transforming-growth-factor-beta and Edema

Topics: Animals; Atrophy; Bone Marrow Transplantation; Disease Models, Animal; Edema; Graft vs Host Disease; Interleukin-2; Lymphocyte Activation; Mice; Mice, Inbred Strains; Radiation Chimera; Scleroderma, Systemic; Sclerosis; Spleen; T-Lymphocytes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Breast cancer-related lymphedema (BCRL) is a treatment-related inflammatory complication in breast cancer survivors (BCSs). This study was aimed to evaluate the effect of synbiotic supplementation on serum concentrations of IL-10, TGF-β, VEGF, adiponectin, and edema volume among overweight or obese BCSs with lymphedema following a low-calorie diet (LCD).. In a randomized double-blind, controlled clinical trial, 88 obese and overweight BCSs women were randomized to synbiotic supplement (. There were no significant differences among participants in the baseline, except for IL-10 and adiponectin. Post-intervention, no significant differences were observed regarding the anti-inflammatory markers, including IL-10, VEGF, adiponectin, and TGF-β between the groups. After 10 weeks of intervention edema volume significantly decreased in the synbiotic group; additionally, anthropometric measurements (body weight, BMI, body fat percent, and WC) decreased in both groups significantly (. Synbiotic supplementation coupled with an LCD in a 10-week intervention had beneficial effects on increasing the serum TGF-β, IL-10, and adiponectin levels in women with BCRL. It also reduced arm lymphedema volume. Therefore, synbiotic supplementation can be effective in improving health status in BCRL patients.

Topics: Adiponectin; Anti-Inflammatory Agents; Biomarkers; Breast Neoplasms; Caloric Restriction; Cancer Survivors; Double-Blind Method; Edema; Female; Humans; Interleukin-10; Lymphedema; Obesity; Overweight; Synbiotics; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Independent, retrospective clinical record review with a concurrent control.. To identify whether rhBMP-2 is associated with an increased incidence of clinically relevant postoperative prevertebral swelling problems in patients undergoing anterior cervical fusions.. Bone Morphogenetic Protein-2 (rhBMP-2) is FDA approved as a bone graft substitute in anterior lumbar interbody fusions. rhBMP-2 has also been used "off-label" in anterior cervical fusions. We suspected that rhBMP-2 might increase the incidence of adverse swelling events.. A total of 234 consecutive patients (ages 12-82 years) undergoing anterior cervical fusion with and without rhBMP-2 over a 2-year period at one institution comprised the study population. The incidence of clinically relevant prevertebral swelling was calculated. The populations were compared and statistical significance was determined.. A total of 234 patients met the study criteria, 69 of whom underwent anterior cervical spine fusions using rhBMP-2; 27.5% of those patients in the rhBMP-2 group had a clinically significant swelling event versus only 3.6% of patients in the non-rhBMP-2 group. This difference was statistically significant (P < 0.0001) and remained so after controlling for other significant predictors of swelling.. Off-label use of rhBMP-2 in the anterior cervical spine is associated with an increased rate of clinically relevant swelling events.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Cervical Vertebrae; Child; Deglutition Disorders; Edema; Female; Humans; Incidence; Male; Middle Aged; Neck; Postoperative Complications; Recombinant Proteins; Spinal Fusion; Transforming Growth Factor beta

TGF-β is known as an important stress factor of podocytes in glomerular diseases. Apart from activation of direct pro-apoptotic pathways we wanted to analyze micro-RNA (miRs) driven regulation of components involved in the integrity of the glomerular filtration barrier induced by TGF-β. Since miR-143-3p (miR-143) is described as a TGF-β inducible miR in other cell types, we examined this specific miR and its ability to induce glomerular pathology.. We analyzed miR-143 expression in cultured human podocytes after stimulation with TGF-β. We also microinjected zebrafish eggs with a miR-143 mimic or with morpholinos specific for its targets syndecan and versican and compared phenotype and proteinuria development.. We detected a time dependent, TGF-β inducible expression of miR-143 in human podocytes. Targets of miR-143 relevant in glomerular biology are syndecans and versican, which are known components of the glycocalyx. We found that syndecan 1 and 4 were predominantly expressed in podocytes while syndecan 3 was largely expressed in glomerular endothelial cells. Versican could be detected in both cell types. After injection of a miR-143 mimic in zebrafish larvae, syndecan 3, 4 and versican were significantly downregulated. Moreover, miR-143 overexpression or versican knockdown by morpholino caused loss of plasma proteins, edema, podocyte effacement and endothelial damage. In contrast, knockdown of syndecan 3 and syndecan 4 had no effects on glomerular filtration barrier.. Expression of versican and syndecan isoforms is indispensable for proper barrier function. Podocyte-derived miR-143 is a mediator for paracrine and autocrine cross talk between podocytes and glomerular endothelial cells and can alter expression of glomerular glycocalyx proteins.

Topics: Animals; Base Sequence; Blood Proteins; Cells, Cultured; Edema; Endothelial Cells; Gene Knockdown Techniques; Glomerular Filtration Barrier; Glycocalyx; Humans; Kidney Glomerulus; Larva; MicroRNAs; Morpholinos; Podocytes; Proteinuria; Proteoglycans; Syndecans; Transforming Growth Factor beta; Up-Regulation; Versicans; Zebrafish; Zebrafish Proteins

To evaluate the evolution of facial edema in the postoperative period after alveolar graft surgeries performed with collagen membrane soaked with recombinant human bone morphogenetic protein-2 (rhBMP-2) in individuals with cleft lip and palate.. Longitudinal prospective.. Tertiary craniofacial center.. One hundred fifty individuals submitted to alveolar graft.. In the preoperative consultation and 4 days after surgery, the individuals were assessed as to age, professional performing the surgery, duration of the procedure, type of cleft, measurement of facial edema, mouth opening, and global evaluation of the postoperative period.. Statistical analysis was performed to compare the facial edema and different variables, at a significance level of .05.. The maximum facial edema occurred between 3 and 4 days postoperatively, was inversely proportional to age and mouth opening, greater for female patients compared with male patients, for incomplete unilateral cleft lip and palate compared with other types of clefts, and for surgeon 1 compared with the other surgeons at some moment postoperatively. The surgeries were longer for complete unilateral and bilateral clefts. The difference was statistically significant for these variables.. The facial edema was influenced by the rhBMP-2 used in alveolar graft, and trismus was proportional to the intensity of facial edema.

Topics: Adolescent; Alveolar Bone Grafting; Bone Morphogenetic Protein 2; Cleft Lip; Cleft Palate; Collagen; Edema; Female; Humans; Male; Membranes, Artificial; Postoperative Complications; Prospective Studies; Recombinant Proteins; Transforming Growth Factor beta; Treatment Outcome

Prospective in vivo rodent model of bone morphogenetic protein (BMP)-induced inflammation.. To evaluate the effects of the coadministration of the nonsteroidal anti-inflammatory drug, diclofenac, on BMP-induced inflammation using our rodent model.. The use of BMP-2 is associated with inflammation in the neck and back. We have previously reported on a rodent model of BMP-2-induced inflammation.. Seven treatment groups were: Surgery alone; absorbable collagen sponges (ACS) alone; 20 μg rhBMP-2 on ACS with no diclofenac; 20 μg rhBMP-2 on ACS+50 mg diclofenac injections; 20 μg rhBMP-2 on ACS+75 mg diclofenac; 20 μg rhBMP-2 on ACS+100 mg diclofenac; and 20 μg rhBMP-2 on ACS+125 mg diclofenac. Using magnetic resonance imaging, inflammation (soft tissue edema volume) was assessed at 3 hours and at 2, 7, and 14 days after implantation. Western blot analysis, histology, and immunohistochemical staining were performed to compare the inflammatory response between groups. The mass size and tissue density of bone formation were compared between groups using plain radiography.. Soft-tissue edema volumes in all diclofenac-treated groups were significantly lower than those observed in the rhBMP-2 alone. There was no significant difference in soft tissue edema volumes between 4 diclofenac-treated groups. The expression of NF-κB signaling pathway related proteins (p65 and p-p65) were increased in the rhBMP-2+ACS group and decreased in diclofenac treatment groups. Histological findings and immunohistochemical staining were consistent with the Western blot results. There was no significant difference between the rhBMP-2+ACS group and diclofenac treatment groups in terms of the mass size and tissue density of bone formation.. Coadministration of diclofenac sodium can reduce the inflammatory response to BMP-2 without impairing heterotopic bone formation in our rodent model of BMP-2-induced inflammation.. N/A.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Back; Bone Morphogenetic Protein 2; Cytokines; Diclofenac; Drug Implants; Edema; Inflammation; Magnetic Resonance Imaging; Male; Osteogenesis; Porifera; Prospective Studies; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Transforming Growth Factor beta

We have previously shown that diabetic rats are more susceptible to sepsis, but that the Acute lung injury (ALI) secondary to sepsis is less intense than in non-diabetics. In the present study, we further investigated the ALI-secondary to sepsis in diabetic rats and the effect of insulin treatment.. Diabetes was induced in male Wistar rats by alloxan and sepsis by cecal ligation and puncture surgery (CLP). Some diabetic rats were given neutral protamine Hagedorn (NPH) insulin (4 IU, s.c.) 2 h before CLP. Six h later, the lungs were examined for edema, cell infiltration and prostaglandin-E2 (PGE2) levels in the bronchoalveolar lavage (BAL).. The results confirmed that leukocyte infiltration and edema were milder in diabetic rats with sepsis. After insulin treatment, the lung inflammation in diabetics increased to levels comparable to the non-diabetics. The BAL concentration of PGE2 was also lower in diabetics with sepsis, and increased after insulin treatment. Sepsis was followed by early fibroblast activation in the lung parenchyma, evaluated by increased transforming growth factor (TGF)-β and smooth muscle actin (α-SMA) expression, as well as an elevated number of cells with myofibroblasts morphology. These events were significantly lower in diabetic rats and increased after insulin treatment.. The results show that insulin modulates the early phase of inflammation and myofibroblast differentiation in diabetic rats.

Topics: Actins; Acute Lung Injury; Alloxan; Animals; Bronchoalveolar Lavage Fluid; Cell Count; Diabetes Mellitus, Experimental; Dinoprostone; Edema; Insulin; Leukocytes; Male; Myofibroblasts; Pneumonia; Rats; Rats, Wistar; Sepsis; Specific Pathogen-Free Organisms; Transforming Growth Factor beta

Garlic is used for both culinary and medicinal purposes by many cultures. The garlic organosulfur compounds (GOSCs) are thought to be bioactive components. This study aims to clarify the antiinflammatory effects and molecular mechanisms of GOSCs in both cell and animal models.. RAW264.7 cells were treated with six kinds of GOSCs to screen their influence on cyclooxygenase-2 and inducible nitric oxide synthase expression by Western blotting. Prostaglandin E2 and nitrite were measured by ELISA and Griess reaction, respectively. Cytokines in culture medium were assayed by the multiplex technology. Proteins were detected by Western blotting. Mouse paw edema was induced by LPS. The results revealed that diallyl trisulfide (DATS) was a strongest inhibitor for cyclooxygenase and inducible nitric oxide synthase among GOSCs, and reduced the levels of LPS-induced IL-6, IL-10, IL-12(p70), KC, MCP-1, and TNF-α. Cellular signaling analysis revealed that DATS downregulated AKT1/TGF-β-activated kinase-mediated mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. Furthermore, DATS activated Nrf2-mediated expression of HO-1 and NQO1 and reduced LPS-induced intracellular reactive oxygen species, which may contribute to suppress inflammatory mediator production. Finally, in vivo data demonstrated that DATS attenuated LPS-induced mouse paw edema.. DATS as a potential inhibitor revealed antiinflammatory effect in both cell and animal models by downregulating AKT1/TGF-β-activated kinase-mediated NFκB and MAPK signaling pathways.

Topics: Allyl Compounds; Animals; Anti-Inflammatory Agents; Cell Line, Tumor; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Down-Regulation; Edema; Garlic; Heme Oxygenase-1; Inflammation; Interleukin-10; Interleukin-12; Interleukin-6; Lipopolysaccharides; MAP Kinase Kinase Kinases; Membrane Proteins; Mice; Mitogen-Activated Protein Kinases; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; NF-kappa B; Nitric Oxide Synthase Type II; Phosphorylation; Plant Extracts; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; Sulfides; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

In vivo rodent model.. Investigate the effect of systemic corticosteroid administration on soft-tissue inflammation after local delivery of recombinant human bone morphogenetic protein-2 (rhBMP-2).. Corticosteroid use in cases of soft-tissue inflammation associated with the use of rhBMP-2 has been reported in clinical studies, but the effectiveness of its use and appropriate timing remain unclear.. Absorbable collagen sponges were implanted with control or rhBMP-2 into the lumbar region of rats subcutaneously and intramuscularly. Four groups were studied: group I, control sponge only; group 2, BMP-2 sponge only; group III, BMP-2 sponge and preoperative intraperitoneal methylprednisolone (MPSS); group IV, BMP-2 sponge with MPSS given on day 2. Using magnetic resonance imaging, inflammation was assessed in terms of soft tissue edema volume at 0, 2, 4, and 7 days. Rats were sacrificed after 7 days for gross and histological analysis.. The peak mean intramuscular inflammatory volume occurred on day 2 in all groups. Group II (BMP-2 without MPSS) had a significantly higher peak mean inflammatory volume (405.46 mm) on day 2 than that of groups I (266 mm), III (278 mm), and IV (291 mm) (P = 0.001). No significant difference in intramuscular soft-tissue inflammation was observed between the control group and the groups receiving MPSS on day 0 or day 2 at any time point. No differences in the area of inflammatory cell infiltrate surrounding the sponge was observed histologically, after sacrificing them, in groups treated with BMP-2.. Systemic MPSS administration reduced soft tissue edema associated with rhBMP-2 as measured by magnetic resonance imaging, but no effect was observed on the histological area of inflammation. Further studies are required to elucidate if there is any benefit to the use of corticosteroid administration in reducing the area of inflammation associated with the use of rhBMP-2.

Topics: Animals; Anti-Inflammatory Agents; Bone Morphogenetic Protein 2; Disease Models, Animal; Drug Delivery Systems; Edema; Humans; Inflammation; Injections, Intraperitoneal; Magnetic Resonance Imaging; Methylprednisolone; Muscles; Rats; Rats, Inbred Lew; Recombinant Proteins; Surgical Sponges; Time Factors; Transforming Growth Factor beta; Treatment Outcome

Topics: Bone Morphogenetic Proteins; Cervical Vertebrae; Deglutition Disorders; Diskectomy; Edema; Female; Humans; Ketones; Male; Polyethylene Glycols; Postoperative Complications; Prostheses and Implants; Pseudarthrosis; Recombinant Proteins; Spinal Fusion; Titanium; Transforming Growth Factor beta

Concern has been raised because of reports of inflammatory swelling following the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) and recombinant human bone morphogenetic protein-7 (rhBMP-7). The purpose of this study is to compare the inflammatory action of rhBMP-7 with those of rhBMP-2. ELISA assays (IL-6, TNF-α) were used to measure the cytokine response to different concentrations of rhBMP-7 and -2. Recombinant human BMP-7 was absorbed into absorbable collagen sponges and different amounts were implanted either subcutaneously (SC) or intramuscularly (IM) into the backs of rats. Using MRI and MIPAV software, we measured the degree of soft tissue edema at 3 h and at 2, 4, and 7 days postoperatively. After sacrificing rats on day 7 the inflammatory zone and mass were measured and the tissue examined histologically. Soft tissue edema after rhBMP-7 and rhBMP-2 implantation was dose-dependent and peaked at 3 h for the subcutaneous implants and at 2 days for the intramuscular implants. RhBMP-7 was associated with a significantly smaller soft tissue edema volume than was rhBMP-2 only at the highest dose (20 µg/ml). Both rhBMP-2 and rhBMP-7 triggered dose-dependent inflammatory reactions. Compared to rhBMP-2, rhBMP-7 is associated with somewhat smaller soft tissue edema volumes. Although rhBMP-7 is associated with an inflammatory reaction leading to soft tissue edema, at high doses this response is significantly less than that seen with rhBMP-2. Our animal model can be used to test materials that could ameliorate this reaction.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 7; Cell Line; Cytokines; Edema; Enzyme-Linked Immunosorbent Assay; Granuloma; Humans; Inflammation; Injections, Intramuscular; Injections, Subcutaneous; Interleukin-6; Lipopolysaccharides; Magnetic Resonance Imaging; Male; Rats; Rats, Inbred Lew; Recombinant Proteins; Time Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The goal of this study was to demonstrate the incidence of fusion and soft-tissue swelling in multilevel anterior cervical discectomies and fusions (ACDFs) using polyetheretherketone (PEEK) spacers with recombinant human bone morphogenetic protein-2 (rhBMP-2) impregnated in a Type I collagen sponge and titanium plates.. A single surgeon performed 30 multilevel ACDFs using PEEK spacers with an rhBMP-2 impregnated collagen sponge (0.4 ml, or the equivalent of 0.6 mg rhBMP-2). Soft-tissue swelling was assessed using cervical spine radiographs on postoperative Day 1 and at 2, 6, and 10 weeks and 6 months after surgery. Incidence of dysphagia was assessed with the Cervical Spine Research Society Swallowing-Quality of Life tool. Clinical success was evaluated with the Neck Disability Index, neck pain scores, and arm pain scores. Final fusion was assessed with CT by an independent neuroradiologist.. Patients were followed for 6 months unless they had an incomplete fusion; those patients were reassessed at 9 months. Twenty-four patients underwent 2-level ACDFs and 6 underwent 3-level ACDFs were performed on patients with the following risk factors for pseudarthrosis: smoking (33%), diabetes (13%), and obesity (body mass index ≥ 30 [43%]). Seventeen percent of the patients had multiple risk factors. Soft-tissue swelling peaked at 2 weeks regardless of level of surgery or number of levels treated surgically and decreased to near preoperative levels by 6 months. At 2 weeks, Swallowing-Quality of Life evaluation showed 19% of patients frequently choking on food, 4.8% frequently choking when drinking, and 47.6% with frequent food sticking in the throat. Scores continued to improve, and at 6 months, 0% had frequent choking on food, 6.7% had frequent difficulty drinking, and 6.7% had frequent food sticking in the throat. The Neck Disability Index, neck pain, and arm pain scores all improved progressively over 6 months. Incidence of fusion was 95% at 6 months and 100% at 9 months. There were no rehospitalizations or reoperations for soft-tissue swelling or dysphagia.. Multilevel ACDF procedures using PEEK grafts and rhBMP-2 can be performed safely in patients with multiple risk factors for pseudarthrosis with excellent fusion outcomes.

Topics: Adult; Aged; Benzophenones; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Cervical Vertebrae; Deglutition Disorders; Diskectomy; Dose-Response Relationship, Drug; Edema; Female; Humans; Ketones; Male; Middle Aged; Polyethylene Glycols; Polymers; Postoperative Complications; Prostheses and Implants; Pseudarthrosis; Recombinant Proteins; Reoperation; Retrospective Studies; Risk Factors; Spinal Fusion; Titanium; Tomography, X-Ray Computed; Transforming Growth Factor beta

Periapical lesions are a host response that involves immune reaction to prevent dissemination of bacteria from an infected root canal. The purpose of this study was to evaluate the levels of nitric oxide (NO), IL-4, TGF-beta, tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) in chronic periapical lesions and to determine their possible association with clinical and radiographic parameters.. Seventeen human radicular cysts and 30 periapical granulomas were used in this study. Cytokines and NO were assessed by enzyme-linked immunosorbent assay and by the Griess reaction respectively confirmed by immunohistochemical.. TNF-alpha and IFN-gamma were detected in 10% of granulomas and in 41.2% and 70% of radicular cysts. IL-4 was reactive in 24% of cysts, and TGF-beta was positive in all samples. Patients with tenderness showed significantly higher levels of IFN-gamma and IL-4 (P < 0.05). Swelling was associated with high levels of TNF-alpha, IFN-gamma, and IL-4 (P < 0.05). Lesions presenting bone resorption were associated with high levels of NO (P < 0.05).. Periapical granulomas display a regulatory environment characterized by high TGF-beta and low inflammatory cytokine levels, while radicular cysts has mist Th1 and Th2 inflammatory reaction with the presence of IFN-gamma, TNF-alpha, and IL-4.

Topics: Bone Resorption; Chronic Disease; Cytokines; Edema; Female; Humans; Interferon-gamma; Interleukin-4; Male; Nitric Oxide; Pain; Periapical Granuloma; Radicular Cyst; Radiography; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The authors present a case of scalp and facial edema following craniofacial reconstruction for metopic craniosynostosis in which recombinant human bone morphogenetic protein-2 (rhBMP-2) was used to treat cranial defects related to the frontoorbital reconstruction. The extent of swelling, the onset, and duration were unusual for such cases and suggested a possible role of rhBMP-2 in inducing a local inflammatory response. The edema rapidly resolved after the patient underwent surgery to remove the rhBMP-2 implants.

Topics: Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Plates; Child, Preschool; Cranial Sutures; Craniosynostoses; Craniotomy; Drug Implants; Edema; Facial Dermatoses; Frontal Bone; Humans; Male; Orbit; Plastic Surgery Procedures; Recombinant Proteins; Scalp Dermatoses; Transforming Growth Factor beta

Transforming growth factors betas (TGF-betas) are implicated in pancreatic tissue repair but their role in acute pancreatitis is not known. To determine whether endogenous TGF-betas modulate the course of caerulein induced acute pancreatitis, caerulein was administered to wild-type (FVB-/-) and transgenic mice that are heterozygous (FVB+/-) for expression of a dominant negative type II TGF-beta receptor.. After 7 hourly supramaximal injections of caerulein, the pancreas was evaluated histologically and serum was assayed for amylase and lipase levels. Next, the effects of caerulein on amylase secretion were determined in mouse pancreatic acini, and cholecystokinin (CCK) receptor expression was assessed.. The normal mouse pancreas was devoid of inflammatory cells whereas the pancreas from transgenic mice contained lymphocytic infiltrates. Caerulein injection in wild-type mice resulted in 6- and 36-fold increases in serum amylase and lipase levels, respectively, increased serum trypsinogen activation peptide (TAP) levels, gross oedema and a marked inflammatory response in the pancreas that consisted mainly of neutrophils and macrophages. By contrast, FVB+/- mice exhibited minimal alterations in response to caerulein with attenuated neutrophil-macrophage infiltrates. Moreover, acini from FVB+/- mice did not exhibit restricted stimulation at high caerulein concentrations, even though CCK receptor mRNA levels were not decreased.. Our findings indicate that a functional TGF-beta signalling pathway may be required for caerulein to induce acute pancreatitis and for the CCK receptor to induce acinar cell damage at high ligand concentrations. Our results also support the concept that restricted stimulation at high caerulein concentrations contributes to the ability of caerulein to induce acute pancreatitis.

Topics: Acute Disease; Amylases; Animals; Blotting, Northern; Ceruletide; Edema; Ligands; Lipase; Mice; Mice, Transgenic; Oligopeptides; Pancreatic Diseases; Pancreatitis; Receptors, Cholecystokinin; Severity of Illness Index; Signal Transduction; Transforming Growth Factor beta

Our aim was to assess whether adrenomedullin (AM), a potent vasodilator peptide with a variety of cardioprotective effects, has a therapeutic potential for the treatment of acute myocarditis in a rat model.. One week after myosin injection, rats received a continuous infusion of AM or vehicle for 2 weeks, and pathological and physiological investigations were performed.. AM treatment significantly reduced the infiltration of inflammatory cells in myocarditic hearts, and decreased the expressions of macrophage chemoattractant protein-1, matrix metalloproteinase-2 and transforming growth factor-beta. Myocardial edema indicated by increased heart weight to body weight ratio and wall thickness was attenuated by AM infusion (5.7+/-0.5 vs. 6.5+/-0.4 g/kg, and 1.9+/-0.3 vs. 2.8+/-0.5 mm, respectively). Infusion of AM significantly improved left ventricular maximum dP/dt and fractional shortening of myocarditic hearts (4203+/-640 vs. 3450+/-607 mm Hg/s, and 21.3+/-4.1 vs. 14.7+/-5.1%, respectively).. Infusion of AM improved cardiac function and pathological findings in a rat model of acute myocarditis. Thus, infusion of AM may be a potent therapeutic strategy for acute myocarditis.

Topics: Acute Disease; Adrenomedullin; Animals; Biomarkers; Blotting, Western; Chemokine CCL2; Echocardiography; Edema; Heart Rate; Immunohistochemistry; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Myocarditis; Myocardium; Myosins; Neovascularization, Physiologic; Rats; Rats, Inbred Lew; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta

Acute lung injury (ALI) is a devastating syndrome characterized by diffuse alveolar damage, elevated airspace levels of pro-inflammatory cytokines, and flooding of the alveolar spaces with protein-rich edema fluid. Interleukin-1beta (IL-1beta) is one of the most biologically active cytokines in the distal airspaces of patients with ALI. IL-1beta has been shown to increase lung epithelial and endothelial permeability. In this study, we hypothesized that IL-1beta would decrease vectorial ion and water transport across the distal lung epithelium. Therefore, we measured the effects of IL-1beta on transepithelial current, resistance, and sodium transport in primary cultures of alveolar epithelial type II (ATII) cells. IL-1beta significantly reduced the amiloride-sensitive fraction of the transepithelial current and sodium transport across rat ATII cell monolayers. Moreover, IL-1beta decreased basal and dexamethasone-induced epithelial sodium channel alpha-subunit (alpha ENaC) mRNA levels and total and cell-surface protein expression. The inhibitory effect of IL-1beta on alpha ENaC expression was mediated by the activation of p38 MAPK in both rat and human ATII cells and was independent of the activation of alpha v beta6 integrin and transforming growth factor-beta. These results indicate that IL-1beta may contribute to alveolar edema in ALI by reducing distal lung epithelial sodium absorption. This reduction in ion and water transport across the lung epithelium is in large part due to a decrease in alpha ENaC expression through p38 MAPK-dependent inhibition of alpha ENaC promoter activity and to an alteration in ENaC trafficking to the apical membrane of ATII cells.

Topics: Animals; Antigens, Neoplasm; Biological Transport; Biotinylation; Blotting, Western; Cell Membrane; Cell Survival; Cells, Cultured; Dexamethasone; DNA Primers; Dose-Response Relationship, Drug; Edema; Electrophysiology; Epithelial Cells; Epithelial Sodium Channels; Epithelium; Humans; Integrins; Interleukin-1; Luciferases; p38 Mitogen-Activated Protein Kinases; Promoter Regions, Genetic; Pulmonary Alveoli; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Sodium; Sodium Channels; Time Factors; Transforming Growth Factor beta; Water

In this study, we evaluated the effects of trapidil on crush injury by monitoring nitric oxide, malondialdehyde and transforming growth factor-Beta2 levels and by transmission electron microscopy in the rat sciatic nerve. The sciatic nerve was compressed for 20 sec by using a jewelers forceps. Trapidil treatment groups were administrated a single dose of trapidil (8 mg/kg) intraperitoneally just after the injury. The crush and crush + trapidil treatment groups were evaluated on the 2nd, 7th, 15th, 30th and 45th days of the post-crush period. On the 7th and 15th days, damage in thin and thick myelinated axons, endoneural edema and mitochondrial swelling were less severe in the trapidil group histopathologically. These findings supported the idea that trapidil prevented cell damage and edema at the injury site. Day/group interaction with regard to serum nitric oxide, malondialdehyde and transforming growth factor-Beta2 levels did not show significant changes.

Topics: Animals; Edema; Female; Injections, Intraperitoneal; Malondialdehyde; Microscopy, Electron, Transmission; Myelin Sheath; Nerve Crush; Nitrates; Nitrites; Rats; Rats, Inbred Strains; Sciatic Nerve; Sciatic Neuropathy; Transforming Growth Factor beta; Transforming Growth Factor beta2; Trapidil; Vasodilator Agents

Clinical trials of therapeutic angiogenesis for the treatment of cardiovascular ischemia have failed to meet the expectations with the use of single growth factors, namely VEGF and bFGF. We show here that a bovine bone-derived growth factor mixture (GFM) of TGFbetas, BMPs, and no more than 0.1% aFGF can initiate a dose-dependent angiogenic response in subcutaneously implanted Growth Factor Reduced Matrigel plugs that includes abundant smooth muscle actin positive (SMA+) tubes and functional CD31+, red blood cell filled, capillaries. Tube forming activity of the single factors, recombinant bFGF and bone-derived TGF-beta2, were comparable to GFM, but only the bone-derived factors were able to create a larger fraction of SMA+ tubes than Matrigel alone at an equal dose. Basic FGF formed a greater number of RBC-filled capillaries within the plugs than GFM or TGF-beta2 at the highest doses, although GFM created RBC-filled capillaries that penetrated deeper into the plugs than bFGF. However, bFGF showed the greatest number of non-cell-lined, RBC-filled pools, suggestive of vessel rupture, and the largest number of plugs showing signs of fluid accumulation in the form of large, cell-lined clefts in the implants. TGF-beta2 showed less RBC-filled pools, but a significant number of implants with signs of fluid accumulation. At high doses of GFM penetration by blood vessels and mesenchymal cells was obstructed by cartilage development within the plugs accompanied by a prominent band of SMA+ granulation tissue with abundant RBC-filled capillaries encapsulating the implants. Thus, GFM is also capable of dramatically remodeling the vascular system in the interstitial space surrounding the plug. These results show that GFM is capable of inducing the formation of a more mature vascular system than that formed by the single factors bFGF and TGFbeta-2. Natural mixtures of TGFbetas, BMPs, and FGFs may have superior clinical utility in therapeutic angiogenesis applications.

Topics: Actins; Animals; Capillaries; Cell Line, Tumor; Edema; Erythrocytes; Female; Femur; Fibroblast Growth Factor 2; Humans; Mice; Mice, Inbred C57BL; Multigene Family; Neovascularization, Physiologic; Rats; Rats, Nude; Transforming Growth Factor beta; Transforming Growth Factor beta2

To examine the effect of transforming growth factor (TGF)-beta1 on the regulation of cartilage synthesis and other articular pathologies, we used adenovirus-mediated intra-articular gene transfer of TGF-beta1 to both naïve and arthritic rabbit knee joints. Increasing doses of adenoviral vector expressing TGF-beta1 were injected into normal and antigen-induced arthritis rabbit knee joints through the patellar tendon, with the same doses of an adenoviral vector expressing luciferase injected into the contralateral knees as the control. Intra-articular injection of adenoviral vector expressing TGF-beta1 into the rabbit knee resulted in dose-dependent TGF-beta1 expression in the synovial fluid. Intra-articular TGF-beta1 expression in both naïve and arthritic rabbit knee joints resulted in significant pathological changes in the rabbit knee as well as in adjacent muscle tissue. The observed changes induced by elevated TGF-beta1 included inhibition of white blood cell infiltration, stimulation of glycosaminoglycan release and nitric oxide production, and induction of fibrogenesis and muscle edema. In addition, induction of chondrogenesis within the synovial lining was observed. These results suggest that even though TGF-beta1 may have anti-inflammatory properties, it is unable to stimulate repair of damaged cartilage, even stimulating cartilage degradation. Gene transfer of TGF-beta1 to the synovium is thus not suitable for treating intra-articular pathologies.

Topics: Adenoviridae; Adjuvants, Immunologic; Animals; Arthritis, Experimental; Cartilage; Disease Models, Animal; Dose-Response Relationship, Immunologic; Edema; Gene Expression Regulation, Viral; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Glycosaminoglycans; Humans; Injections, Intra-Articular; Knee Joint; Leukocytes; Muscle, Skeletal; Nitric Oxide; Rabbits; Transforming Growth Factor beta; Transforming Growth Factor beta1

The expression of the inducible isoform of nitric oxide synthase (NOS2, iNOS) is increased in patients undergoing sepsis as well as in animal models in which septic shock is induced by injection of bacterial lipopolysaccharide (LPS). Transforming growth factor-beta1 (TGF-beta1) potently suppresses NO production both in vitro and in vivo. After intraperitoneal injection of LPS, mice over-expressing a cDNA coding for active TGF-beta1 in the liver (Alb/ TGF-beta1) exhibited reduced serum levels of the NO reaction products NO2(-) + NO3(-) compared with controls. Paradoxically, while endotoxemic Alb/ TGF-beta1 mice expressed much less NOS2 protein in peritoneal exudate cells than did endotoxemic wild-type mice, Alb/TGF-beta1 mice expressed more NOS2 mRNA and protein in both liver and kidney. Alb/ TGF-beta1 mice treated with LPS had eightfold higher serum tumor necrosis factor alpha (TNF-alpha) levels and experienced increased mortality compared with wild-type mice, which was associated with renal insufficiency. These results suggest that renal dysfunction, decreased production of NO, and/or increased production of TNF-alpha are associated with increased mortality of endotoxemic Alb/TGF-beta1 mice.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Cell Adhesion; Edema; Endotoxemia; Gene Expression Regulation, Enzymologic; Kidney Diseases; Liver; Mice; Mice, Transgenic; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrites; RNA, Messenger; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Increased TGF-beta1 protein expression in tunica albuginea has been found to be associated with Peyronie's disease. The present study is designed to investigate whether surgical trauma induces TGF-beta up-regulation and histological changes in rat penis.. Thirty-two adult male Sprague-Dawley rats were divided into two groups. The first group (n=24) underwent incision and suture repair of the tunica albuginea of the penis. The second group (n=8) received sham surgery (incision of the penile skin and underlying fascia) as the control group. The trauma-induced group was divided into four subgroups in which the rats were euthanized at 6 hours (n=6), 1 day (n=6), 3 days (n=6), and 8 weeks (n=6). Two sham-operated (control) animals were also euthanized at each of the above time points. All tunical tissues from the trauma-induced and sham-operated rats were collected and examined histologically using Trichrome and Hart elastic fiber stain. Electron microscopy was used to study the ultrastructural changes of both trauma induced and control specimens. Western blotting technique was performed to study TGF-beta protein expression in both experimental and sham-operated groups.. Tissue edema and hemorrhage between collagen bundles are noted in the experimental groups after 6 hours, 1 day and 3 days. At 8 weeks the most prominent changes observed were inflammatory cellular infiltration and disorganization of the collagen bundles. In the control group the tunica albuginea retains normal wavy regular appearance in all rats. This histological analysis is similar to the reported description of histological features of the acute phase of Peyronie's disease. Electron microscopy showed packed collagen bundles in the trauma-induced group with normal appearing elastic fibers. No abnormal change was detected in the control group. Immunoblot results revealed remarkable TGF-beta1 protein expression in 1, 5, 3, and 0 rats of trauma induced subgroups after 6 hours, 1 day, 3 days, and 8 weeks respectively. No TGF-beta1 protein expression in any rats in the control group was detected. No significant TGF-beta2 or TGF-beta3 protein expression was observed either in the trauma induced group or in the control group.. Trauma can induce histological changes similar to the acute phase of Peyronie's disease but not the overt picture of the chronic phase of Peyronie's disease. It can also result in an early but transient up-regulation of TGF-beta1 protein expression in the rat penis. We conclude that surgical incisional trauma does not result in Peyronie's disease-like changes in the tunica.

Topics: Animals; Blotting, Western; Edema; Immunoblotting; Male; Penis; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Up-Regulation

Transforming growth factor beta isoforms (TGF beta s) belong to a family of multifunctional regulators of cellular growth and differentiation. They are mitogenic and chemotactic for fibroblasts and are potent stimulators of extracellular matrix production (collagen) and deposition. Upregulation of TGF beta transcription has been reported for several in vivo systems during repair after injury.. To study the expression of the three mammalian isoforms of TGF beta (TGF beta 1-3) and their relation to collagen expression as a marker for fibroblast response in acute oedematous pancreatitis in rats.. Using northern blot analysis and immunohistochemistry, the expression and localisation of TGF beta isoforms, collagen, and amylase were analysed during the course of acute oedematous pancreatitis in rats, experimentally induced by intravenous caerulein infusion.. Induction of acute pancreatitis resulted in a biphasic peak pattern of expression of TGF beta 1, beta 2, and beta 3 mRNA, with a pronounced increase from day 1 to day 3 (sixfold, 2.5-fold, fivefold, respectively) and again from day 5 to day 7 (three-fold, 2.3-fold, 3.5-fold, respectively). The temporal changes in TGF beta mRNA identically paralleled the expression in collagen mRNA. In contrast, amylase mRNA expression, used as a general indicator of acinar cell integrity, was slightly decreased after induction of acute pancreatitis. Immunohistochemical analysis of pancreatitis tissue showed that increased expression of TGF beta s was mainly present in the pancreatic acinar and ductal cells; this was evident within one day after pancreatitis induction.. Overexpression of TGF beta s after induction of acute pancreatitis suggests a role for these proteins in pancreatic repair and remodelling. The increased levels of TGF beta s may help suppress immune activation, and may contribute to the increase in the extracellular matrix including collagen and to the repair of the pancreatic parenchyma.

Topics: Acute Disease; Amylases; Animals; Blotting, Northern; Ceruletide; Collagen; Edema; Gastrointestinal Agents; Gene Expression; Immunohistochemistry; Male; Pancreatitis; Rats; Rats, Wistar; RNA, Messenger; Transforming Growth Factor beta

Dexamethasone (Dex, 0.3 mg/kg, s.c.) did not suppress histamine and ischemic paw edema of mice up to 1 hr. However, given TGF-beta 1 (0.3 microgram/kg, i.p.), Dex suppression appeared early as 30 min (36% and 42%). When Dex (0.1 mg/kg, s.c.) was injected 6 hr before the assay, Dex alone, TGF-beta 1 +/- Dex, FK506 (10 mg/kg, oral) +/- Dex, cyclosporin (CsA, 30 mg/kg, oral) +/- Dex, rapamycin (Rapa, 10 mg/kg, i.p.) +/- Dex, deoxyspergualin (DSP, 10 mg/kg, i.p.) +/- Dex, did not suppress the edemata (less than 11%). Nevertheless, if Dex and TGF-beta 1 were dosed together with one of these immunosuppressants, suppressions of histamine and ischemic edema were 53%, 45% (FK506), 45%, 49% (CsA), 44%, 48% (Rapa) and 39%, 51% (DSP), respectively. Glucocorticoid (GC) receptor (GR) complex contains heat shock proteins such as hsp56 (or CsA-binding protein: CyP-40), hsp70 and hsp90. FK506, Rapa and TGF-beta 1 receptor I (TR-I) bind FK-binding protein-12 (FKBP-12). FK506 and Rapa bind also hsp56. CsA binds CyP-40. DSP binds hsp70 and/or hsp90. These bindings might change or stabilize the conformation of GR complex resulting in edema suppressions. Nitric oxide synthase (NOS) inhibitors, superoxide dismutase (SOD), catalase, mannitol and cycloheximide, reversed the edema suppressions by TGF-beta1 +/- immunosuppressant at 30 min and 6 hr after Dex. Endogenous NO, O2- and/or .OH seemed to be essential for edema suppressions. Our demonstration in vivo may offer a theoretical support for clinicians to adopt combination therapy of immunosuppressant(s) and GC.

Topics: Animals; Dexamethasone; Edema; Foot; Histamine Release; Immunosuppressive Agents; Ischemia; Male; Mice; Nitric Oxide; Reactive Oxygen Species; Transforming Growth Factor beta

The effects of exogenous TGF-beta 2 on normally healing fractures were investigated to see if healing can be accelerated; TGF-beta s stimulate bone and cartilage formation on calvariae and long bones. TGF-beta 2 (60 or 600 ng) was injected around the developing callus of rabbit tibial fractures healing under stable, or unstable, mechanical conditions 4 days after fracture. The fractures were examined 5, 7, 10, and 14 days after fracture. A large amount of edema developed around the injection sites. The callus of fractures healing under stable mechanical conditions consists almost entirely of bone. The effects of 60-ng injections of TGF-beta 2 are minimal, but 600-ng doses lead to a small increase in the size of the callus. The callus of fractures healing under unstable mechanical conditions has a large area of cartilage over the fracture site with bone on each side. The effects of TGF-beta 2 on unstable fractures are to retard and reduce bone and cartilage formation in the callus. The overall size of the callus is not affected. In conclusion, TGF-beta 2 does not stimulate fracture healing under either stable, or unstable, mechanical conditions during the initial healing phase. It is argued that agents which stimulate bone formation can retard remodeling when treatment is extended into the remodeling phase of healing.

Topics: Animals; Bone Development; Bone Remodeling; Bony Callus; Cartilage; Dose-Response Relationship, Drug; Edema; Fracture Healing; Male; Rabbits; Tibia; Transforming Growth Factor beta

Transforming growth factor beta (TGF-beta) is a multifunctional homodimeric polypeptide with potent actions upon many target cells, including those of mesenchymal and haemopoietic lineage. The recent reports of high levels of the cytokine in rheumatoid synovium and synovial fluid, prompted this study into the effect of intra-articular injection of TGF beta-2 into rabbit knee-joints. Four daily injections of 1 microgram caused swelling, probably as a consequence of prostaglandin E2 production, synovial fibroblastic hyperplasia and a striking loss of femoral condyle proteoglycan. Using the polymerase chain reaction, no evidence could be obtained for the induction of interleukin-1 alpha gene expression in either synovial tissue or synovial fluid cells. These findings suggest that the TGF-beta present in the rheumatoid joint may contribute directly to the pathogenesis of rheumatoid arthritis.

Topics: Animals; Arthritis; Cartilage, Articular; Dinoprostone; Edema; Hyperplasia; Injections, Intra-Articular; Interleukin-1; Polymerase Chain Reaction; Proteoglycans; Rabbits; Recombinant Proteins; Synovial Membrane; Transforming Growth Factor beta