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Hyaluronan Synthase 3 Null Mice Exhibit Decreased Intestinal Inflammation and Tissue Damage in the DSS-Induced Colitis Model.

Kessler SP, Obery DR, de la Motte C - Int J Cell Biol (2015)

Bottom Line: Hyaluronan (HA) overproduction is a hallmark of multiple inflammatory diseases, including inflammatory bowel disease (IBD).Therefore, we hypothesized that, during a pathologic challenge, HA promotes inflammation.Our data suggest, HAS3 plays a crucial role in driving gut inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology, Lerner Research Institute Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

ABSTRACT
Hyaluronan (HA) overproduction is a hallmark of multiple inflammatory diseases, including inflammatory bowel disease (IBD). Hyaluronan can act as a leukocyte recruitment molecule and in the most common mouse model of intestinal inflammation, the chemically induced dextran sodium sulfate (DSS) experimental colitis model, we previously determined that changes in colon distribution of HA occur before inflammation. Therefore, we hypothesized that, during a pathologic challenge, HA promotes inflammation. In this study, we tested the progression of inflammation in mice for the hyaluronan synthase genes (HAS1, HAS3, or both HAS1 and HAS3) in the DSS-colitis model. Our data demonstrate that both the HAS1/HAS3 double and the HAS3 mice are protected from colitis, compared to wild-type and HAS1 mice, as determined by measurement of weight loss, disease activity, serum IL-6 levels, histologic scoring, and immunohistochemistry. Most notable is the dramatic increase in submucosal microvasculature, hyaluronan deposition, and leukocyte infiltration in the inflamed colon tissue of wild-type and HAS1 mice. Our data suggest, HAS3 plays a crucial role in driving gut inflammation. Developing a temporary targeted therapeutic intervention of HAS3 expression or function in the microcirculation may emerge as a desirable strategy toward tempering colitis in patients undergoing flares of IBD.

No MeSH data available.


Related in: MedlinePlus

Disease activity index (DAI) during DSS-induced colitis. (a) All mice were observed for outward signs of disease including weight loss, hunched posture, ruffled fur, bloody stools, and rectum prolapse. Data bars reflect the average of six or more mice per time point for each genotype with error bars set at the ±SEM. (b) DAI at day 7. Significance of day 7 weight loss of genotypes compared to the wild-type groups: ∗∗∗P < 0.002 and ∗P < 0.05 in a Mann-Whitney nonparametric unpaired t-test, 95% confidence.
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fig2: Disease activity index (DAI) during DSS-induced colitis. (a) All mice were observed for outward signs of disease including weight loss, hunched posture, ruffled fur, bloody stools, and rectum prolapse. Data bars reflect the average of six or more mice per time point for each genotype with error bars set at the ±SEM. (b) DAI at day 7. Significance of day 7 weight loss of genotypes compared to the wild-type groups: ∗∗∗P < 0.002 and ∗P < 0.05 in a Mann-Whitney nonparametric unpaired t-test, 95% confidence.

Mentions: In addition to weight loss, 2.5% DSS-treated c57B/6 background strain wild-type mice typically exhibit rectal bleeding between day 5 and day 7 with stools becoming soft and loose to the point of being liquid by day 10. At day 10, mouse fur can take on a ruffled appearance as the mice display reduced motility and adopt a hunched posture. We therefore noted this disease activity (DAI) by assigning points by following a previously reported scoring index as described in the methods section, based on weight loss, ruffled fur, hunched posture, rectal bleeding, bloody stools, and rectal prolapse [21]. Our data revealed that the HAS3 mice displayed the lowest disease activity score at all time points (Figure 2(a)) compared to the other three groups. Comparing the DAI at day 7, we observed that HAS1 mice were more severely affected compared to wild-type mice (P < 0.05) while both HAS3 and HAS1/HAS3 mice were significantly more protected (P < 0.002 and P < 0.05, resp.) (Figure 2(b)). Another associated marker of colitis scoring for this model is colon shortening. During the progression of disease, overall colon length shortens from 9.5–10 cm in untreated mice to approximately 5.5–6 cm in wild-type mice treated with DSS for 10 days. Figure 3 illustrates the shortening of the colon in all genotypes over the course of the DSS treatment with HAS3 mice retaining the most colon length at day 7 (P < 0.05) and day 10 (P < 0.001) time points, respectively.


Hyaluronan Synthase 3 Null Mice Exhibit Decreased Intestinal Inflammation and Tissue Damage in the DSS-Induced Colitis Model.

Kessler SP, Obery DR, de la Motte C - Int J Cell Biol (2015)

Disease activity index (DAI) during DSS-induced colitis. (a) All mice were observed for outward signs of disease including weight loss, hunched posture, ruffled fur, bloody stools, and rectum prolapse. Data bars reflect the average of six or more mice per time point for each genotype with error bars set at the ±SEM. (b) DAI at day 7. Significance of day 7 weight loss of genotypes compared to the wild-type groups: ∗∗∗P < 0.002 and ∗P < 0.05 in a Mann-Whitney nonparametric unpaired t-test, 95% confidence.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4581575&req=5

fig2: Disease activity index (DAI) during DSS-induced colitis. (a) All mice were observed for outward signs of disease including weight loss, hunched posture, ruffled fur, bloody stools, and rectum prolapse. Data bars reflect the average of six or more mice per time point for each genotype with error bars set at the ±SEM. (b) DAI at day 7. Significance of day 7 weight loss of genotypes compared to the wild-type groups: ∗∗∗P < 0.002 and ∗P < 0.05 in a Mann-Whitney nonparametric unpaired t-test, 95% confidence.
Mentions: In addition to weight loss, 2.5% DSS-treated c57B/6 background strain wild-type mice typically exhibit rectal bleeding between day 5 and day 7 with stools becoming soft and loose to the point of being liquid by day 10. At day 10, mouse fur can take on a ruffled appearance as the mice display reduced motility and adopt a hunched posture. We therefore noted this disease activity (DAI) by assigning points by following a previously reported scoring index as described in the methods section, based on weight loss, ruffled fur, hunched posture, rectal bleeding, bloody stools, and rectal prolapse [21]. Our data revealed that the HAS3 mice displayed the lowest disease activity score at all time points (Figure 2(a)) compared to the other three groups. Comparing the DAI at day 7, we observed that HAS1 mice were more severely affected compared to wild-type mice (P < 0.05) while both HAS3 and HAS1/HAS3 mice were significantly more protected (P < 0.002 and P < 0.05, resp.) (Figure 2(b)). Another associated marker of colitis scoring for this model is colon shortening. During the progression of disease, overall colon length shortens from 9.5–10 cm in untreated mice to approximately 5.5–6 cm in wild-type mice treated with DSS for 10 days. Figure 3 illustrates the shortening of the colon in all genotypes over the course of the DSS treatment with HAS3 mice retaining the most colon length at day 7 (P < 0.05) and day 10 (P < 0.001) time points, respectively.

Bottom Line: Hyaluronan (HA) overproduction is a hallmark of multiple inflammatory diseases, including inflammatory bowel disease (IBD).Therefore, we hypothesized that, during a pathologic challenge, HA promotes inflammation.Our data suggest, HAS3 plays a crucial role in driving gut inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology, Lerner Research Institute Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

ABSTRACT
Hyaluronan (HA) overproduction is a hallmark of multiple inflammatory diseases, including inflammatory bowel disease (IBD). Hyaluronan can act as a leukocyte recruitment molecule and in the most common mouse model of intestinal inflammation, the chemically induced dextran sodium sulfate (DSS) experimental colitis model, we previously determined that changes in colon distribution of HA occur before inflammation. Therefore, we hypothesized that, during a pathologic challenge, HA promotes inflammation. In this study, we tested the progression of inflammation in mice for the hyaluronan synthase genes (HAS1, HAS3, or both HAS1 and HAS3) in the DSS-colitis model. Our data demonstrate that both the HAS1/HAS3 double and the HAS3 mice are protected from colitis, compared to wild-type and HAS1 mice, as determined by measurement of weight loss, disease activity, serum IL-6 levels, histologic scoring, and immunohistochemistry. Most notable is the dramatic increase in submucosal microvasculature, hyaluronan deposition, and leukocyte infiltration in the inflamed colon tissue of wild-type and HAS1 mice. Our data suggest, HAS3 plays a crucial role in driving gut inflammation. Developing a temporary targeted therapeutic intervention of HAS3 expression or function in the microcirculation may emerge as a desirable strategy toward tempering colitis in patients undergoing flares of IBD.

No MeSH data available.


Related in: MedlinePlus