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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

Change in body weight during DSS-induced colitis. (a) Groups of 6 or more adult mice of each indicated genotype were provided with 2.5% DSS in their drinking water for up to 10 days. Body weight measured at days 3, 5, 7, and 10 was compared to starting weight at day 0 for each mouse. The data points reflect the average change in body weight with error bars representing ±SEM. (b) Significance of day 7 weight loss of genotypes compared to the wild-type group: ∗∗∗P < 0.0001, ∗∗P < 0.005, and  ∗P < 0.05 in Student's unpaired t-test, 95% confidence. One-way ANOVA test for the mean weight loss compared for all groups #P < 0.005.
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fig1: Change in body weight during DSS-induced colitis. (a) Groups of 6 or more adult mice of each indicated genotype were provided with 2.5% DSS in their drinking water for up to 10 days. Body weight measured at days 3, 5, 7, and 10 was compared to starting weight at day 0 for each mouse. The data points reflect the average change in body weight with error bars representing ±SEM. (b) Significance of day 7 weight loss of genotypes compared to the wild-type group: ∗∗∗P < 0.0001, ∗∗P < 0.005, and  ∗P < 0.05 in Student's unpaired t-test, 95% confidence. One-way ANOVA test for the mean weight loss compared for all groups #P < 0.005.

Mentions: To test our hypothesis that HA is a key molecule that drives inflammation in the gut during intestinal inflammation, we treated mice that were for either HAS1 or HAS3 or both HAS1/HAS3 in the experimental DSS-colitis model. Weight loss is a reliable and accepted measure of disease activity in this model [22, 25]. Figure 1 illustrates that all genotypes, except the HAS1 mice, gain a small amount (1–3%) of body weight during the first three days of DSS treatment. Continued exposure to DSS, however, causes dramatic weight loss in the wild-type group between day 5 and day 7 but is less severe in the three HAS groups, on these days. While all three groups were protected from weight loss at all time points compared to wild-type mice, the HAS3 group lost significantly (P < 0.0001) less body weight by day 7 (Figure 1(b)). Although the mean weight loss measured between HAS3 and HA1 groups is notable, it approached but did not fully reach statistical significance at day 7 time point. HAS3 mice lost an average of less than 5% bodyweight compared to the average loss of 11% by the wild-type group. We focused on day 7 time point because this is the time point where the most dramatic changes in disease progression occur, although the animals continue to lose weight through day 10 and are variably distressed.


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)

Change in body weight during DSS-induced colitis. (a) Groups of 6 or more adult mice of each indicated genotype were provided with 2.5% DSS in their drinking water for up to 10 days. Body weight measured at days 3, 5, 7, and 10 was compared to starting weight at day 0 for each mouse. The data points reflect the average change in body weight with error bars representing ±SEM. (b) Significance of day 7 weight loss of genotypes compared to the wild-type group: ∗∗∗P < 0.0001, ∗∗P < 0.005, and  ∗P < 0.05 in Student's unpaired t-test, 95% confidence. One-way ANOVA test for the mean weight loss compared for all groups #P < 0.005.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig1: Change in body weight during DSS-induced colitis. (a) Groups of 6 or more adult mice of each indicated genotype were provided with 2.5% DSS in their drinking water for up to 10 days. Body weight measured at days 3, 5, 7, and 10 was compared to starting weight at day 0 for each mouse. The data points reflect the average change in body weight with error bars representing ±SEM. (b) Significance of day 7 weight loss of genotypes compared to the wild-type group: ∗∗∗P < 0.0001, ∗∗P < 0.005, and  ∗P < 0.05 in Student's unpaired t-test, 95% confidence. One-way ANOVA test for the mean weight loss compared for all groups #P < 0.005.
Mentions: To test our hypothesis that HA is a key molecule that drives inflammation in the gut during intestinal inflammation, we treated mice that were for either HAS1 or HAS3 or both HAS1/HAS3 in the experimental DSS-colitis model. Weight loss is a reliable and accepted measure of disease activity in this model [22, 25]. Figure 1 illustrates that all genotypes, except the HAS1 mice, gain a small amount (1–3%) of body weight during the first three days of DSS treatment. Continued exposure to DSS, however, causes dramatic weight loss in the wild-type group between day 5 and day 7 but is less severe in the three HAS groups, on these days. While all three groups were protected from weight loss at all time points compared to wild-type mice, the HAS3 group lost significantly (P < 0.0001) less body weight by day 7 (Figure 1(b)). Although the mean weight loss measured between HAS3 and HA1 groups is notable, it approached but did not fully reach statistical significance at day 7 time point. HAS3 mice lost an average of less than 5% bodyweight compared to the average loss of 11% by the wild-type group. We focused on day 7 time point because this is the time point where the most dramatic changes in disease progression occur, although the animals continue to lose weight through day 10 and are variably distressed.

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