vasoactive-intestinal-peptide and Fibrosis

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

Dialysis requiring renal failure is a silent epidemic. Despite an annual mortality of 24% the dialysis population has increased by 1-4% per annum. Regardless of the initial injury, tubulointerstitial fibrosis is a feature of the renal pathology and it inversely correlates with declining renal function. Current agents display little efficacy against tubulointerstitial fibrosis. Clearly, therapies effective against tubulointerstitial fibrosis and able to preserve kidney function are needed. Vasoactive intestinal peptide (VIP) has been shown to reverse pre-existing cardiac fibrosis. We sought to determine whether VIP is effective in tubulointerstitial fibrosis. Spontaneous hypertensive rats (SHR) on a 2.2% salt diet were randomised to zero time control, 4 week infusion of VIP (5 pmol/kg/min) or vehicle control infusion. A fourth group, to match the blood pressure reduction achieved in the VIP infused group was included. Fibrosis was quantitated by computerised histomorphometry, changes in pro-fibrotic mediators were measured by quantitative rt-PCR and macrophage activation assessed by cyclic adenosine monophosphate (c-AMP) response to incubation with VIP. Tubulointerstitial fibrosis in the VIP treated rats was significantly lower than the zero time control (P < 0.0005), the vehicle infused control (P < 0.0005) and the blood pressure matched group (P < 0.01). Although all six profibrotic mediators increased over the 4 week experimental period VIP infusion only decreased tumour necrosis alpha (TNFα) expression significantly (P < 0.001). Incubation of RAW264 macrophages with VIP significantly increased c-AMP (P < 0.01). We conclude that VIP infusion reversed existing tubulointerstitial fibrosis suggesting a possible therapeutic role for a VIP based therapy in chronic kidney disease.

Topics: Animals; Blood Pressure; Cyclic AMP; Fibrosis; Gene Expression; Infusions, Intravenous; Kidney; Macrophage Activation; Macrophages; Mice; Nephritis, Interstitial; Rats; Rats, Inbred SHR; RAW 264.7 Cells; Sodium, Dietary; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide

Congestive cardiac failure has become one of the major health challenges of the 21st century and new therapies are needed to address this problem. The concentration of vasoactive intestinal peptide (VIP) in the heart has been shown to decrease as fibrosis (the pathology leading to heart failure) increases and to become undetectable in end stage cardiomyopathy. We sought to determine whether replenishment of myocardial VIP might treat myocardial fibrosis and therefore represent a new therapeutic target. Wistar Kyoto rats on a high (4.4%) salt diet were randomised to zero time control, 4 week infusion of VIP (5 pmol/kg/min) or vehicle control infusion. Myocardial VIP concentration was measured by radioimmunoassay, fibrosis was quantitated by computerised histomorphometry and changes in pro-fibrotic mediators were measured by quantitative rt-PCR. Myocardial VIP increased significantly in VIP treated rats compared with vehicle treated controls (P < 0.01) while fibrosis in the VIP treated rats was significantly lower than in both the zero time control (P < 0.05) and the vehicle infused control (P < 0.0005). Although all six profibrotic mediators which were measured increased over the 4 week experimental period VIP infusion only affected angiotensinogen (Agt) and angiotensin receptor type 1a (AT

Topics: Angiotensinogen; Animals; Biomarkers; Cardiomyopathies; Disease Models, Animal; Fibrosis; Humans; Infusions, Intravenous; Male; Myocardium; Rats; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Sodium, Dietary; Vasoactive Intestinal Peptide

We have shown previously that the concentration of Vasoactive Intestinal Peptide (VIP) in the heart is inversely correlated with the degree of fibrosis in a number of experimental models of early myocardial fibrosis. Vasopeptidase inhibition and angiotensin converting enzyme inhibition both decrease myocardial fibrosis. In this study, we sought to determine whether this myocardial protective effect might reflect increased VIP concentrations in the heart. We compared the effects of 4 weeks treatment of the vasopeptidase inhibitor omapatrilat and the angiotensin converting enzyme inhibitor enalapril on the degree of fibrosis and the concentration of VIP in the heart in salt sensitive hypertension induced by treatment with L-nitro-omega-methylarginine (L-NAME). Systolic blood pressure decreased in both treatment groups compared with control (omapatrilat P<0.005; enalapril P<0.001). Myocardial fibrosis was less for omapatrilat than control (P<0.0005) and enalapril (P<0.0005) groups. Myocardial VIP was greater in omapatrilat than in controls (P<0.005) and enalapril-treated rats (P<0.05). We conclude that vasopeptidase inhibition exerts a greater myocardial protective effect than angiotensin converting enzyme inhibition. Further, this myocardial protective effect is associated with increased VIP in the heart suggesting a pathogenetic role for VIP depletion in the development of fibrosis in the heart.

Topics: Animals; Enalapril; Fibrosis; Hypertension; Male; Myocardium; Peptide Hydrolases; Protease Inhibitors; Pyridines; Rats; Rats, Inbred WKY; Thiazepines; Vasoactive Intestinal Peptide

In both normotensive and hypertensive rats, the degree of myocardial fibrosis is inversely correlated with the concentration of vasoactive intestinal peptide (VIP) in the myocardium. Treatment with nitric oxide (NO) synthase inhibitors also causes myocardial fibrosis. In this study, we sought to determine whether the myocardial fibrosis induced by treatment with the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) was also associated with depletion of VIP in the myocardium.. Male Wistar Kyoto (WKY) and spontaneous hypertensive rats (SHR) rats treated with l-NAME were randomized to low, intermediate or high salt content diets. After 4 weeks, the hearts were harvested, the degree of fibrosis quantified and VIP concentration measured.. In WKY, systolic blood pressure increased with increasing dietary sodium (P < 0.05). Myocardial fibrosis also increased with increasing dietary sodium (P < 0.005). Myocardial VIP concentration decreased with increasing dietary sodium (P < 0.025). In contrast, in the SHR treated with l-NAME, systolic blood pressure increased but the increase was not affected by sodium intake. Further, myocardial fibrosis and myocardial VIP were unchanged by increased dietary sodium. Higher doses of l-NAME in the SHR did not increase the systolic blood pressure, increase the degree of myocardial fibrosis or decrease the myocardial concentration of VIP. These differences in myocardial VIP concentration may reflect differing effects of l-NAME on VIP metabolism, as l-NAME increased VIP metabolism in the WKY (P < 0.05) but did not change VIP metabolism in the SHR.. We conclude that depletion of VIP in the myocardium is associated with increasing myocardial fibrosis in l-NAME treated WKY. As VIP depletion occurs in other models of myocardial fibrosis, it appears to be a common mechanism. Myocardial VIP depletion may therefore be a new and important factor in the pathogenesis of cardiac fibrosis.

Topics: Animals; Blood Pressure; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fibrosis; Heart; Male; Metabolic Clearance Rate; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Organ Size; Random Allocation; Rats; Rats, Inbred SHR; Rats, Wistar; Sodium, Dietary; Vasoactive Intestinal Peptide

In this study we sought to determine whether early myocardial fibrosis is associated with depletion of vasoactive intestinal peptide (VIP) in the heart, thereby suggesting a possible pathogenetic role for depletion of myocardial VIP levels in the development of fibrosis in the heart. Spontaneously hypertensive rats (SHRs) and normotensive control Wistar-Kyoto rats (WKYs) were assigned randomly to low, intermediate or high sodium diets and their blood pressure was recorded twice weekly for 4 weeks. At the end of this period the rats were anaesthetised, blood was sampled for plasma VIP concentration and the hearts were harvested for histology and determination of the concentration of VIP in the heart. The degree of myocardial fibrosis increased with increasing dietary sodium intake in both the WKYs (P < 0.001) and the SHRs (P < 0.01). Myocardial VIP concentration decreased with increasing dietary sodium intake in the WKYs (P < 0.01) and in the SHRs (P < 0.01). There was a negative correlation between myocardial VIP concentration and the degree of myocardial fibrosis in both the WKYs (P < 0.0005) and the SHRs (P < 0.005). Dietary sodium intake induces myocardial fibrosis in a dose-dependent manner. Further, in early myocardial fibrosis resulting from increasing dietary sodium intake in both normotensive and hypertensive rats the concentration of VIP in the heart was negatively correlated with the degree of fibrosis. This suggests a possible role for depletion of VIP in the myocardium in the pathogenesis of myocardial fibrosis.

Topics: Animals; Blood Pressure; Fibrosis; Heart Diseases; Male; Myocardium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium, Dietary; Vasoactive Intestinal Peptide

To study the effect of experimentally induced osteoarthrosis, or non-inflammatory degenerative changes, on the innervation of the sheep temporomandibular joint (TMJ) through the use of indirect immunohistochemistry and image analysis quantification.. Bilateral condylar scarification was performed in 8 sheep, which were killed at 16 weeks post-operation; 3 unoperated sheep served as controls. Tissues from 8 osteoarthrotic joints and 4 control joints were processed for the immunostaining with antisera for protein gene product 9.5 (PGP 9.5), substance P (SP), calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), and tyrosine hydroxylase (TH). An additional 10 joints were decalcified to study the morphologic changes induced by the condylar abrasion.. Osteoarthrotic changes were commonly seen in the anterior and lateral regions of the joint and included fibrosis, peripheral osteophyte formation, cysts, and erosion of articular surfaces. In the osteoarthrotic joints, the distribution of PGP 9.5-, CGRP-, and SP-immunoreactive (IR) nerve fibers was similar to that observed for control joints in the capsule, synovium, and capsule/disc junction. There were statistically detectable decreases in the percent surface area of IR nerve fibers in the capsule for both PGP 9.5 and CGRP in arthrotic joints compared with control joints. The lateral and anterior regions of the capsule had greater density of PGP 9.5- and CGRP-IR nerve fibers than other parts of the capsule in both control and arthrotic joints, and the medial capsule was poorly innervated in all joints. Immunostaining for substance P was always weaker.. This study suggests that while inflammatory arthritis has a marked influence on the density of sensory and autonomic nerve fibers in synovium in a variety of joints in different species, experimentally induced non-inflammatory osteoarthrosis in the sheep TMJ also leads to a depletion of the density of nerve fibers in the capsule, especially in the lateral part of the joint. Further work is required to determine whether other parts of the joint, such as synovium and marrow, respond differently to experimentally induced osteoarthrosis.

Topics: Analysis of Variance; Animals; Autonomic Nervous System; Calcitonin Gene-Related Peptide; Cicatrix; Cysts; Disease Models, Animal; Fibrosis; Image Processing, Computer-Assisted; Immunohistochemistry; Joint Capsule; Male; Mandibular Condyle; Nerve Fibers; Nerve Tissue Proteins; Neurons, Afferent; Neuropeptide Y; Osteoarthritis; Sheep; Statistics, Nonparametric; Substance P; Synovial Membrane; Temporomandibular Joint; Temporomandibular Joint Disc; Temporomandibular Joint Disorders; Thiolester Hydrolases; Tyrosine 3-Monooxygenase; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide

Oncostatin M (OM), a member of the IL-6 gene family, stimulates a variety of functions implicated in wound repair. Transgenic mice that express this cytokine in islet beta-cells develop a connective tissue disorder that typifies excessive healing with severe fibrosis and lymphocytic infiltration. To compare this phenotype with the normal progression of connective tissue disease, we measured the expression patterns of genes encoding proinflammatory cytokines, fibrogenic cytokines, and ECM components by in situ hybridization. To test whether the OM effect was caused by its ability to regulate IL-6, we crossed the OM transgene into IL-6-deficient mice. Our data suggest that the fibrosis in these animals is not a secondary consequence of inflammation, or IL-6 expression, but is a direct effect by OM on extracellular matrix production. In a separate experiment, we observed that OM could regulate vasoactive intestinal peptide gene expression in the neurons that innervate the transgenic pancreas. This nerve healing response, in combination with its fibrogenic activity, suggests that OM functions downstream of inflammation in the wound repair cascade. These transgenic mice represent a useful model in which the fibroproliferative phase of connective tissue disease is uncoupled from inflammation.

Topics: Animals; Animals, Newborn; Cattle; Connective Tissue Diseases; Crosses, Genetic; Cytokines; Disease Models, Animal; Extracellular Matrix Proteins; Fibrosis; Gene Expression Regulation; Growth Substances; Interleukin-6; Islets of Langerhans; Leukocytes, Mononuclear; Mice; Mice, Transgenic; Oncostatin M; Pancreas; Peptides; RNA, Messenger; Sympathetic Nervous System; Transgenes; Vasoactive Intestinal Peptide; Wound Healing

A case of duodenal somatostatinoma is described in a patient with Von Recklinghausen neurofibromatosis. The patient presented with exocrine pancreatic insufficiency, probably due to distal obstruction of the pancreatic duct by the tumor. Preoperative evaluation with calcium-pentagastrin and tolbutamide stimulation tests were nondiagnostic. At laparotomy, local excision of the tumor was performed. Pathological findings were compatible with duodenal somatostatinoma, causing pancreatic fibrosis. Somatostatin extracted from the tumor coeluted with the somatostatin-14 standard on high performance liquid chromatography (HPLC).

Topics: Adult; Biopsy; Chromatography, High Pressure Liquid; Duodenal Neoplasms; Exocrine Pancreatic Insufficiency; Female; Fibrosis; Gastrins; Glucagon; Humans; Microscopy, Electron; Neurofibromatosis 1; Pancreas; Pancreatic Polypeptide; Radioimmunoassay; Somatostatin; Somatostatinoma; Vasoactive Intestinal Peptide