and 4) effect of cytokines on the neuroendocrine system. This reduces traditional differences between neurotransmitters, hormones, and immune mediators and raises the following question: what can we now regard as immune or neuroendocrine? Vasoactive intestinal peptide (VIP) is one example of this paradigm. VIP has traditionally been classified as a neuropeptide/neurotransmitter based in its capacity to mediate and regulate neuronal functions. Recent work has demonstrated that VIP is produced by T cells, especially Th2 cells, and that through specific receptors it exerts immunological functions typically ascribed to Th2 cytokines in nervous and immune systems. Here, we postulate that instead of a neuropeptide, VIP could be fully considered a type 2 cytokine with a key role in neuroimmunology.

Topics: Allergy and Immunology; Animals; Cytokines; Humans; Inflammation; Models, Biological; Neurology; Neuropeptides; Receptors, Vasoactive Intestinal Peptide; Th2 Cells; Vasoactive Intestinal Peptide

In many studies, it has been reported that vasoactive intestinal peptide (VIP) may play an important role in modulation of the immunological response. VIP can be produced by immunological cells, and also the receptors for this neuropeptide are present in many of these cells. The aim of our study was to estimate the effects of the administration of exogenous VIP on serum concentrations of proinflammatory cytokines [interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha] and an anti-inflammatory cytokine (IL-10) during lipopolysaccharide (LPS)-induced acute inflammation. We also estimated the influence of VIP on pituitary [FSH, LH, TSH and prolactin (PRL)], thyroid (T3 and T4), adrenal (corticosterone) and gonadal (testosterone) hormones in response to LPS-induced acute inflammation.. Male Wistar-Kyoto rats were divided into four groups, which received, respectively, placebo (0.9% NaCl), LPS, VIP and VIP with LPS. The TNF-alpha and IL-6 serum concentrations were measured after 2 h from the time of the administration of the agents, IL-10 was measured after 4 h, and the pituitary, thyroid, adrenal and gonadal hormone concentrations were measured after 2 and 4 h. Cytokine concentrations were estimated using ELISA tests, and hormone concentrations were measured using RIA tests.. In our experiments, LPS administration dramatically increased serum proinflammatory cytokine concentrations (TNF-alpha and IL-6) after 2 h and the anti-inflammatory cytokine (IL-10) after 4 h, as well as increasing the serum corticosterone concentration (after 2 and 4 h) and LH (after 2 h). LPS application decreased serum concentrations of T3 and TSH (both after 2 h), testosterone (after 2 and 4 h), FSH after 4 h and PRL after 4 h. VIP administration decreased the serum IL-10 concentration after 4 h and T3 concentration after 2 h and increased serum concentrations of FSH and corticosterone after 4 h. VIP administrated simultaneously with LPS decreased the LPS-induced increase in IL-6 and corticosterone concentrations (consecutively after 2 and 4 h). VIP also enhanced LPS-induced thyroid hormone (T3 and T4) suppression after 4 h and testosterone suppression after 4 h.. We conclude that VIP can modulate not only immune responses but also hormonal responses during acute inflammation.

Topics: Acute Disease; Animals; Cytokines; Disease Models, Animal; Down-Regulation; Endocrine System; Gonads; Hypothalamo-Hypophyseal System; Immune System; Immunologic Factors; Inflammation; Lipopolysaccharides; Male; Pituitary Hormones; Pituitary-Adrenal System; Rats; Rats, Inbred WKY; Steroids; Thyroid Gland; Up-Regulation; Vasoactive Intestinal Peptide

Although interleukin-8 (IL-8) is a chemokine that plays a beneficial and central role in the inflammatory response, hematopoiesis, and angiogenesis, excessive IL-8 production can be deleterious to the host, and its selective inhibition represents an important therapeutic goal. Vasoactive intestinal peptide (VIP) is a neuropeptide that acts as a potent anti-inflammatory agent inhibiting the function of activated macrophages/monocytes. The present study reports the effect of VIP on IL-8 production by stimulated human THP1 monocytes. VIP inhibits IL-8 production in a dose- and time-dependent manner at the mRNA level. VIP seems to act by inhibiting the NF-kappaB-dependent IL-8 gene activation. The specific VPAC1 receptor mediates the inhibitory effect of VIP. Two transduction pathways appear to be involved, a major cAMP-independent pathway that preferentially blocks nuclear translocation of NF-kappaB and its binding to the kappaB site of the IL-8 promoter, and a cAMP-dependent pathway that inhibits the activation and binding to the IL-8 promoter of both CREB-binding protein (CBP) and TATA box-binding protein (TBP), two transcriptional cofactors strictly required for the transactivating activity of NF-kappaB. These findings support the proposed role of VIP as a key endogenous anti-inflammatory agent and describe a novel mechanism, i.e., the inhibition of the production of monocyte-derived IL-8, and are of obvious physiological significance, because VIP, through the inhibition of IL-8 production, could reduce the monocyte-induced neutrophil chemotaxis/infiltration, an important event in the pathogenesis of several inflammatory and autoimmune disorders.

Topics: Down-Regulation; Humans; Inflammation; Interleukin-8; Monocytes; NF-kappa B; Transcription, Genetic; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Intercellular adhesion molecule-1 (ICAM-1) is an important adhesion molecule leading to adhesion between cells; NF-kappaB, being universally distributed in the organism, is an important nuclear transcription factor leading to a rapid response to the stimuli. Line of evidence have shown that ICAM-1 transcription and NF-kappaB activation is an important step of inflammatory reaction. To testify that intrapulmonary regulatory peptides modulate inflammatory lesion of bronchial epithelial cells (BECs) through their effect on ICAM-1 expression and nuclear factor kappaB (NF-kappaB) activation, we used immunocytochemistry, RT-PCR, and electrophoretic mobility-shift assay (EMSA) to determine the ICAM-1 expression and NF-kappaB activity in BECs. The effects of NF-kappaB inhibitor MG-132 on ICAM-1 expression were also observed. The results showed that vasoactive intestinal peptide (VIP) and epidermal growth factor (EGF) decreased ICAM-1 expression in O(3)-stressed BECs, while endothelin-1 (ET-1) and calcitonin gene-related peptides (CGRP) increased ICAM-1 expression in resting BECs. MG-132 blocked ICAM-1 expression induced by O(3), ET-1 and CGRP. The results obtained by using EMSA confirmed that VIP and EGF restrained the activation of NF-kappaB in O(3)-stressed BECs; CGRP and ET-1 promoted activation of NF-kappaB. These observations indicate that VIP and EGF abated the injury by means of down-regulatory effects on ICAM-1 transcription and NF-kappaB activation, while ET-1 and CGRP enhanced the inflammation reaction by an up-regulatory effect. It is suggested that a developing and intensive airway inflammation correlates closely with a persistent expression of ICAM-1 and repeated activation of NF-kappaB.

Topics: Animals; Bronchi; Cell Adhesion; Cells, Cultured; Endothelin-1; Epithelial Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; NF-kappa B; Peptides; Rabbits; Vasoactive Intestinal Peptide

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating peptide (PACAP) are induced strongly in neurons after several types of injury, and exhibit neuroprotective actions in vitro and in vivo. It is thought that changes in expression of neuropeptides and other molecules in injured neurons are mediated by new factors produced in Schwann and immune cells at the injury site, a loss of target-derived factors, or a combination of mediators. To begin to determine the role of the inflammatory mediators, we investigated axotomy-induced changes in VIP and PACAP gene expression in the facial motor nucleus in severe combined immunodeficient (SCID) mice, and in mice with targeted mutations in specific cytokine genes. In normal mice, VIP and PACAP mRNA was induced strongly in facial motor neurons 4 days after axotomy. The increase in PACAP mRNA was blocked selectively in SCID mice, indicating that mechanisms responsible for VIP and PACAP gene induction are not identical. The loss of PACAP gene expression in SCID mice after axotomy was fully reversed by an infusion of normal splenocytes, suggesting that PACAP mRNA induction requires inflammatory mediators. PACAP and VIP mRNA inductions, however, were maintained in mice lacking leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), and in mice lacking both receptors for tumor necrosis factor alpha (TNFalpha). The data suggest that an inflammatory response, most likely involving T lymphocytes, is necessary for the axotomy-induced increase in PACAP but not in VIP. LIF, IL-6, and TNFalpha, however, are not required for this response to injury.

Topics: Animals; Axotomy; Cytokines; Facial Nerve; Facial Nerve Injuries; Gene Expression Regulation; Inflammation; Male; Mice; Mice, Knockout; Mice, SCID; Motor Neurons; Mutation; Neuropeptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Rats, Wistar; Retrograde Degeneration; RNA, Messenger; T-Lymphocytes; Transcriptional Activation; Up-Regulation; Vasoactive Intestinal Peptide

Inhibition of neutrophil apoptosis has been identified as a prominent feature in chronic inflammation, parenchymal damage, and unresolved organ dysfunction. Lung injury animal models suggest that the neuropeptides vasoactive intestinal peptide and bombesin are protective. Therefore, in vitro effects of VIP and bombesin on apoptosis of normal human neutrophils were tested. For measuring effects on cell survival and apoptosis, trypan dye exclusion, colorimetric MTT assay to assess cell survival, and caspase-3 assay and annexin-V binding for analysing apoptosis rates were used. Foetal calf serum, Fas ligand, and tumour necrosis factor-alpha served as modulatory control agents; survival-promoting and apoptosis-inducing activities of the respective agents were confirmed. Vasoactive intestinal peptide and bombesin, however, failed to significantly affect cell death in neutrophils. Data suggest that direct regulation of neutrophil apoptosis is unlikely to be among the mechanisms of lung-protective actions of VIP and bombesin.

Topics: Apoptosis; Bombesin; Caspase 3; Caspases; Cell Membrane; Cell Survival; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Inflammation; Membrane Lipids; Neutrophils; Phosphatidylserines; Vasoactive Intestinal Peptide

The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), two immunomodulatory neuropeptides, act as anti-inflammatory factors for activated microglia, by inhibiting the production of pro-inflammatory factors, mainly mediated through the inhibition of NF-kappaB nuclear translocation and DNA binding. An additional regulatory element in the NF-kappaB transcriptional activity is the coactivator CBP, which links p65 with components of the basal transcriptional machinery. The present report demonstrates that VIP and PACAP inhibit the formation of p65/CBP complexes and that this event is directly related to the neuropeptide inhibition of NF-kappaB transcriptional activity. Since CBP is in limiting amounts in the nucleus and is capable of interacting with several transcriptional factors, competition for CBP provides another mechanism for transcriptional regulation. VIP and PACAP increase CBP-binding to CREB, replacing p65/CBP with CREB/CBP complexes in activated microglia. This is due to VIP/PACAP-induced increases in CREB phosphorylation/activation and is mediated through the specific VPAC1 receptor and the cAMP/PKA pathway. The VIP/PACAP interference with the p65/CBP interaction in activated microglia may represent a significant element in the regulation of the inflammatory response in the CNS by the endogenous neuropeptides.

Topics: Active Transport, Cell Nucleus; Animals; Blotting, Western; Cell Division; Cell Nucleus; Cells, Cultured; CREB-Binding Protein; Cyclic AMP; Inflammation; Mice; Microglia; Neuropeptides; NF-kappa B; Nuclear Proteins; Phosphorylation; Pituitary Adenylate Cyclase-Activating Polypeptide; Precipitin Tests; Protein Binding; Trans-Activators; Transcription Factor RelA; Transcription, Genetic; 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

The present study was aimed at disclosing axotomy- and inflammation-induced changes in the chemical coding of retrogradely labelled distal bowel-projecting neurons in the porcine IMG. Particular attention was paid to the changes in the expression pattern of vasoactive intestinal polypeptide and nitric oxide synthase (as a marker of nitric oxide) in affected cells, as these substances are thought to play a crucial role in the regeneration of injured sympathetic neurons. However, while both pathological processes failed to induce an increase in the number of sympathetic bowel-projecting neurons exhibiting vasoactive intestinal polypeptide or nitric oxide synthase, axotomy, but not target-tissue inflammation, led to the upregulation in the expression pattern of galanin, pituitary adenylate cyclase-activating peptide and/or Leu5-enkephalin in the affected perikarya. On the other hand, axotomy resulted in a diminished density of vasoactive intestinal polypeptide-immunoreactive intraganglionic nerve fibres, whilst target-tissue inflammation evoked a distinct increase in the number of visible vasoactive intestinal polypeptide-immunoreactive terminals, especially in those regions where bowel-projecting neurons were located. Thus, the data obtained in the present study run counter to the results of the injury-related responses observed in neurons of the sympathetic chain ganglia, suggesting the existence of either species- or target tissue-dependent differences in the injury-induced responses of the affected sympathetic neurons.

Topics: Animals; Axotomy; Enkephalin, Leucine; Female; Ganglia, Sympathetic; Immunohistochemistry; Inflammation; Interneurons; Intestinal Mucosa; Intestines; Kinetics; Neuropeptides; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Pituitary Adenylate Cyclase-Activating Polypeptide; Swine; Vasoactive Intestinal Peptide

Rheumatoid arthritis (RA) is a chronic and debilitating autoimmune disease of unknown etiology, characterized by chronic inflammation in the joints and subsequent destruction of the cartilage and bone. We describe here a new strategy for the treatment of arthritis: administration of the neuropeptide vasoactive intestinal peptide (VIP). Treatment with VIP significantly reduced incidence and severity of arthritis in an experimental model, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of VIP was associated with downregulation of both inflammatory and autoimmune components of the disease. Our data indicate VIP as a viable candidate for the development of treatments for RA.

Topics: Animals; Arthritis, Rheumatoid; Down-Regulation; Inflammation; Inflammation Mediators; Male; Matrix Metalloproteinase 2; Mice; Mice, Inbred DBA; Th1 Cells; Th2 Cells; Vasoactive Intestinal Peptide

Topics: Humans; Inflammation; Neuropeptides; Pain; Pituitary Adenylate Cyclase-Activating Polypeptide; Vasoactive Intestinal Peptide

Irradiation was administered to the upper abdomen of rats, whereupon the duodenum was examined. Numerous vasoactive intestinal peptide (VIP)- and substance P (SP)-like immunoreactive nerve fibers were seen in the damaged mucosa, often in close association to each other. The intensity of the SP- and VIP-like immunoreaction was increased in several of the tissue compartments and, as measured with radioimmunoassay, the contents of SP- and VIP-like materials were increased after 30 Gray. The results show that SP and VIP levels increase after irradiation and suggest that SP and VIP are involved in interactive reactions in the reorganization and inflammatory processes in the gut after abdominal irradiation.

Topics: Animals; Duodenum; Female; Fluorescent Antibody Technique; Histocytochemistry; Inflammation; Intestinal Mucosa; Muscle, Smooth, Vascular; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Substance P; 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

Topics: Animals; Cytokines; Endotoxemia; Gene Expression; Inflammation; Inflammation Mediators; Macrophage Activation; Macrophages, Peritoneal; Male; Mice; Mice, Inbred BALB C; Models, Biological; Neuropeptides; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Pituitary Adenylate Cyclase-Activating Polypeptide; RNA, Messenger; Vasoactive Intestinal Peptide

VIP and PACAP modulate the function of inflammatory cells through specific receptors. VIP/PACAP inhibit the production of TNF alpha, IL-6, IL-12, and nitric oxide (NO), and stimulate IL-10 in peritoneal macrophages and Raw 264.7 cells. Here we report on the specific VIP/PACAP receptors, transduction pathways, and transcriptional factors involved in the regulation of these macrophage factors by VIP and PACAP. Both neuropeptides inhibit IL-6 production mainly through PAC1 binding, PKC activation, and the subsequent shedding of the LPS receptor CD14 in macrophages. However, the effects on TNF alpha, IL-10, IL-12, and NO are mostly mediated through the constitutively expressed VPAC1 receptor, although the inducible expressed VPAC2 may also participate. VIP/PACAP binding to VPAC1 induces both a cAMP-dependent and a cAMP-independent pathways that regulate cytokine and NO production at the transcriptional level. VIP/PACAP inhibit TNF alpha through reduction in NFkB binding and changes in the composition of CRE-binding complexes; they inhibit IL-12 through reduction in NFkB binding and changes in the composition of the ets-2 complexes. VIP/PACAP inhibit iNOS expression through reduction in NFkB and IRF-1 binding, and augment IL-10 by increasing CREB-binding. Whereas the inhibition of IRF-1 and CRE-binding complexes seems to be mediated through the cAMP-dependent pathway, VIP/PACAP inhibition of NFkB nuclear translocation is mediated through a reduction in IkB alpha degradation mediated by the cAMP-independent pathway. This study provides new evidence for the understanding of the molecular mechanism by means of which VIP and PACAP attenuate the inflammatory response.

Topics: Animals; Cytokines; Gene Expression; Inflammation; Interleukin-10; Interleukin-12; Lipopolysaccharide Receptors; Macrophages; Mice; Models, Biological; Neuropeptides; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Receptors, Pituitary Hormone; Receptors, Vasoactive Intestinal Peptide; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; RNA, Messenger; Signal Transduction; Transcription Factors; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide

Topics: Animals; Dyspepsia; Gastrointestinal Motility; Helicobacter Infections; Helicobacter pylori; Humans; Inflammation; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is a neuropeptide synthesized by immune cells that can modulate several immune aspects, including the function of cells involved in the inflammatory response, such as macrophages and monocytes. The production and release of cytokines by activated phagocytes are important events in the pathogenesis of ischemia-reperfusion injury. There is abundant evidence that the proinflammatory cytokine TNF-alpha is an important mediator of shock and organ failure complicating Gram-negative sepsis. VIP has been shown to attenuate the deleterious consequences of this pathologic phenomenon. In this study we have investigated the effects of VIP and the structurally related neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP38) on the production of TNF-alpha by endotoxin-activated murine peritoneal macrophages. Both neuropeptides rapidly and specifically inhibit the LPS-stimulated production of TNF-alpha, exerting their action through the binding to VPAC1 receptor and the subsequent activation of the adenylate cyclase system. VIP and PACAP regulate the production of TNF-alpha at a transcriptional level. In vitro results were correlated with an inhibition of both TNF-alpha expression and release in endotoxemic mice in vivo. The immunomodulatory role of VIP in vivo is supported by the up-regulation of VIP release in serum and peritoneal fluid by LPS and proinflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6. These findings support the idea that under toxicity conditions associated with high LPS doses, VIP and PACAP could act as protective mediators that regulate the excessive release of TNF-alpha to reduce inflammation or shock.

Topics: Animals; Cells, Cultured; Cytokines; Female; Inflammation; Injections, Intraperitoneal; Intracellular Fluid; Lipopolysaccharides; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Neuropeptides; Pituitary Adenylate Cyclase-Activating Polypeptide; RNA, Messenger; Signal Transduction; Time Factors; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide

The effect of potential mediators of mucus secretion was investigated in the isolated vascularly perfused rat colon by using a sandwich enzyme-linked immunosorbent assay for rat colonic mucin and by histochemical analysis. Bethanechol (100-200 microM), bombesin (100 nM), and vasoactive intestinal peptide (VIP, 100 nM) provoked a dramatic mucin discharge (maximal response at 900, 900, and 600% of control loops, respectively). VIP-stimulated mucin secretion was abolished by tetrodotoxin, whereas atropine was without effect. In contrast, both tetrodotoxin and atropine significantly decreased mucin release induced by bombesin. Isoproterenol or calcitonin gene-related peptide was without effect. Serotonin (1-5 microM) and peptide YY (10 nM) evoked mucin discharge, whereas glucagon-like peptide-1 did not release mucin. Finally, bromolasalocid (20 microM), interleukin-1beta (0.25 nM), sodium nitroprusside (1 mM), and dimethyl-PGE2 (2.5 microM) induced mucus discharge. The results demonstrated a good correlation between the immunological method and histological analysis. In conclusion, these findings suggest a role for the enteric nervous system, the enteroendocrine cells, and resident immune cells in mediation of colonic mucus release.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Atropine; Bethanechol; Bombesin; Calcitonin Gene-Related Peptide; Colon; Enteric Nervous System; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Inflammation; Interleukin-1; Intestinal Mucosa; Isoproterenol; Lasalocid; Male; Mucus; Neurotransmitter Agents; Nitroprusside; Peptide Fragments; Peptide YY; Protein Precursors; Rats; Rats, Wistar; Serotonin; Tetrodotoxin; Vasoactive Intestinal Peptide

In 1993, a study was undertaken at the Hand Clinics of Loyola University Medical Center in Chicago to investigate the role of the neuropeptides in the pathogenesis of Reflex Sympathetic Dystrophy. All of the patients had recurrent or continuous pain, swelling, and stiffness of one or both extremities following either acute trauma or surgical intervention. All of the patients showed a markedly increased level of bradykinin as well as calcitonin gene-related peptide. The levels of bradykinin were four times as high as the controls. A few showed increased levels of the other neuropeptides. With these results, we agree with Veldman, Goris and others who consider Reflex Sympathetic Dystrophy to be an exaggerated regional inflammatory disorder.

Topics: Adult; Aged; Bradykinin; Calcitonin Gene-Related Peptide; Female; Humans; Inflammation; Male; Middle Aged; Neuropeptides; Reflex Sympathetic Dystrophy; Substance P; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) binding to resident and stimulated-rat peritoneal macrophages was studied. No specific VIP binding was obtained with resident rat peritoneal macrophages. In contrast, VIP bound specifically to casein-elicited macrophages. The Scatchard analysis of binding data was consistent with the presence of two classes of VIP binding sites, but may represent a receptor site and internalized VIP. Both specific VIP binding and number of specific high affinity binding sites for VIP augmented progressively after sodium caseinate injection, reaching maximum at days 4-5. Macrophages obtained 1 day after injection showed a minimal specific VIP binding (0.3 +/- 0.1% of total), but cells obtained 4 days after injection showed a maximal binding to the peptide (3.1+/-0.2% of total). The number of high affinity binding sites per cell raised also progressively after sodium caseinate injection: 2650+/-301 at day 2, 4939 +/-723 at day 3, 6684+/-903 at day 4 and 9636+/-1626 at day 5 (P = 0.0035). The number of low affinity binding sites per cell exhibited the same changes. In contrast, the Kd values of both high and low affinity VIP binding sites did not vary significantly (P>0.05). These results demonstrate that VIP binding sites are only displayed by stimulated macrophages, suggesting that VIP binding sites could be considered to be a pre-activation marker in macrophages and could be used to recognize inflammatory or stimulated macrophages.

Topics: Animals; Binding Sites; Female; Inflammation; Macrophages, Peritoneal; Rats; Rats, Wistar; Vasoactive Intestinal Peptide

Recent studies suggest that the intestinal polypeptides substance P (SP) and vasoactive intestinal polypeptide (VIP) play a role in the bowel inflammatory processes. The aim of this study was to evaluate the distribution of SP and VIP immunoreactivities in the ileal pouch of the patients with ulcerative colitis (UC). Thirty-six patients underwent clinical evaluation, endoscopy, and histological examinations. Samples were taken from normal ileum (N = 9), ileum of UC patients (N = 9), normal ileal pouch (N = 9) and pouchitis (N = 9). SP- and VIP-containing nerve fibers were visualized in sections processed for immunofluorescence microscopy. The number and intensity of SP and VIP immunoreactivities were subjected to quantitative scoring. On samples from all groups lamina propria contained fibers showing bright immunofluorescence for SP and VIP. The number and intensity of SP immunoreactive nerve fibers were markedly increased in pouchitis as compared to normal pouch (P < 0.005), to ileum of UC patients (P < 0.001), and to normal ileum (P < 0.05). The number and intensity of VIP-immunoreactive nerve fibers in the lamina propria were markedly increased in pouchitis patients and in those having a normal pouch as compared to pooled values of ileum of UC patients and normal ileum (P < 0.05). The results suggest that SP, which may play a role in mediating inflammatory processes, is increased in pouchitis and that VIP, which may contribute to the regulation of intestinal motility, is increased in the pouch.

Topics: Adult; Aged; Colitis, Ulcerative; Female; Humans; Ileum; Immunohistochemistry; Inflammation; Male; Middle Aged; Nerve Fibers; Postoperative Complications; Proctocolectomy, Restorative; Substance P; Vasoactive Intestinal Peptide

Recent studies suggest that substance P (SP), vasoactive intestinal polypeptide (VIP), and mast cells play a role in inflammatory processes of the bowel. The aim of this study was to evaluate the distribution of SP and VIP immunoreactivities and to count mast cells in the ileal pouch of patients, who had pouchitis after restorative proctocolectomy performed for treatment of ulcerative colitis (UC), and to compare the findings in the same patients after a follow-up period. Nine patients with pouchitis underwent clinical evaluation, endoscopy of the pouch, and histological examination, which were repeated after the follow-up period of 14 months on average. The number and intensity of SP- and VIP-immunoreactive nerve fibers were visualized by immunofluorescence microscopy and subjected to quantitative scoring, and the number of mast cells per unit area was counted. The results were compared to the histological findings and the clinical status. Lamina propria contained fibers showing bright immunofluorescence for SP and VIP. The mean fluorescence intensity score of SP-immunoreactive nerve fibers in the lamina propria remained similar after the follow-up period (2.99 +/- 0.79 and 2.06 +/- 0.82, NS). SP-immunoreactive innervation correlated with the grade of acute (R2 = 0.5396, P = 0.0242) and chronic inflammation (R2 = 0.4561, P = 0.0459), while SP and VIP immunoreactivity, mast cell count, and histological changes did not correlate with the clinical status. The present study demonstrates an increase in the density of SP-immunoreactive nerve fibers in inflamed ileal pouch mucosa of clinically asymptomatic pouchitis patients. These results raise the possibility of therapeutic interference of SP-related processes in treatment of pouchitis.

Topics: Adult; Biopsy; Cell Count; Colitis, Ulcerative; Endoscopy, Gastrointestinal; Female; Follow-Up Studies; Humans; Ileum; Immunohistochemistry; Inflammation; Male; Mast Cells; Middle Aged; Nerve Fibers; Postoperative Complications; Proctocolectomy, Restorative; Substance P; Vasoactive Intestinal Peptide

Ionized calcium (Ca2+) and bicarbonate (HCO(3)-) are important ions for gallstone formation. In the present study the effect of indomethacin and vasoactive intestinal peptide-antiserum (VIP-antiserum) on the Ca2+, HCO(3)- and fluid secretion in the inflamed gallbladder were tested in a validated experimental model in cats. The animals were studied in acute experiments 6 weeks after cystic duct ligation and gallstone implantation. During basal conditions there was a continuous secretion of Ca2+, HCO(3)- and fluid into the lumen of the inflamed gallbladder. Indomethacin and VIP-antiserum inhibited the Ca2+, HCO(3)- and fluid secretion across the inflamed gallbladder mucosa. Intraluminal amiloride inhibited the absorption of Ca2+, HCO(3)- and fluid after indomethacin infusion. An impaired absorption of Ca2+, HCO(3)- and fluid in the inflamed gallbladder is probably important for the solubility of calcium salts in the early stages of inflammation in the gallbladder mucosa.

Topics: Animals; Bicarbonates; Biological Transport; Calcium; Cats; Female; Gallbladder; Immune Sera; Indomethacin; Inflammation; Male; Vasoactive Intestinal Peptide

Our aim was to characterize and quantitate changes in two key neuropeptides, substance P (SP) and vasoactive intestinal peptide (VIP), that are involved in governing neurally-mediated gastrointestinal (GI) reflex activity during enteric inflammation in the ferret. Neuropeptide content was determined by radioimmunoassay of extracts of jejunal, ileal and colonic muscularis externa from uninfected ferrets and ferrets infected with enteric stages of the parasitic nematode, Trichinella spiralis. Increased myeloperoxidase activity (MPO), an enzymatic marker of inflammation, occurred in all three gut regions. Histopathological changes were present only in the small intestine. Significant reductions were detected in both SP (72% decrease) and VIP (62% decrease) in the inflamed jejunum. Ileal concentrations of both SP (77% decrease) and VIP (46% decrease) were also decreased during T. spiralis infection compared to uninfected ferrets. Only SP (58% decrease) concentration showed a significant change in colonic tissues from infected ferrets; colonic VIP was unaltered. Parasite-induced inflammation caused significant changes in peptide-containing enteric neural pathways and might contribute to functional GI motor disturbances that occur during nematode infections in mammalian hosts.

Topics: Animals; Colon; Ferrets; Ileum; Inflammation; Intestinal Mucosa; Jejunum; Male; Peroxidase; Radioimmunoassay; Substance P; Trichinella spiralis; Trichinellosis; Vasoactive Intestinal Peptide

Neuropeptides (NP) are protein compounds contained both in the central and peripheral nervous system. They can be antidromically released from sensory nerves and are implicated in the so-called neurogenic inflammation. They also exert a number of functions within the immune system and are thought to act as trophic as well as mitogenic substances. Several NP have been detected in human skin by immunohistochemical and radioimmunological techniques, and recent reports have demonstrated that NP could be involved in the mechanisms of certain dermatoses. The involvement of NP in either physiological or pathophysiological skin conditions is discussed. Moreover, a few questions, which still need to be addressed, are raised, and future directions this field of research should take are outlined.

Topics: Calcitonin Gene-Related Peptide; Dermatitis; Humans; Inflammation; Neuropeptides; Skin; Skin Physiological Phenomena; Somatostatin; Stress, Psychological; Substance P; Vasoactive Intestinal Peptide

Effects of vasoactive intestinal peptide (VIP) on superoxide anion (O2-) formation by N-formyl-methionyl-leucyl-phenylalanine (fMLP)-activated inflammatory cells from healthy volunteers were investigated using 2-methyl-6-[p-methoxyphenyl]-3,7-dihydroimidazo [1,2-a]pyrazin-3-one (MCLA) as a chemiluminescence probe. VIP inhibited the maximal light intensity of MCLA-dependent luminescence in a dose-dependent manner by the activated peripheral blood neutrophils, mononuclear cells and also by the human monoblast cell line U937, the capacity of which for O2- formation was induced by pretreatment with interferon-gamma. 3 x 10(-6) M VIP also inhibited O2- formation by the activated peripheral blood eosinophils and alveolar macrophages obtained by bronchoalveolar lavage.

Topics: Eosinophils; Humans; Inflammation; Luminescent Measurements; Macrophages, Alveolar; Monocytes; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Superoxides; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

The present in vitro study was conducted to investigate possible alterations in the control of colonic electrolyte transport in an experimental model of colitis. Intrarectal administration of trinitrobenzenesulfonic acid induced a colitis-like inflammation in the rabbit distal colon. Responses to amiloride and residual short-circuit current after this treatment were unchanged, suggesting that the absorptive and secretory mechanisms remained intact. Electrical field stimulation and vasoactive intestinal polypeptide, a candidate secretomotor neurotransmitter, both elicited similar responses in control and colitic tissue. This suggests that communication at the neuroepithelial junction was unimpaired. In untreated tissue, the effects of prostaglandin E2 (PGE2) and of acetylcholine were attenuated by tetrodotoxin, suggesting, therefore, that both play a role in the modulation of secretomotor neurons. In addition, PGE2 had an appreciable direct epithelial effect. Responses to both of these agonists were absent in colitis. The effects of N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate were unchanged in colitis, suggesting that altered PGE2 responsiveness may involve changes in epithelial receptor number, affinity, or in their ability to mediate an increase in adenosine 3',5'-cyclic monophosphate levels. It is concluded that this rabbit model of colitis exhibits 1) defects in the modulation of secretomotor neurons by acetylcholine and PGE2 and 2) an attenuated epithelial response to PGE2.

Topics: Acetylcholine; Amiloride; Animals; Bucladesine; Colitis; Colon; Dinoprostone; Disease Models, Animal; Epithelium; Inflammation; Male; Membrane Potentials; Motor Neurons; Muscle, Smooth; Rabbits; Tetrodotoxin; Trinitrobenzenesulfonic Acid; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is suspected to be a neurotransmitter of nonadrenergic and noncholinergic inhibitory nerves in human respiratory tracts. Although VIP affects T lymphocytes through its specific receptor, the effects of VIP on inflammatory cells except T lymphocytes are obscure. We investigated the effects of VIP on superoxide anion (O2-) generation from five kinds of human cells; neutrophils, eosinophils and mononuclear cells isolated from peripheral blood, alveolar macrophages obtained from the bronchoalveolar lavage, and human monocyte cell line, U937, the capacity of which for O2- generation was induced by interferon-gamma. O2- generation from human cells stimulated by 10(-5) M fMLP was measured by the cypridina luciferin analog, MCLA, -dependent chemiluminescence method. VIP inhibited O2- generation from fMLP-stimulated neutrophils, mononuclear cells and U937 in a dose-dependent manner. 3 x 10(-6) M VIP inhibited O2- generation from fMLP-stimulated eosinophils and alveolar macrophages significantly. These results indicate that VIP might inhibit the activation of inflammatory cells and act as an antiinflammatory agent.

Topics: Cells, Cultured; Depression, Chemical; Dose-Response Relationship, Drug; Humans; Inflammation; Macrophages, Alveolar; Monocytes; Neutrophils; Superoxides; Vasoactive Intestinal Peptide

1. Release of the tachykinin, substance P, from the peripheral terminals of polymodal afferent C-fibres is thought to be largely responsible for the vasodilatation and plasma protein extravasation described as neurogenic inflammation. The effects of CP-96,345, a non-peptide antagonist at the substance P (NK1) receptor, on these vascular reactions were investigated in the rat. 2. Intravenously (i.v.) injected CP-96,345 (0.4-3.0 mumol kg-1) prevented the drop in blood pressure, a measure of the peripheral vasodilatation, evoked by substance P and neurokinin A in a dose- and time-dependent manner, but did not affect that elicited by the non-tachykinin peptides calcitonin gene-related peptide and vasoactive intestinal polypeptide. 3. Plasma protein extravasation evoked by i.a. infusion of substance P, antidromic stimulation of the saphenous or the vagus nerve, and stimulation of cutaneous afferent nerves with mustard oil, were each significantly inhibited by CP-96,345 (3.0-9.0 mumol kg-1, i.v.). Furthermore, CP-96,345 was orally active in blocking mustard oil-induced plasma extravasation with an ED50 of 10 mumol kg-1. 4. The inhibition of substance P-induced vasodilatation and of neurogenic plasma extravasation by CP-96,345 was stereospecific as the inactive isomer CP-96,344 (2R, 3R enantiomer of CP-96,345) had no effect. 5. Thus CP-96,345 is a specific, highly potent, long-acting and orally active inhibitor of tachykinin-mediated neurogenic inflammation.

Topics: Animals; Biphenyl Compounds; Blood Pressure; Blood Proteins; Evans Blue; Female; Inflammation; Mustard Plant; Plant Extracts; Plant Oils; Pregnancy; Rats; Rats, Inbred Strains; Receptors, Neurokinin-1; Receptors, Neurotransmitter; Substance P; Vasoactive Intestinal Peptide

Topics: Animals; Digestive System; Electrolytes; Humans; Immunity; Inflammation; Lymphocytes; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide

Topics: Animals; Antibody Formation; Humans; Inflammation; Intestinal Mucosa; Lymphocyte Activation; Lymphocytes; Mast Cells; Neuropeptides; Receptors, Cell Surface; Somatostatin; Substance P; Vasoactive Intestinal Peptide

Substance P (SP), a putative mediator of neurogenic inflammation, has previously been shown to induce plasma extravasation when exogenously perfused over a blister base induced on the rat hind foot pad. Using the same animal model, we have studied the role of vasoactive intestinal polypeptide (VIP), one of the neuromodulators in primary afferent neurons, on SP-induced plasma extravasation. At all concentrations tested (2.5, 5 and 10 microM), VIP did not cause plasma extravasation by itself, however, it increased that due to 1 microM SP, in a dose-related manner. We have also studied the effect of VIP on the local blood flow in the blister base using a laser doppler-flowmeter. VIP was also found to increase the local blood flow in a dose-dependent manner. The present results provide evidence for the first time in vivo of a role for VIP in modulating a neurogenic inflammatory response induced by SP. The mechanism underlying this action is probably related to the vasodilator activity of VIP.

Topics: Animals; Drug Synergism; Female; Inflammation; Male; Rats; Rats, Inbred Strains; Regional Blood Flow; Skin; Substance P; Vasoactive Intestinal Peptide; Vasodilation

Topics: Animals; Basophils; Humans; Inflammation; Lung; Mast Cells; Neuropeptides; Pneumonia; Respiratory Tract Diseases; Vasoactive Intestinal Peptide

Evidence is rapidly accumulating to support the existence of a neuroimmune axis. However, the precise role of individual neurotransmitters in regulating immune function remains to be elucidated. In this review we focus on the role of vasoactive intestinal peptide (VIP) in modulation of lymphocyte function. We examine its status as a neurotransmitter, including evidence for neuronal and possible extraneuronal sites of synthesis. Further, we present data to demonstrate the presence of VIP receptors in human lymphocytes and, using the Molt 4b lymphoblastic cell line as a model, show VIP-mediated activation of adenylate cyclase leading to cAMP-dependent protein kinase-mediated phosphorylation of a specific Molt protein. Finally, we discuss the functional significance of VIP receptors on lymphocytes and present a model of neuropeptide-induced inflammation with possible therapeutic applications of this exciting new field of neuroimmunology.

Topics: Adenylyl Cyclases; Animals; Cell Line; Humans; Immunity; Inflammation; Lymphocytes; Molecular Weight; Neurotransmitter Agents; Phosphoproteins; Protein Kinases; Receptors, Cell Surface; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide

Topics: Animals; Bradykinin; Eledoisin; Eye; Inflammation; Intraocular Pressure; Miotics; Peptide Fragments; Peptides; Pituitary Hormones, Posterior; Prostaglandins E; Rabbits; Somatostatin; Substance P; Vasoactive Intestinal Peptide