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Inflammatory Bowel Disease

发布时间 2018-02-02
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Inflammatory Bowel Disease


Introduction


Inflammatory bowel disease (IBD) is a chronic relapsing and remitting inflammatory condition of the gastrointestinal tract that is usually manifest as 1 of 2 distinct, but sometimes overlapping clinical entities; ulcerative colitis (UC) and Crohn’s disease (CD). While CD is a multifocal, transmural inflammatory process that can affect any part of the digestive tract, UC is characterized by a superficial, continuous inflammation, which is limited to the large intestine. IBD is most commonly diagnosed between the third Inflammatory Bowel Diseaseand fourth decade of life, with no difference noted between males and females.

Until recently, the clinical treatments for UC and CD are relatively limited, essentially comprising of 5-aminosalicylic acid (ASA) compounds, steroids and azathioprine/ 6-mercaptopurine. In the 1990s, immunoregulatory agents used in IBD were expanded to include methotrexate and cyclosporine in select patient populations. The approval of infliximab (Remicade; Centocor), a chimeric monoclonal antibody directed against tumor-necrosis factor-α (TNFα), for the treatment of CD in 1998 by the FDA launched the era of biologic therapy for IBD.


PharmaLegacy Models and Research Tools



IBD models can be either induced or spontaneously occurring in animals. Models including: (i) Animals treated with agents that promote intestinal inflammation, (ii) Rodents that have been genetically manipulated (iii) Immunodeficient animals. As the onset of inflammation is immediate and the procedure is relatively straightforward, chemically induced models of intestinal inflammation have become the most commonly used IBD animal models. At PharmaLegacy we have validated a complete set of IBD models in rodents.



             Model

DNBS induced colitisOxazolone induced colitisDSS induced colitis
             AnimalSJL/J miceWistar ratsSJL/J miceC57BL/6 mice

         Humandisease

                               CD
UCUC

 

         Pathogenesis

 

A Th1-polarized type of T-cell response

A Th2-polarized type of response

Th1 and Th2 cells play a pathogenic role in the chronic phase
       Clinical symptoms

           Weight loss, loose stool/diarrhea, hematochezia (mice), colon shortening


             Pathology    

               change

Leukocyte infiltration associated with deep chronic ulceration; Submucosal edema; Inflammation involving the entire length of the bowelProminent mucosal and submucosal leukocyte infiltration associated with ulceration; Severe damage of the epithelial cell layer and crypts; Submucosal edema; Inflammation confined to the distal segment of the colon
         1° Endpoints

Colonic weight, colonic length, colonic damage score, body weight change.

         2° EndpointsHistopathology;Immunohistochemistry;Cytokines/Chemokine  Analysis; T  cell  proliferation; Infiltration cell types

*DNBS =dinitrobenzene sulfonic acid*DSS = dextran-sulfate sodium



Related Capabilities



*Antigen-specific T-cell responses

*Detection of tissue cytokine levels (protein, mRNA) by ELISA or real time RT-PCR

*Histopathology and immunohistochemistry changes in colonic tissues

*Flow cytometry analysis of cell functions including intracellular staining of cytokines

*Detection of signal transduction by western blot



Case Study - DNBS Induced IBD in Wistar Rats


Inhibitory effect of sulfasalazine on DNBS induced IBD in Wistar rats

Male Wistar rats (150−160 g) were used in the study. Colitis was induced by intracolonic administration of 0.5 mL DNBS in 30% ethanol. Animals were then treated orally with 300 mg/kg sulfasalazine-1 once daily for 7 days. An equal volume of 30% ethanol was administered as the control. Animals were sacrificed 2 hrs after the last dose.


Group

    Ulcer area  Colon weight  Body weight  Colon length                        Ratio

       (cm2)        (g)             (g)               (cm)          CW/CL/BW x1000

 IR

(%)


    Ration

CW/CL/BW x100


IR

(%) 

Control0.13±0.131.31±0.05196.02±2.7816.19±0.44    0.423±0.03
0.67±0.03
DNBS 50mg/ml2.36±0.790.71±0.13*182.43±4.3013.09±0.35    0.73±0.07**
0.95±0.09
Sulfasalazine -10.77±0.481.39±0.08183.05±4.9613.63±0.69    0.59±0.07  46%0.77±0.0765%

                                                                                                                                              (*p<0.05, **p<0.01 vs Control group by Student's t-test)



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