ABSTRACT
OBJECTIVE: Chronic inflammation has been recognized as having a prominent role pathogenesis of benign prostatic hyperplasia (BPH) and cancer. It is believed that chronic inflammation induces prostatic fibromuscular growth. This correlation has been clearly illustrated by both in vivo and in vitro studies; however, current experimental models of BPH require complex surgery or hormonal treatment. Therefore, the aim of the present study was to propose a new murine model of BPH/prostatitis induced by intraurethral injection of LPS. METHODS: Male Swiss and C57Bl/6 mice were then sacrificed 3, 7, 10, and 14 days after intraurethral injection of LPS. The prostates were quickly dissected and fixed for morphological and immunohistochemical analyses. RESULTS: The results showed that LPS played an important role in the cell proliferation of the prostate. Histological and ultrastructural analysis showed epithelial hyperplasia, clear stromal cells, little inflammatory infiltration, and heavy bleeding. Treatment with LPS also promoted the increase of growth factor (FGF-7 and TGF-ß), α-actin, and proinflammatory cytokines (IL-1, IL-6, IL-17), both in the stroma and epithelium. CONCLUSION: According to the present findings, it can be concluded that the intraurethral administration of LPS promotes tissue remodeling, as well as stimulating the pattern of pro-inflammatory cytokines, and therefore, constitutes an effective experimental model of BPH/inflammation.
Subject(s)
Inflammation/chemically induced , Lipopolysaccharides/toxicity , Prostate/drug effects , Prostatic Hyperplasia/chemically induced , Animals , Cytokines/immunology , Disease Models, Animal , Fibroblast Growth Factor 7/immunology , Inflammation/immunology , Inflammation/pathology , Injections , Male , Mice, Inbred C57BL , Prostate/immunology , Prostate/pathology , Prostatic Hyperplasia/immunology , Prostatic Hyperplasia/pathology , UrethraABSTRACT
The present study demonstrated the potential effects of diethylcarbamazine (DEC) on monocrotaline (MCT)-induced pulmonary hypertension. MCT solution (600mg/kg) was administered once per week, and 50mg/kg body weight of DEC for 28days. Three C57Bl/6 male mice groups (n=10) were studied: Control; MCT28, and MCT28/DEC. Echocardiography analysis was performed and lung tissues were collected for light microscopy (hematoxylin-eosin and Masson's trichrome staining), immunohistochemistry (αSMA, FADD, caspase 8, caspase 3, BAX, BCL2, cytochrome C and caspase 9) western blot (FADD, caspase 8, caspase 3, BAX, BCL2, cytochrome C and caspase 9) and qRt-PCR (COL-1α and αSMA). Echocardiography analysis demonstrated an increase in the pulmonary arterial blood flow gradient and velocity in the systole and RV area in the MCT28 group, while treatment with DEC resulted in a significant reduction in these parameters. Deposition of collagen fibers and αSMA staining around the pulmonary arteries was evident in the MCT28 group, while treatment with DEC reduced both. Western blot analysis revealed a decrease in BMPR2 in the MCT28 group, in contrast DEC treatment resulted in a significant increase in the level of BMPR2. DEC also significantly reduced the level of VEGF compared to the MCT28 group. Apoptosis extrinsic and intrinsic pathway markers were reduced in the MCT28 group. After treatment with DEC these levels returned to baseline. The results of this study indicate that DEC attenuates PH in an experimental monocrotaline-induced model by inhibiting a series of markers involved in cell proliferation/death.
Subject(s)
Diethylcarbamazine/therapeutic use , Hypertension, Pulmonary/drug therapy , Actins/genetics , Animals , Apoptosis/drug effects , Apoptosis Regulatory Proteins/metabolism , Bone Morphogenetic Protein Receptors, Type II/metabolism , Collagen Type I/genetics , Diethylcarbamazine/pharmacology , Hypertension, Pulmonary/chemically induced , Hypertension, Pulmonary/pathology , Hypertension, Pulmonary/physiopathology , Hypertrophy, Right Ventricular/chemically induced , Hypertrophy, Right Ventricular/drug therapy , Hypertrophy, Right Ventricular/pathology , Hypertrophy, Right Ventricular/physiopathology , Lung/drug effects , Lung/metabolism , Lung/pathology , Lung/physiopathology , Male , Mice, Inbred C57BL , Monocrotaline , Pulmonary Artery/drug effects , Pulmonary Artery/pathology , Ventricular Function, Left/drug effectsABSTRACT
BACKGROUND: Acute lung injury (ALI) is characterized by extensive neutrophil infiltration, and apoptosis delay considered part of the pathogenesis of the condition. Despite great advances in treatment strategies, few effective therapies are known for ALI. Diethylcarbamazine (DEC) is used against lymphatic filariasis, a number of studies have described its anti-inflammatory activities and pro-apoptotic effect. These properties have been associated with nuclear factor kappa-B inactivation. The aim of the present study was to investigate the effect of DEC on ALI induced by lipopolysaccharide (LPS) in mice. METHODS: DEC effect was evaluated by histological and ultrastructural analysis, immunohistochemistry and western blot (WB). Also TUNEL assays were performed and as well as myeloperoxidase (MPO) levels and nitric oxide (NO) were measured. RESULTS: The results demonstrate that LPS induced histological and ultrastructural changes with tissue damage, intense cell infiltration and pulmonary edema, and also increased levels of MPO and NO. DEC reversed these effects, confirming its anti-inflammatory action. DEC pro-apoptotic activity was also evaluated. The expression of TUNEL-positive cells and caspase-3 was increased in DEC treated group. Furthermore, immunohistochemical and WB analysis showed that DEC increased the expression of pro-apoptotic proteins in both the intrinsic (Bax, cytochrome c and caspase-9) and the extrinsic pathways of apoptosis (Fas, FADD and caspase-8). Additionally, DEC reduced the expression of the anti-apoptotic protein Bcl-2. CONCLUSION: Our results suggest that DEC attenuates ALI through the prevention of inflammatory cells accumulation by stimulating apoptosis. DEC accelerates the resolution of inflammation and may be a potential pharmacological treatment for ALI.
Subject(s)
Acute Lung Injury/prevention & control , Apoptosis/drug effects , Diethylcarbamazine/therapeutic use , Inflammation Mediators/antagonists & inhibitors , Lipopolysaccharides/toxicity , Acute Lung Injury/chemically induced , Acute Lung Injury/metabolism , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Apoptosis/physiology , Diethylcarbamazine/pharmacology , Inflammation/chemically induced , Inflammation/metabolism , Inflammation/prevention & control , Inflammation Mediators/metabolism , Male , Mice , Mice, Inbred C57BLABSTRACT
BACKGROUND: Atherosclerosis is a complex disorder with a multifactorial pathogenesis. We previously indicated that the new TZD LPSF/GQ-02 inhibits hepatic steatosis and inflammation, which are reported as risk factors for atherosclerosis development. Here, we explored the effects of LPSF/GQ-02 on atherosclerosis in LDLr-/- mice comparing two treatment periods. METHODS AND RESULTS: LDLr-/- mice were fed a high-fat diet for 10 and 12 weeks and received oral treatment with LPSF/GQ-02 (30mg/kg/day) or pioglitazone (20mg/kg/day) for 15 and 30 days, respectively. Both treatment protocols with LPSF/GQ-02 resulted in lower collagen density in the atherosclerotic lesions. In addition, the treatment for 15 days also decreased mRNA levels of CD40, MCP-1, ABCG1 and upregulated PPARα, whereas the 30-days treatment reduced the protein levels of LOX-1, p-IκBα and p-NFκB. CONCLUSION: This study provides evidence that LPSF/GQ-02 affects the composition and growth of atherosclerotic lesions in LDLr-/- mice. Moreover, our data also support previous findings showing anti-inflammatory properties of LPSF/GQ-02 and reinforce the therapeutic potential of this TZD for treating atherosclerosis and inflammation-related disorders.