transforming-growth-factor-beta and Weight-Gain

Transforming growth factor beta (TGF-β) signaling in hepatocytes promotes steatosis and body weight gain. However, processes that TGF-β signaling in hepatocytes promote pathological body weight gain in nonalcoholic fatty liver disease (NAFLD) are incompletely understood. Obesity and NAFLD were induced by 16 weeks of feeding a high-fat diet (HFD) in hepatocyte-specific TGF-β receptor II-deficient (Tgfbr2

Topics: Adipose Tissue, White; Animals; Hepatocytes; Mice; MicroRNAs; Non-alcoholic Fatty Liver Disease; Obesity; Receptor, Transforming Growth Factor-beta Type II; Transforming Growth Factor beta; Weight Gain

Hyperinsulinemia is an important causative factor of prostate enlargement in type 2 diabetes (T2D), however, clinically prostate weight increases during hypoinsulinemic condition. To investigate the pathogenesis of prostate enlargement and effects of phosphodiesterase 5 inhibitor (PDE5i), male Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats were used as T2D and control, respectively.. OLETF and LETO rats were treated with oral tadalafil (100 μg/kg/day) or vehicle for 12 wks from at the age of 36 wks.. Prostate weight of OLETF rats was significantly higher than that of LETO at 36 wks, and increased at 48 wks. In OLETF rats, prostate blood flow was significantly lower at 48 wks versus 36 wks. Twelve-week-tadalafil treatment increased prostate blood flow and suppressed prostate weight increase in both strains. This change was inversely correlated with changes in prostate expressions of hypoxia-inducible factor-1 alpha (HIF-1α) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Increases with age were observed in mRNA and/or protein levels of cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha (TNF-α) and cell growth factors insulin-like growth factor-1 (IGF-1), basic fibroblast growth factor (bFGF), and transforming growth factor-beta (TGF-β); especially IL-6, TNF-α, IGF-1, bFGF and TGF-β increased with T2D. Tadalafil suppressed these cytokines and growth factors.. These data suggest chronic ischemia caused by T2D leads to oxidative stress, resulting in prostate enlargement through upregulation of several cytokines and growth factors. Treatment with PDE5i improves prostate ischemia and might prevent enlargement via suppression of cytokines and growth factors in T2D.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Insulin-Like Growth Factor I; Male; Phosphodiesterase 5 Inhibitors; Prostate; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Tadalafil; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Weight Gain

The present study evaluated the protective effect and the regulatory mechanism of taurine on growth inhibition and intestinal damage induced by glycinin in juvenile Rhynchocypris lagowskii Dybowski. The control diets had no glycinin and taurine, the glycinin diets contained only 80 g/kg glycinin, and the glycinin + taurine diets contained 80 g/kg glycinin+10 g/kg taurine. Juvenile Rhynchocypris lagowskii Dybowski (4.65 ± 0.03 g/tail) were respectively fed with these 3 diets for 8 weeks. The results showed that glycinin significantly decreased the final body weight, weight gain rate, specific growth rate, protein efficiency rate, feed efficiency rate and feeding rate of fish compared with the control group (P < 0.05). While taurine supplementation improved the growth performance and feed efficiency, but final body weight, weight gain rate, specific growth rate of the glycinin + taurine group were still significantly lower than the control group (P < 0.05). Compared with the glycinin group, taurine supplementation significantly increased whole-body and muscle crude protein content, and hepatopancreas and intestinal protease activities (P < 0.05). Distal intestinal villous dysplasia and mucosal damage, and increased intestinal mucosal permeability were observed in the glycinin group, while taurine supplementation alleviated these adverse effects. Usefully, taurine supplementation could also partially restore the impaired immune function and antioxidant capacity of fish fed glycinin diets. Compared with the glycinin group, taurine supplementation down-regulated pro-inflammatory cytokines TNF-α and IL-1β mRNA levels, and up-regulated anti-inflammatory cytokines IL-10 and TGF-β mRNA levels. Furthermore, taurine partially reversed the reduction of antioxidant genes Nrf2、HO-1, CAT and GPx mRNA levels in distal intestine induced by glycinin. Concluded, 80 g/kg glycinin led to intestinal damage, digestive dysfunction and increased intestinal mucosal permeability in juvenile Rhynchocypris lagowskii Dybowski, and these adverse effects were ultimately manifested in growth inhibition. But taurine supplementation could partially mitigate the negative effects induced by glycinin.

Topics: Animal Feed; Animals; Anti-Inflammatory Agents; Antioxidants; Body Weight; Diet; Dietary Supplements; Interleukin-10; NF-E2-Related Factor 2; Peptide Hydrolases; RNA, Messenger; Taurine; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Weight Gain

Eimeria magna is a common coccidia in the intestines of rabbits, causing anorexia, weight loss, diarrhea, and bloody stools. This study cloned and determined the expression levels of four Eimeria surface antigens (EmSAGs) at different developmental stages and showed that EmSAG10 and EmSAG11 are highly expressed at the merozoite stage. Rabbits were immunized with rEmSAG10 and rEmSAG11, and then challenged with E. magna after 2 weeks. Serum-specific antibodies and cytokine levels were detected using ELISA. Immune protection was evaluated based on the rate of the oocysts decrease, the output of oocysts (p < 0.05), the average weight gain, and the feed: meat ratio. Our results showed that rabbits immunized with rEmSAG10 and rEmSAG11 had a higher average weight gain (62.7%, 61.1%), feed; meat ratio (3.8:1, 4.5:1), and the oocysts decrease rate (70.8%, 81.2%) than those in the control group, and also significantly reduced intestinal lesions. The specific IgG level increased one week after the first rEmSAG10 and rEmSAG11 immunization and was maintained until two weeks after the challenge (p < 0.05). The TGF-β, IL-4, and IL-10 levels in the serum increased significantly after the secondary immunization with rEmSAG10 and rEmSAG11, while the IL-2 levels increased significantly after the secondary immunization with rEmSAG11 (both p < 0.05), suggesting that rEmSAG10 can induce a humoral and cellular immunity, while rEmSAG11 can only induce a humoral immunity. Therefore, rEmSAG10 is a candidate antigen for E. magna recombinant subunit vaccines.

Topics: Animals; Antigens, Surface; Coccidiosis; Eimeria; Immunoglobulin G; Interleukin-10; Interleukin-2; Interleukin-4; Oocysts; Protein Subunits; Protozoan Vaccines; Rabbits; Recombinant Proteins; Transforming Growth Factor beta; Vaccines, Subunit; Weight Gain

Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease characterized by fat accumulation and inflammation in liver. Yet, the mechanistic insight and diagnostic and therapeutic options of NASH remain incompletely understood. This study tested the roles of cysteine protease cathepsin B (CatB) in mouse NASH development. Immunoblot revealed increased liver CatB expression in NASH mice. Fructose-palmitate-cholesterol diet increased body weight gain, liver to body weight ratio, blood fasting glucose, plasma total cholesterol and alanine transaminase levels, and liver triglyceride, but decreased plasma high-density lipoprotein in wild-type mice. All these changes were blunted in CatB-deficient (Ctsb

Topics: Animals; Cadherins; Cathepsin B; Cell Polarity; Diet, High-Fat; Inflammation; Lipid Metabolism; Liver; Liver Cirrhosis; Macrophages; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Weight Gain

Increasing evidence suggests that maternal diet during pregnancy modifies an offspring's microbiota composition and intestinal development in a long-term manner. However, the effects of maternal soluble fiber diet during pregnancy on growth traits and the developing intestine are still underexplored. Sows were allocated to either a control or 2.0% pregelatinized waxy maize starch plus guar gum (SF) dietary treatment during gestation. Growth performance, diarrhea incidence, gut microbiota composition and metabolism, and gut permeability and inflammation status of 14-day-old suckling piglets were analyzed. The maternal SF diet improved the growth rate and decreased the incidence of diarrhea in the piglets. Next-generation sequencing analysis revealed that the intestinal microbiota composition was altered by a maternal SF diet. The fecal and plasma levels of acetate and butyrate were also increased. Furthermore, a maternal SF diet reduced the levels of plasma zonulin and fecal lipocalin-2 but increased the plasma concentrations of interleukin 10 (IL-10) and transforming growth factor β (TGF-β). Additionally, the increased relative abundances of

Topics: Acetates; Animals; Bacteria; Bilophila; Butyrates; Cholera Toxin; Diarrhea; Diet; Dietary Fiber; Disease Resistance; Female; Gastrointestinal Microbiome; Haptoglobins; High-Throughput Nucleotide Sequencing; Interleukin-10; Intestines; Lactobacillus; Lipocalin-2; Permeability; Pregnancy; Protein Precursors; RNA, Ribosomal, 16S; Swine; Transforming Growth Factor beta; Weight Gain

Pulmonary fibrosis is a multifaceted disease with high mortality and morbidity, and it is commonly nonresponsive to conventional therapy.. We explore the possible discourse of sinapic acid (SA) against the prevention of bleomycin (BLM)-instigated lung fibrosis in rats through modulation of Nrf2/HO-1 and NF-κB signaling pathways.. Lung fibrosis was persuaded in Sprague-Dawley rats by a single intratracheal BLM (6.5 U/kg) injection. Then, these rats were treated with SA (10 and 20 mg/kg, p.o.) for 28 days. The normal control rats provided saline as a substitute of BLM. The lung function and biochemical, histopathological, and molecular alterations were studied in serum, bronchoalveolar lavage fluid (BALF), and the lungs tissues.. SA treatment significantly restored BLM-induced alterations in body weight index and serum biomarkers [lactate dehydrogenase (LDH) and alkaline phosphatase (ALP)]. SA (10 and 20 mg/kg) treatment appeared to show a pneumoprotective effect through upregulation of antioxidant status, downregulation of inflammatory cytokines and MMP-7 expression, and reduction of collagen accumulation (hydroxyproline). Nrf2, HO-1, and TGF-β expression was downregulated in BLM-induced fibrosis model, while the reduced expression levels were significantly and dose-dependently upregulated by SA (10 and 20 mg/kg) treatment. We demonstrated that SA ameliorates BLM-induced lung injuries through inhibition of apoptosis and induction of Nrf2/HO-1-mediated antioxidant enzymes via NF-κB inhibition. The histopathological findings also revealed that SA treatment (10 and 20 mg/kg) significantly ameliorated BLM-induced lung injury.. The present results showed the ability of SA to restore the antioxidant system and to inhibit oxidative stress, proinflammatory cytokines, extracellular matrix, and TGF-β. This is first report demonstrating that SA amoleriates BLM induced lung injuries through inhibition of apoptosis and induction of Nrf2 and HO-1 mediated antioxidant enzyme via NF-κB inhibition. The histopathological finding reveals that SA treatment (10 and 20 mg/kg) significantly ameliorates BLM induced lung injuries.

Topics: Animals; Antioxidants; Apoptosis; Biomarkers; Bleomycin; Bronchoalveolar Lavage Fluid; Coumaric Acids; Disease Models, Animal; Heme Oxygenase-1; Hydroxyproline; Inflammation; Lung; Matrix Metalloproteinase 7; NF-E2-Related Factor 2; NF-kappa B; Organ Size; Oxidative Stress; Pulmonary Fibrosis; Rats, Sprague-Dawley; Transforming Growth Factor beta; Weight Gain

There are no approved therapies for muscle wasting in children infected with human immunodeficiency virus (HIV), which portends poor disease outcomes. To determine whether a soluble ActRIIb receptor Fc fusion protein (ActRIIB.Fc), a ligand trap for TGF-β/activin family members including myostatin, can prevent or restore loss of lean body mass and body weight in simian immunodeficiency virus (SIV)-infected juvenile rhesus macaques (Macaca mulatta). Fourteen pair-housed, juvenile male rhesus macaques were inoculated with SIVmac239 and, 4 wk postinoculation (WPI) treated with intramuscular injections of 10 mg ⋅ kg(-1) ⋅ wk(-1) ActRIIB.Fc or saline placebo. Body weight, lean body mass, SIV titers, and somatometric measurements were assessed monthly for 16 wk. Age-matched SIV-infected rhesus macaques were injected with saline. Intervention groups did not differ at baseline. Gains in lean mass were significantly greater in the ActRIIB.Fc group than in the placebo group (P < 0.001). Administration of ActRIIB.Fc was associated with greater gains in body weight (P = 0.01) and upper arm circumference than placebo. Serum CD4(+) T-lymphocyte counts and SIV copy numbers did not differ between groups. Administration of ActRIIB.Fc was associated with higher muscle expression of myostatin than placebo. ActRIIB.Fc effectively blocked and reversed loss of body weight, lean mass, and fat mass in juvenile SIV-infected rhesus macaques.

Topics: Activin Receptors, Type II; Animals; Disease Models, Animal; Hematocrit; HIV Wasting Syndrome; Humans; Immunoglobulin Fc Fragments; Ligands; Macaca mulatta; Male; Muscle, Skeletal; Myostatin; Recombinant Fusion Proteins; RNA, Messenger; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Transforming Growth Factor beta; Up-Regulation; Weight Gain

Changes in lifestyle such as increase in high-fat food consumption are an important cause for vascular diseases. The present study aimed to investigate the involvement of ACE and TGF- β in the aorta stiffness induced by high-fat diet. C57BL/6 male mice were divided in two groups according to their diet for 8 weeks: standard diet (ST) and high-fat diet (HF). At the end of the protocol, body weight gain, adipose tissue content, serum lipids and glucose levels, and aorta morphometric and biochemical measurements were performed. Analysis of collagen fibers by picrosirius staining of aorta slices showed that HF diet promoted increase of thin (55%) and thick (100%) collagen fibers deposition and concomitant disorganization of these fibers orientations in the aorta vascular wall (50%). To unravel the mechanism involved, myeloperoxidase (MPO) and angiotensin I converting enzyme (ACE) were evaluated by protein expression and enzyme activity. HF diet increased MPO (90%) and ACE (28%) activities, as well as protein expression of ACE. TGF-β was also increased in aorta tissue of HF diet mice after 8 weeks. Altogether, we have observed that the HF diet-induced aortic stiffening may be associated with increased oxidative stress damage and activation of the RAS in vascular tissue.

Topics: Animals; Aorta; Biomarkers; Diet, High-Fat; Gene Expression Regulation; Humans; Inflammation; Mice; Oxidative Stress; Peptidyl-Dipeptidase A; Transforming Growth Factor beta; Vascular Stiffness; Weight Gain

Intrauterine growth restriction (IUGR) is intimately linked with postnatal catch-up growth, leading to impaired lung structure and function. However, the impact of catch-up growth induced by early postnatal hyperalimentation (HA) on the lung has not been addressed to date.. The aim of this study was to investigate whether prevention of HA subsequent to IUGR protects the lung from 1) deregulation of the transforming growth factor-β(TGF-β)/bone morphogenetic protein (BMP) pathway, 2) activation of interleukin (IL)-6 signaling, and 3) profibrotic processes.. IUGR was induced in Wistar rats by isocaloric protein restriction during gestation by feeding a control (Co) or a low-protein diet with 17% or 8% casein, respectively. On postnatal day 1 (P1), litters from both groups were randomly reduced to 6 pups per dam to induce HA or adjusted to 10 pups and fed with standard diet: Co, Co with HA (Co-HA), IUGR, and IUGR with HA (IUGR-HA).. Birth weights in rats after IUGR were lower than in Co rats (P < 0.05). HA during lactation led to accelerated body weight gain from P1 to P23 (Co vs. Co-HA, IUGR vs. IUGR-HA; P < 0.05). At P70, prevention of HA after IUGR protected against the following: 1) activation of both TGF-β [phosphorylated SMAD (pSMAD) 2; plasminogen activator inhibitor 1 (Pai1)] and BMP signaling [pSMAD1; inhibitor of differentiation (Id1)] compared with Co (P < 0.05) and Co or IUGR (P < 0.05) rats, respectively; 2) greater mRNA expression of interleukin (Il) 6 and Il13 (P < 0.05) as well as activation of signal transducer and activator of transcription 3 (STAT3) signaling (P < 0.05) after IUGR-HA; and 3) greater gene expression of collagen Iα1 and osteopontin (P < 0.05) and increased deposition of bronchial subepithelial connective tissue in IUGR-HA compared with Co and IUGR rats. Moreover, HA had a significant additive effect (P < 0.05) on the increased enhanced pause (indicator of airway resistance) in the IUGR group (P < 0.05) at P70.. This study demonstrates a dual mechanism in IUGR-associated lung disease that is 1) IUGR-dependent and 2) HA-mediated and thereby offers new avenues to develop innovative preventive strategies for perinatal programming of adult lung diseases.

Topics: Animals; Animals, Newborn; Bone Morphogenetic Proteins; Diet, Protein-Restricted; Female; Fetal Growth Retardation; Gene Expression Regulation; Interleukin-6; Lactation; Lung; Lung Diseases; Male; Overnutrition; Rats; Rats, Wistar; Signal Transduction; STAT3 Transcription Factor; Transforming Growth Factor beta; Weight Gain

Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating and fatal lung disorder with high mortality rate. Unfortunately, to date the treatment for IPF remains unsatisfying and in severe cases lung transplantations are performed as a therapeutic measure. Thus, it becomes great interest to find novel agents to treat IPF. Berberine, a plant alkaloid known for its broad pharmacological activities remains a remedy against multiple diseases. This study was hypothesized to investigate the antifibrotic potential of berberine against bleomycin-induced lung injury and fibrosis, a tentative animal model. Male wistar rats were subjected to single intratracheal instillation of 2.5 U/kg of bleomycin on day 0. Berberine treatments were either provided in preventive or therapeutic mode respectively. Berberine administration significantly ameliorated the bleomycin mediated histological alterations and reduced the inflammatory cell infiltrate in BALF. Berberine significantly blocked collagen accumulations with parallel reduction in the hydroxyproline level. The immunological sign of bleomycin stimulated mast cell deposition and histamine release were considerably reduced by berberine. Berberine enhanced the antioxidant status, through upregulating the redox sensing transcription factor nuclear factor E2-related factor 2 (Nrf2). Berberine inhibited the bleomycin mediated activation of inflammatory mediator nuclear factor kappa B (NF-κB) and suppressed its downstream target inducible nitric oxide synthase (iNOS). Strikingly, berberine exhibited target attenuation of tumor necrosis factor alpha (TNF-α) and key pro-fibrotic mediator, transforming growth factor beta 1 (TGF-β1). Taken together, this study reveals the beneficial effects of berberine against bleomycin mediated fibrotic challenge through activating Nrf2 and suppressing NF-κB dependent inflammatory and TGF-β1 mediated fibrotic events.

Topics: Animals; Antimetabolites; Berberine; Bleomycin; Blotting, Western; Bronchoalveolar Lavage Fluid; Collagen; Histamine Release; Hydroxyproline; Immunohistochemistry; Lung Diseases; Male; Malondialdehyde; Microscopy, Confocal; NF-E2-Related Factor 2; NF-kappa B; Nitric Oxide Synthase Type II; Nitrites; Oxidative Stress; Peroxidase; Pulmonary Fibrosis; Rats; Rats, Wistar; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Weight Gain

Although IL-17 is a key factor in Th17 lineage host responses and plays critical roles in immunological control of a variety of infectious diseases, the contribution of IL-17 to immune function during Eimeria tenella infection is unknown. In the present study, we used an experimental E. tenella infection model to clarify the role of Th17-associated response in the resulting immune response by quantitative real-time PCR assays. We observed robust production of STAT-3 (the transcription factors), IL-1β, IL-6 and IL-17 in cecal intraepithelial lymphocytes during the early infection, peaking at 6h p.i. and declining thereafter. The expression of TGF-β was moderately upregulated and had 2 peaks at 6 and 72h p.i. during the early infection. To further investigate the role of chIL-17 during the infection, we treated the infected chickens with IL-17 and its neutralized antibody. As a result, the reduced fecal oocyst shedding and cecal lesion scores, but enhanced body weight gains were observed in IL-17 neutralized chickens. The results of histopathology showed that the neutrophils recruitment diminished and the parasite burden in IL-17 neutralized chickens decreased. These results may be due to the significant decrease in the production of IL-17, IL-6 and TGF-β, but enhanced IL-12 and IFN-γ expression in IL-17 neutralized chickens. The converse results were shown in IL-17 treated infected-chickens in which chickens showed increased fecal oocyst shedding, exacerbated lesion scores, and reduced body weight gains. These results suggested that chicken IL-17 might mediate E. tenella - induced immunopathology during the infection.

Topics: Animals; Antibodies, Protozoan; Cecum; Chickens; Cloning, Molecular; Coccidiosis; Eimeria tenella; Feces; Gene Expression Regulation; Interferon-gamma; Interleukin-12; Interleukin-17; Interleukin-1beta; Interleukin-6; Neutrophils; Polymerase Chain Reaction; Poultry Diseases; Rabbits; Recombinant Proteins; Specific Pathogen-Free Organisms; STAT3 Transcription Factor; Th17 Cells; Transforming Growth Factor beta; Weight Gain

In obesity, rapidly expanding adipose tissue becomes hypoxic, precipitating inflammation, fibrosis, and insulin resistance. Compensatory angiogenesis may prevent these events. Mice lacking the intracellular glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1(-/-)) have "healthier" adipose tissue distribution and resist metabolic disease with diet-induced obesity. Here we show that adipose tissues of 11βHSD1(-/-) mice exhibit attenuated hypoxia, induction of hypoxia-inducible factor (HIF-1α) activation of the TGF-β/Smad3/α-smooth muscle actin (α-SMA) signaling pathway, and fibrogenesis despite similar fat accretion with diet-induced obesity. Moreover, augmented 11βHSD1(-/-) adipose tissue angiogenesis is associated with enhanced peroxisome proliferator-activated receptor γ (PPARγ)-inducible expression of the potent angiogenic factors VEGF-A, apelin, and angiopoietin-like protein 4. Improved adipose angiogenesis and reduced fibrosis provide a novel mechanism whereby suppression of intracellular glucocorticoid regeneration promotes safer fat expansion with weight gain.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Actins; Adipokines; Adipose Tissue; Angiopoietin-Like Protein 4; Angiopoietins; Animals; Apelin; Fibrosis; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, Knockout; Neovascularization, Physiologic; Obesity; PPAR gamma; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Weight Gain

Granulocyte colony stimulating factor (G-CSF) has been known to increase neutrophil production and have anti-inflammatory properties, but the effect of G-CSF on pulmonary system is in controversy. We investigated whether G-CSF treatment could attenuate hyperoxia-induced lung injury, and whether this protective effect is mediated by the down-modulation of inflammatory responses in a neonatal rat model.. Newborn Sprague-Dawley rats (Orient Co., Seoul, Korea) were subjected to 14 days of hyperoxia (90% oxygen) beginning within 10 h after birth. G-CSF (20 μg/kg) was administered intraperitoneally on the fourth, fifth, and sixth postnatal days.. This treatment significantly improved hyperoxia-induced reduction in body weight gain and lung pathology such as increased mean linear intercept, mean alveolar volume, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling positive cells. Hyperoxia- induced activation of nicotinamide adenine dinucleotide phosphate oxidase, which is responsible for superoxide anion production, as evidenced by upregulation and membrane translocation of p67(phox) was significantly attenuated after G-CSF treatment, as were inflammatory responses such as increased myeloperoxidase activity and mRNA expression of transforming growth factor-β. However, the attenuation of other proinflammatory cytokines such as tumor necrosis factor-α and interleukin- 6 was not significant.. In sum, G-CSF treatment significantly attenuated hyperoxia-induced lung injury by down-modulating the inflammatory responses in neonatal rats.

Topics: Animals; Animals, Newborn; Blotting, Western; Female; Granulocyte Colony-Stimulating Factor; Hyperoxia; In Situ Nick-End Labeling; Interleukin-6; Lung; Lung Injury; NADPH Oxidases; Peroxidase; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Weight Gain

Evidence for the important role for poly(ADP-ribose) polymerase (PARP) in the pathogenesis of diabetic nephropathy is emerging. We previously reported that PARP inhibitors counteract early Type 1 diabetic nephropathy. This study evaluated the role for PARP in kidney disease in long-term Type 1 diabetes. Control and streptozotocin-diabetic rats were maintained with or without treatment with the PARP inhibitor 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15,427, Eisai Inc.), 30mgkg(-1)d(-1), for 26 weeks after first 2 weeks without treatment. PARP activity in the renal cortex was assessed by Western blot analysis of poly(ADP-ribosyl)ated proteins. Urinary albumin, isoprostane, and 8-hydroxy-2'-deoxyguanosine excretion, and renal concentrations of transforming growth factor-beta(1), vascular endothelial growth factor, soluble intercellular adhesion molecule-1, fibronectin, and nitrotyrosine were evaluated by ELISA, and urinary creatinine and renal lipid peroxidation products by colorimetric assays. PARP inhibition counteracted diabetes-associated increase in renal cortex poly(ADP-ribosyl)ated protein level. Urinary albumin, isoprostane, and 8-hydroxy-2'-deoxyguanosine excretions and urinary albumin/creatinine ratio were increased in diabetic rats, and all these changes were at least partially prevented by GPI-15,427 treatment. PARP inhibition counteracted diabetes-induced renal transforming growth factor-beta(1), vascular endothelial growth factor, and fibronectin, but not soluble intercellular adhesion molecule-1 and nitrotyrosine, accumulations. Lipid peroxidation product concentrations were indistinguishable among control and diabetic rats maintained with or without GPI-15,427 treatment. In conclusion, PARP activation plays an important role in kidney disease in long-term diabetes. These findings provide rationale for development and further studies of PARP inhibitors and PARP inhibitor-containing combination therapies, for prevention and treatment of diabetic nephropathy.

Topics: Albuminuria; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enzyme Inhibitors; Fibronectins; Intercellular Adhesion Molecule-1; Kidney Cortex; Male; Organic Chemicals; Oxidative Stress; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Wistar; Streptozocin; Transforming Growth Factor beta; Weight Gain

In addition to regulating blood pressure and body fluid homeostasis, the renin-angiotensin system is also involved in lung fibrogenesis.. To study the effect of losartan, an angiotensin II antagonist, on bleomycin-induced pulmonary fibrosis in rats and its possible mechanism.. Pulmonary fibrosis was induced in SD rats by intratracheal instillation of bleomycin (5 mg x kg(-1)). Subsequently, the rats received daily losartan (3, 9 and 27 mg x kg(-1)) or prednisone (20 mg x kg(-1)) orally. Six rats in each group were sacrificed 14 and 21 days after intratracheal instillation. Hydroxyproline, superoxide dismutase (SOD), and malondialdehyde (MDA) levels in lung tissues were determined by spectroscopy. The levels of TGF-beta1 in serum were measured by ELISA. Histological changes in the lungs were evaluated by hematoxylin-eosin stain, and scored.. Rat body weight evidently decreased while the indices of lung and hydroxyproline contents in lung tissue were significantly increased 14 and 21 days after intratracheal bleomycin instillation. Inflammatory cell infiltration and fibrotic scores were more prominent in the model group compared to the sham group. Losartan (3, 9 and 27 mg.kg(-1), i.g.) apparently attenuated the degree of pulmonary fibrosis. Further study showed that losartan significantly increased SOD levels while it decreased MDA contents in lung homogenates. Serum TGF-beta1 levels of pulmonary fibrosis rats were also decreased by losartan.. Losartan had an inhibitory effect on bleomycin-induced pulmonary fibrosis, and its effect may be associated with its anti-free radicals and the reduction in TGF-beta1.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antibiotics, Antineoplastic; Bleomycin; Body Weight; Glucocorticoids; Hydroxyproline; Losartan; Lung; Male; Malondialdehyde; Prednisone; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Transforming Growth Factor beta; Transforming Growth Factor beta1; Weight Gain

To determine if myostatin deficiency attenuates body fat gain with increased dietary fat intake.. Normal and myostatin-deficient mice were fed control (8-10 kcal %fat) and high-fat (HF) (45 kcal %fat) diets for a period of 8 weeks, starting at 2 months of age. Body composition, including percent body fat, lean mass, and fat mass, were measured using DXA. Serum adipokines were measured using a Beadlyte assay.. Two-factor ANOVA revealed significant treatment x genotype interactions for body fat (g), percent body fat, and serum leptin. The HF diet significantly increased body fat, percent body fat, and serum leptin in normal mice but not in myostatin-deficient mice.. Loss of myostatin function not only increases muscle mass in animal models but also attenuates the body fat accumulation that usually accompanies an HF diet.

Topics: Adiposity; Animals; Body Composition; Dietary Fats; Genotype; Leptin; Mice; Mice, Knockout; Models, Animal; Muscle, Skeletal; Myostatin; Transforming Growth Factor beta; Weight Gain

The aim of this study was to investigate the effects of a secondary renal insult, due to chronic infusion of AGEs on renal function, and on early pathological markers in rats with a developmental nephron deficit.. Female Wistar-Kyoto rats were fed a low-protein diet (LPD; 8.7% casein) or a normal-protein diet (NPD; 20% casein) during pregnancy and lactation. Nephron number was estimated in 4-week-old female offspring. Male offspring were allowed to grow to 20 weeks of age, when AGEs derived from BSA (AGE-BSA) or BSA was infused subcutaneously (20 mg kg(-1) day(-1)) for 4 weeks. At 24 weeks, blood pressure, renal function and circulating and renal AGEs were assessed. Real-time PCR was used to investigate early molecular markers of renal pathology.. As expected, maternal protein restriction led to reduced nephron endowment in LPD offspring. This alone did not affect blood pressure or lead to hyperfiltration in adulthood. However, when coupled with the secondary renal insult, the expression of the genes encoding transforming growth factor-beta(1) and procollagen III was significantly upregulated in the kidneys. In addition, there was renal accumulation of AGEs in LPD offspring, and this was exacerbated by AGE infusion.. Our results demonstrate that the adult kidney with a reduced nephron endowment is more vulnerable to secondary renal insult from AGE-BSA. Since AGE formation is markedly elevated with hyperglycaemia, our findings suggest that a developmental or acquired deficit may render the kidney susceptible to diabetic renal disease.

Topics: Aging; Animals; Blood Pressure; Chemokine CCL2; Collagen; Disease Susceptibility; Eating; Extracellular Matrix Proteins; Female; Fibronectins; Glycation End Products, Advanced; Glycosylation; Hemoglobins; Kidney Diseases; Male; Molecular Weight; Nephrons; Organ Size; Rats; Rats, Inbred WKY; Transforming Growth Factor beta; Transforming Growth Factor beta1; Weight Gain

The aim of this study is to investigate whether ambroxol inhibits inflammatory responses in a murine model of lipopolysaccharide-induced acute lung injury (ALI).. Mice (n=295) were first intratracheally instilled with lipopolysaccharide (LPS) to induce ALI and then received an intraperitoneal (i.p.) injection of either normal saline (NS), ambroxol (30 or 90 mg/kg per day) or dexamethasone (2.5 or 5 mg/kg per day) for 7 days. Metabolism (n=10, each), lung morphology (n=5, each) and wet-to-dry lung weight ratio (n=10, each) were studied. The levels of tumor necrosis factor (TNF-alpha), interleukin-6 (IL-6) and transforming growth factor (TGF-beta1) and the protein concentration (n=5 or 7, each) in bronchoalveolar lavage (BAL) were measured.. Mice with LPS-induced ALI that were treated with ambroxol at a dosage of 90 mg/kg per day significantly gained weight compared to the control and dexamethasone-treated groups. Ambroxol and dexamethasone significantly reduced the lung hemorrhage, edema, exudation, neutrophil infiltration and total lung injury histology score at 24 and 48 h. In addition, ambroxol and dexamethasone significantly attenuated the lung wet-to-dry weight ratio at 24 and 48 h (p<0.05). Compared to the control group, TNF-alpha, IL-6 and TGF-beta1 levels in the BAL in both ambroxol- and dexamethasone-treated groups were significantly reduced at 24 and 48 h. The protein in BAL, an index of vascular permeability, was also significantly decreased in the ambroxol- and dexamethasone-treated groups (p<0.05).. Ambroxol inhibited proinflammatory cytokines, reduced lung inflammation and accelerated recovery from LPS-induced ALI.

Topics: Ambroxol; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Dexamethasone; Disease Models, Animal; Drug Administration Schedule; Drug Evaluation, Preclinical; Expectorants; Inflammation; Instillation, Drug; Interleukin-6; Lipopolysaccharides; Mice; Organ Size; Proteins; Respiratory Distress Syndrome; Severity of Illness Index; Sodium Chloride; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Weight Gain

Transforming growth factor-beta (TGF-beta) modulates immune/inflammatory cells, promotes extracellular matrix (ECM) accumulation, and is increased in fibrotic organs. Here we report the effects of administering a puromycin aminonucleoside nephropathy (PAN)-specific TGF-beta neutralizing antibody on glomerulosclerosis in vivo.. Adult male Sprague-Dawley rats underwent uninephrectomy (Nx) followed by intraperitoneal PAN at weeks 2, 6, 7 and 8. Rats were treated with either high (5 mg/kg body weight) (N= 9) or low (0.5 mg/kg body weight) (N= 7) dose TGF-beta antibody intraperitoneally three times weekly until sacrifice at week 10. A PAN untreated control group (N= 7) was dosed with an isotype specific, null antibody. The nephrectomy samples were studied as normal kidney control (NL) (N= 5). Rats undergoing left kidney Nx (N= 5) only were also included as age-matched control. Renal function and morphology were assessed, and molecular studies performed.. Systolic blood pressure was increased in parallel over time in all groups (at 10 weeks, control 137 +/- 10 mm Hg; high 129 +/- 4 mm Hg; low 137 +/- 3 mm Hg) (P= NS). Both TGF-beta antibody treatments decreased renal cortex mRNA expressions similarly for TGF-beta1, TGF-beta2, and collagen III (TGF-beta1, control 0.36 +/- 0.02 mm Hg; high 0.19 +/- 0.01 mm Hg; low 0.19 +/- 0.02 mm Hg; P < 0.01 low and high vs. control; TGF-beta2, control 0.38 +/- 0.03 mm Hg; high 0.19 +/- 0.02 mm Hg; low 0.20 +/- 0.03 mm Hg; P < 0.01 low and high vs. control; and collagen III, control 0.33 +/- 0.01 mm Hg; high 0.14 +/- 0.01 mm Hg; low 0.19 +/- 0.01 mm Hg; P < 0.01 low and high vs. control; P < 0.05 low vs. high, data expressed as mRNA normalized density units vs. 18S RNA). However, only low dose TGF-beta antibody improved renal function and sclerosis measured by serum creatinine and creatinine clearance (serum creatinine, control 2.3 +/- 0.5 mg/dL; high 2.5 +/- 0.5 mg/dL; low 0.8 +/- 0.1 mg/dL; P < 0.05 low vs. control and high; creatinine clearance, control 0.44 +/- 0.11 mL/min; high 0.70 +/- 0.26 mL/min; low 1.34 +/- 0.30 mL/min; P < 0.05 low vs. control, P= NS vs. high). In parallel, sclerosis index (0 to 4+ scale) was improved in low dose (control 2.67 +/- 0.27; high 2.37 +/- 0.30; low 1.78 +/- 0.24; P < 0.05 low vs. control). This improved function and structure was linked to decreased glomerular infiltrating macrophages (0 to 4+ score, control 2.3 +/- 0.2; high 1.8 +/- 0.4; low 0.8 +/- 0.1; P < 0.01 low vs. control; P < 0.05 low vs. high; P= NS high vs. control). Further, plasminogen activator inhibitor-1 (PAI-1) mRNA expression in renal cortex was attenuated after low dose TGF-beta antibody treatment compared to control and high dose group (PAI-1/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA ratio, NL 0.18 +/- 0.003; control 0.45 +/- 0.03; high 0.40 +/- 0.04; low 0.23 +/- 0.01; P < 0.05 low vs. control and high). Matrix metalloproteinase-9 (MMP-9) activity was maintained at higher levels in kidneys of the low dose TGF-beta antibody-treated group.. These results show an in vivo dose-response with an agent that blocks the biologic activity of TGF-beta. Higher dose of TGF-beta antibody was without beneficial effect, suggesting that TGF-beta-mediated effects on PAI-1 and macrophage influx are bimodal and closely regulated. Given that both antibody doses reduced the expression of TGF-beta isoforms and collagen III production, but only low dose ameliorated histologic sclerosis, it appears that pharmacologic effects of anti-TGF-beta antibody on matrix synthesis and degradation are not equivalent.

Topics: Animals; Antibiotics, Antineoplastic; Antibodies; Collagen; Creatinine; Dose-Response Relationship, Immunologic; Gene Expression; Glomerulosclerosis, Focal Segmental; Immunotherapy; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Plasminogen Activator Inhibitor 1; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Weight Gain

To determine whether ascorbic acid might be of benefit for the treatment of spontaneous osteoarthritis (OA) when administered over a long period of time.. We investigated the effects of 8 months' exposure to low, medium, and high doses of ascorbic acid on the in vivo development of histologic knee OA in the male Hartley guinea pig. The low dose represented the minimum amount needed to prevent scurvy. The medium dose was the amount present in standard laboratory guinea pig chow and resulted in plasma levels comparable with those achieved in a person consuming 200 mg/day (5 fruits and vegetables daily). The high dose was the amount shown in a previous study of the guinea pig to slow the progression of surgically induced OA.. We found an association between ascorbic acid supplementation and increased cartilage collagen content but, in contrast to findings in a previous study of surgically induced OA in the guinea pig, ascorbic acid worsened the severity of spontaneous OA. Active transforming growth factor beta (TGF beta) was expressed in marginal osteophytes, whose size and number were significantly increased with increasing intake of ascorbic acid. Synovial fluid levels of cartilage oligomeric matrix protein, a biomarker of cartilage turnover, corroborated the histologic findings.. Ascorbic acid has been shown to activate latent TGF beta. Prolonged intraarticular exposure to TGF beta has been shown to cause OA-like changes. We found expression of active TGF beta in osteophytes, a prominent feature of the joint histology seen in association with ascorbic acid treatment. Thus, the deleterious effects of prolonged ascorbic acid exposure may be mediated in part by TGF beta. This worsening of OA with ascorbic acid supplementation suggests that ascorbic acid intake should not be supplemented above the currently recommended dietary allowance (90 mg/day for men and 75 mg/day for women).

Topics: Animals; Antioxidants; Ascorbic Acid; Bone Density; Cartilage; Collagen; Disease Models, Animal; Extracellular Matrix Proteins; Glycoproteins; Guinea Pigs; Least-Squares Analysis; Male; Matrilin Proteins; Osteoarthritis, Knee; Scurvy; Severity of Illness Index; Synovial Fluid; Transforming Growth Factor beta; Weight Gain

Chronic respiratory infections reduce growth in pigs but protein accretion (PA) during an ongoing multifactorial respiratory infection has not been determined, and the mechanisms underlying growth inhibition are largely unknown. The objectives of this study were to determine whether viral and bacterial pneumonia in young pigs decrease PA, increase serum IL-1beta and IL-6, and increase myostatin (MSTN) mRNA in biceps femoris and triceps muscles. Mycoplasma hyopneumoniae (Mh) or medium was given intratracheally at 4 wk of age, Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) or medium was given intranasally at 6 wk of age, and pigs were killed 7 or 14 d after PRRSV inoculation for body composition analysis. PRRSV but not Mh induced a marked increase (P < 0.01) in IL-1beta, IL-6, and MSTN mRNA and a decrease (P < 0.01) in food intake, daily weight gain, PA, and lipid accretion. PRRSV also reduced (P < 0.01) myofiber area in the biceps femoris. Food intake, weight gain, PA, and weight of biceps femoris and triceps muscles were negatively correlated (r = -0.4 to -0.8, P < 0.05) with serum IL-1beta and IL-6 and with MSTN mRNA in muscle. These results suggest that the magnitude of increases in inflammatory cytokines during a respiratory infection may be predictive of decreases in PA and growth. They further suggest that during infection growth of skeletal muscle is limited in part by myostatin.

Topics: Animals; Body Composition; Eating; Gene Expression; Interleukin-1; Interleukin-6; Lipid Metabolism; Muscle Proteins; Muscle, Skeletal; Mycoplasma hyopneumoniae; Myostatin; Organ Size; Pneumonia of Swine, Mycoplasmal; Porcine Reproductive and Respiratory Syndrome; Porcine respiratory and reproductive syndrome virus; Proteins; RNA, Messenger; Swine; Transforming Growth Factor beta; Weight Gain

A T-->A mutation in the promoter region of porcine myostatin (MSTN) gene has been identified in previous work. Associations of the myostatin genotypes with growth traits are unknown in swine. The present study attempts to analyze the relationship of the mutation with the growth traits which included body weight at 60 d (BW60), average daily gain from 25 kg to 60 kg(ADG1), average daily gain from 60 kg to 100 kg (ADG2) and average daily gain from 25 kg to 100 kg (ADG). Data from 165, 275, 276 and 276 unrelated individuals respectively were collected from three different swine breeding companies. Detections of the mutation were carried out by PCR-RFLP approach. The effect of MSTN genotypes (TT and TA) on growth traits was estimated by GLM procedure. The results showed that for ADG2, individuals with TA genotype were higher than those of TT genotype (P = 0.052), indicating a positive effect for A allele. For BW60, ADG1 and ADG, the effect of porcine MSTN genotype was non-significant (P > 0.1). Studies are still necessary for examining the effects in "double-muscled" pigs.

Topics: Alleles; Animals; Body Weight; Genotype; Myostatin; Point Mutation; Promoter Regions, Genetic; Swine; Transforming Growth Factor beta; Weight Gain

To elucidate the pathophysiology of pulmonary fibrosis, we investigated the involvement of p38 mitogen-activated protein kinase (MAPK), which is one of the major signal transduction pathways of proinflammatory cytokines, in a murine model of bleomycin-induced lung fibrosis. p38 MAPK and its substrate, activating transcription factor (ATF)-2, in bronchoalveolar lavage fluid cells were phosphorylated by intratracheal exposure of bleomycin, and the phosphorylation of ATF-2 was inhibited by subcutaneous administration of a specific inhibitor of p38 MAPK, FR-167653. FR-167653 also inhibited augmented expression of tumor necrosis factor -alpha, connective tissue growth factor, and apoptosis of lung cells induced by bleomycin administration. Moreover, daily subcutaneous administration of FR-167653 (from 1 day before to 14 days after bleomycin administration) ameliorated pulmonary fibrosis and pulmonary cachexia induced by bleomycin. These findings demonstrated that p38 MAPK is involved in bleomycin-induced pulmonary fibrosis, and its inhibitor, FR-167653, may be a feasible therapeutic agent.

Topics: Activating Transcription Factor 2; Animals; Antibiotics, Antineoplastic; Bleomycin; Bronchoalveolar Lavage Fluid; Connective Tissue Growth Factor; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Gene Expression; Growth Inhibitors; Growth Substances; Hydroxyproline; Immediate-Early Proteins; In Situ Nick-End Labeling; Injections, Intravenous; Intercellular Signaling Peptides and Proteins; Lung; Male; Mice; Mice, Inbred ICR; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pulmonary Fibrosis; Pyrazoles; Pyridines; RNA, Messenger; Transcription Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Weight Gain

Eight chicken cytokine genes (IL-1beta, IL-2, IL-8, IL-15, IFN-alpha, IFN-gamma, TGF-beta4, lymphotactin) were evaluated for their adjuvant effect on a suboptimal dose of an Eimeria DNA vaccine carrying the 3-1E parasite gene (pcDNA3-1E). Chickens were given two subcutaneous injections with 50 microg of the pcDNA3-1E vaccine plus a cytokine expression plasmid 2 weeks apart and challenged with Eimeria acervulina 1 week later. IFN-alpha (1 microg) or 10 microg of lymphotactin expressing plasmids, when given simultaneously with the pcDNA3-1E vaccine, significantly protected against body weight loss induced by E. acervulina. Parasite replication was significantly reduced in chickens given the pcDNA3-1E vaccine along with 10 microg of the IL-8, lymphotactin, IFN-gamma, IL-15, TGF-beta4, or IL-1beta plasmids compared with chickens given the pcDNA3-1E vaccine alone. Flow cytometric analysis of duodenum intraepithelial lymphocytes showed chickens that received the pcDNA3-1E vaccine simultaneously with the IL-8 or IL-15 genes had significantly increased CD3+ cells compared with vaccination using pcDNA3-1E alone or in combination with the other cytokine genes tested. These results indicate that the type and the dose of cytokine genes injected into chickens influence the quality of the local immune response to DNA vaccination against coccidiosis.

Topics: Adjuvants, Immunologic; Animals; Chickens; Coccidiosis; Drug Evaluation, Preclinical; Duodenum; Eimeria; Genetic Vectors; Interferon-alpha; Interferon-gamma; Interferons; Interleukin-1; Interleukin-15; Interleukin-2; Interleukin-8; Interleukins; Lymphokines; Parasite Egg Count; Poultry Diseases; Sialoglycoproteins; Specific Pathogen-Free Organisms; Transforming Growth Factor beta; Vaccination; Vaccines, DNA; Weight Gain

Little is known as to how hepatectomy is associated with the growth of hepatic tumours, which may reside in the remaining liver after curative resection for hepatocellular carcinoma. Using an intra-hepatic tumour implantation model in rats, the effects of hepatectomy on tumour growth in the remaining liver were investigated. On post-operative day 7, the tumour weight in the remaining liver following 30% hepatectomy was 0.321+/-0.058 g (mean +/- SD) which was significantly greater than that (0.245+/-0.040 g) in sham operations (P<0.05). However, the tumour weight (0.156+/-0.067 g) in the remaining liver following 60% hepatectomy was significantly lower than that in sham animals (P< 0.005). The number of TdT-mediated dUTP nick-end labelling (TUNEL) positive tumour cells was significantly increased in 60% hepatectomy as compared with the sham and 30% hepatectomy group. The mRNA expression of TGF-beta1, TNF-alpha and Fas in the tumour portion of 60% hepatectomy, was higher than that in 30% hepatectomy group. Plasma levels of TGF-beta1 were inversely correlated with intra-hepatic tumour weights. These results suggest that major hepatic resection may lead to an increased induction of apoptosis for the remaining hepatic tumour.

Topics: Animals; Apoptosis; Cell Division; Disease Models, Animal; Fas Ligand Protein; fas Receptor; Hepatectomy; Liver; Liver Neoplasms, Experimental; Liver Regeneration; Male; Membrane Glycoproteins; Rats; Rats, Inbred Strains; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Weight Gain

Oxidative stress and the fibrogenic cytokine transforming growth factor beta 1 (TGF beta 1) have been implicated in the pathogenesis and progression of IgA nephropathy. In the present study, we used alpha-tocopherol as a dietary supplement to test the hypothesis that the proteinuria, oxidative stress, and TGF beta mRNA can be more effectively lowered with higher doses of alpha-tocopherol. Hematuria, proteinuria, and mesangial IgA deposition are parameters which characterize IgA nephropathy. IgA nephropathy was induced by bovine gamma globulin oral immunization in rats during an 8-week course, and all hallmarks of IgA nephropathy were produced in this 8-week animal model. The elevation in renal malondialdehyde content and TGF beta 1 mRNA, as well as the severity of proteinuria, was blunted by alpha-tocopherol. Our data suggested that conventional dosage of alpha-tocopherol at 100 IU/kg chow lowered kidney TGF beta 1 to control values and increasing the dose by 2 1/2-fold or even 5-fold resulted in no further reduction in TGF beta 1 mRNA. Significant reduction of proteinuria was achieved better with a dose of 250 IU/kg chow of alpha-tocopherol supplementation than with the 100 IU/kg chow. We conclude that alpha-tocopherol at this dose is efficacious in controlling proteinuria, downregulating TGF beta 1, and reducing oxidative stress in experimental IgA nephropathy. Doubling this dose achieved no further benefits.

Topics: Animals; Blotting, Northern; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Glomerulonephritis, IGA; Male; Malondialdehyde; Oxidative Stress; Proteinuria; Rats; Rats, Inbred Lew; RNA, Messenger; Transforming Growth Factor beta; Vitamin E; Weight Gain

Null-mutant (knockout) mice were obtained through disruption of the sixth exon of the endogenous transforming growth factor-beta 1 allele in murine embryonic stem cells via homologous recombination. Mice lacking transforming growth factor-beta 1 (mutants) were born grossly indistinguishable from wild-type littermates. With time, mutant mice exhibited a wasting phenotype that manifested itself in severe weight loss and dishevelled appearance (between 15 and 36 days of age). Examination of these moribund mice histologically revealed that transforming growth factor-beta 1-deficient mice exhibit a moderate to severe, multifocal, organ-dependent, mixed inflammatory cell response adversely affecting the heart, stomach, diaphragm, liver, lung, salivary gland, and pancreas. Because of the known multifunctional nature of transforming growth factor-beta 1 on the control of growth and differentiation of many different cell types, it is important to determine the degree to which the inflammatory response interacts with or masks other deficiencies that are present. To this end, we examined the extent and nature of the inflammatory lesions in different ages of neonatal knockout mice (5, 7, 10, and 14 days of age) and older moribund mice (> 15 days of age) and compared them with the histology seen in wild-type normal animals. Mild inflammatory infiltrates were first observed in 5-day mutant mice in the heart, by day 7 in the lung, salivary gland, and pancreas, and by day 14 inflammatory lesions were found in almost all organs examined. Moderate to severe inflammation was not present until the mice were 10 to 14 days old. In the older animals, there was a slight increase in the severity of the inflammatory lesions as the mice aged.

Topics: Animals; Base Sequence; Disease Models, Animal; Flow Cytometry; Genotype; Inflammation; Mice; Mice, Knockout; Molecular Sequence Data; Transforming Growth Factor beta; Weight Gain