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Temporal and spatial analysis of clinical and molecular parameters in dextran sodium sulfate induced colitis.

Yan Y, Kolachala V, Dalmasso G, Nguyen H, Laroui H, Sitaraman SV, Merlin D - PLoS ONE (2009)

Bottom Line: The MPO value, as inflammation indicator, also increases significantly at all periods of DSS treatment, and even after DSS withdrawal, it still held at very high levels.The production of proinflammatory mediators by colonic mucosa were enhanced during DSS treatment, and then recovered to pre-treated level after DSS withdrawal.Finally, enhanced expression of proinflammatory mediators also revealed a different profile feature in proximal and distal parts of the colon.

View Article: PubMed Central - PubMed

Affiliation: Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA. yyan2@emory.edu

ABSTRACT

Background: Inflammatory bowel diseases (IBD), including mainly ulcerative colitis (UC) and Crohn's disease (CD), are inflammatory disorders of the gastrointestinal tract caused by an interplay of genetic and environmental factors. Murine colitis model induced by Dextran Sulfate Sodium (DSS) is an animal model of IBD that is commonly used to address the pathogenesis of IBD as well as to test efficacy of therapies. In this study we systematically analyzed clinical parameters, histological changes, intestinal barrier properties and cytokine profile during the colitic and recovery phase.

Methods: C57BL/6 mice were administered with 3.5% of DSS in drinking water for various times. Clinical and histological features were determined using standard criteria. Myeloperoxidase (MPO) activity, transepithelial permeability and proinflammatory mediators were determined in whole colon or proximal and distal parts of colon.

Results: As expected after administration of DSS, mice manifest loss of body weight, shortening of colon length and bloody feces. Histological manifestations included shortening and loss of crypts, infiltration of lymphocytes and neutrophil, symptoms attenuated after DSS withdrawal. The MPO value, as inflammation indicator, also increases significantly at all periods of DSS treatment, and even after DSS withdrawal, it still held at very high levels. Trans-mucosal permeability increased during DSS treatment, but recovered to almost control level after DSS withdrawal. The production of proinflammatory mediators by colonic mucosa were enhanced during DSS treatment, and then recovered to pre-treated level after DSS withdrawal. Finally, enhanced expression of proinflammatory mediators also revealed a different profile feature in proximal and distal parts of the colon.

Conclusion: Experimental colitis induced by DSS is a good animal model to study the mechanisms underlying the pathogenesis and intervention against IBD, especially UC.

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Related in: MedlinePlus

5 days of DSS treatment stimulates the production of proinflammatory cytokines differently in proximal and distal parts of colon.After DSS treatment, the production of cytokines TNF-α, IL-1β, IL-6, IL-10, IL-12, IFN-γ and chemokines KC and MIP-2 increases both in proximal and distal parts of colon. But the increasing folds of TNF-α is higher in proximal colon than that in distal colon, the increasing folds of IL-1β, IL-10 and KC are almost same in both proximal and distal colon. There are higher folds increases in distal colon than in proximal colon for IL-6, IL-12, IFN-γ and chemokine MIP-2. But the normalized cycles thresholds (NCT) are always lower in distal colon than in proximal colon which means higher absolute production of these mediators in distal part than in proximal parts of the colon. I: Water drinking mice proximal colon, II: DSS treated mice proximal colon, III: Water drinking mice distal colon, IV: DSS treated mice distal colon. * P<0.05, ** P<0.01.
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pone-0006073-g007: 5 days of DSS treatment stimulates the production of proinflammatory cytokines differently in proximal and distal parts of colon.After DSS treatment, the production of cytokines TNF-α, IL-1β, IL-6, IL-10, IL-12, IFN-γ and chemokines KC and MIP-2 increases both in proximal and distal parts of colon. But the increasing folds of TNF-α is higher in proximal colon than that in distal colon, the increasing folds of IL-1β, IL-10 and KC are almost same in both proximal and distal colon. There are higher folds increases in distal colon than in proximal colon for IL-6, IL-12, IFN-γ and chemokine MIP-2. But the normalized cycles thresholds (NCT) are always lower in distal colon than in proximal colon which means higher absolute production of these mediators in distal part than in proximal parts of the colon. I: Water drinking mice proximal colon, II: DSS treated mice proximal colon, III: Water drinking mice distal colon, IV: DSS treated mice distal colon. * P<0.05, ** P<0.01.

Mentions: In order to understand the cytokine expression in histologically affected distal colon compared to relatively uninvolved proximal colon, we performed real time PCR of pro-inflammatory cytokines for samples from proximal and distal colon. As shown in Fig. 7, with the DSS treatment, the expression of proinflammatory cytokines IL-1β, TNF-α, IFN-γ, IL-6, IL-10, IL-12 and chemokine KC and MIP-2 increase significantly in comparison in samples from control mice both in the proximal and distal colon. Although the absolute increases of these cytokines mRNA were higher in the distal colon than those for the samples from proximal colon, especially IL-1β and IL-6 production made ∼30-fold increase, as reported previously [23]; MIP-2 and IFN-γ increase around 20 times of their control levels; IL-10 and IL-12 expression were enhanced up to 4 times, the proximal colon demonstrated significant increases in these cytokines. IL-6 mRNA increases more than 10 times, IL-1β and IFN-γ increase 5 times of control levels; however, IL-10 and MIP-2 only demonstrated two-fold increases of their production, but no increase IL-12 transcript was detected. TNF-a showed dramatic fold increase in the proximal colon compared to distal colon although the absolute level of this cytokine was higher in the distal colon (Fig. 7).


Temporal and spatial analysis of clinical and molecular parameters in dextran sodium sulfate induced colitis.

Yan Y, Kolachala V, Dalmasso G, Nguyen H, Laroui H, Sitaraman SV, Merlin D - PLoS ONE (2009)

5 days of DSS treatment stimulates the production of proinflammatory cytokines differently in proximal and distal parts of colon.After DSS treatment, the production of cytokines TNF-α, IL-1β, IL-6, IL-10, IL-12, IFN-γ and chemokines KC and MIP-2 increases both in proximal and distal parts of colon. But the increasing folds of TNF-α is higher in proximal colon than that in distal colon, the increasing folds of IL-1β, IL-10 and KC are almost same in both proximal and distal colon. There are higher folds increases in distal colon than in proximal colon for IL-6, IL-12, IFN-γ and chemokine MIP-2. But the normalized cycles thresholds (NCT) are always lower in distal colon than in proximal colon which means higher absolute production of these mediators in distal part than in proximal parts of the colon. I: Water drinking mice proximal colon, II: DSS treated mice proximal colon, III: Water drinking mice distal colon, IV: DSS treated mice distal colon. * P<0.05, ** P<0.01.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2698136&req=5

pone-0006073-g007: 5 days of DSS treatment stimulates the production of proinflammatory cytokines differently in proximal and distal parts of colon.After DSS treatment, the production of cytokines TNF-α, IL-1β, IL-6, IL-10, IL-12, IFN-γ and chemokines KC and MIP-2 increases both in proximal and distal parts of colon. But the increasing folds of TNF-α is higher in proximal colon than that in distal colon, the increasing folds of IL-1β, IL-10 and KC are almost same in both proximal and distal colon. There are higher folds increases in distal colon than in proximal colon for IL-6, IL-12, IFN-γ and chemokine MIP-2. But the normalized cycles thresholds (NCT) are always lower in distal colon than in proximal colon which means higher absolute production of these mediators in distal part than in proximal parts of the colon. I: Water drinking mice proximal colon, II: DSS treated mice proximal colon, III: Water drinking mice distal colon, IV: DSS treated mice distal colon. * P<0.05, ** P<0.01.
Mentions: In order to understand the cytokine expression in histologically affected distal colon compared to relatively uninvolved proximal colon, we performed real time PCR of pro-inflammatory cytokines for samples from proximal and distal colon. As shown in Fig. 7, with the DSS treatment, the expression of proinflammatory cytokines IL-1β, TNF-α, IFN-γ, IL-6, IL-10, IL-12 and chemokine KC and MIP-2 increase significantly in comparison in samples from control mice both in the proximal and distal colon. Although the absolute increases of these cytokines mRNA were higher in the distal colon than those for the samples from proximal colon, especially IL-1β and IL-6 production made ∼30-fold increase, as reported previously [23]; MIP-2 and IFN-γ increase around 20 times of their control levels; IL-10 and IL-12 expression were enhanced up to 4 times, the proximal colon demonstrated significant increases in these cytokines. IL-6 mRNA increases more than 10 times, IL-1β and IFN-γ increase 5 times of control levels; however, IL-10 and MIP-2 only demonstrated two-fold increases of their production, but no increase IL-12 transcript was detected. TNF-a showed dramatic fold increase in the proximal colon compared to distal colon although the absolute level of this cytokine was higher in the distal colon (Fig. 7).

Bottom Line: The MPO value, as inflammation indicator, also increases significantly at all periods of DSS treatment, and even after DSS withdrawal, it still held at very high levels.The production of proinflammatory mediators by colonic mucosa were enhanced during DSS treatment, and then recovered to pre-treated level after DSS withdrawal.Finally, enhanced expression of proinflammatory mediators also revealed a different profile feature in proximal and distal parts of the colon.

View Article: PubMed Central - PubMed

Affiliation: Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA. yyan2@emory.edu

ABSTRACT

Background: Inflammatory bowel diseases (IBD), including mainly ulcerative colitis (UC) and Crohn's disease (CD), are inflammatory disorders of the gastrointestinal tract caused by an interplay of genetic and environmental factors. Murine colitis model induced by Dextran Sulfate Sodium (DSS) is an animal model of IBD that is commonly used to address the pathogenesis of IBD as well as to test efficacy of therapies. In this study we systematically analyzed clinical parameters, histological changes, intestinal barrier properties and cytokine profile during the colitic and recovery phase.

Methods: C57BL/6 mice were administered with 3.5% of DSS in drinking water for various times. Clinical and histological features were determined using standard criteria. Myeloperoxidase (MPO) activity, transepithelial permeability and proinflammatory mediators were determined in whole colon or proximal and distal parts of colon.

Results: As expected after administration of DSS, mice manifest loss of body weight, shortening of colon length and bloody feces. Histological manifestations included shortening and loss of crypts, infiltration of lymphocytes and neutrophil, symptoms attenuated after DSS withdrawal. The MPO value, as inflammation indicator, also increases significantly at all periods of DSS treatment, and even after DSS withdrawal, it still held at very high levels. Trans-mucosal permeability increased during DSS treatment, but recovered to almost control level after DSS withdrawal. The production of proinflammatory mediators by colonic mucosa were enhanced during DSS treatment, and then recovered to pre-treated level after DSS withdrawal. Finally, enhanced expression of proinflammatory mediators also revealed a different profile feature in proximal and distal parts of the colon.

Conclusion: Experimental colitis induced by DSS is a good animal model to study the mechanisms underlying the pathogenesis and intervention against IBD, especially UC.

Show MeSH
Related in: MedlinePlus