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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

Histology of rectal sections from DSS-treated mice. (a) Representative rectal images of hematoxylin and eosin stained cross-sections from mice of each genotype sacrificed on the indicated DSS treatment time point at 10x magnification (scale bar = 200 um). Images captured with a Leica digital brightfield microscope and the Leica application software (LAS). (b) Submucosal swelling of the rectal longitudinal folds (dashed line) in the images presented in panel (a) was measured (area μm2) using ImageProPlus software. The untreated wild-type rectal section illustrates the region measured (yellow).
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fig6: Histology of rectal sections from DSS-treated mice. (a) Representative rectal images of hematoxylin and eosin stained cross-sections from mice of each genotype sacrificed on the indicated DSS treatment time point at 10x magnification (scale bar = 200 um). Images captured with a Leica digital brightfield microscope and the Leica application software (LAS). (b) Submucosal swelling of the rectal longitudinal folds (dashed line) in the images presented in panel (a) was measured (area μm2) using ImageProPlus software. The untreated wild-type rectal section illustrates the region measured (yellow).

Mentions: Histological analysis, utilizing a scoring system described previously [22, 23], is a valuable tool to semi-quantitatively assess the damage in the colon tissue during experimentally induced colitis events as it is to assess the extent of tissue injury observed in tissues surgically removed from IBD patients. Hematoxylin and eosin (H&E) stained rectal sections (the site where colitis begins in this model) from mice sacrificed at each time point were observed and scored for epithelial erosion/crypt damage, submucosal swelling, leukocyte infiltration, muscularis mucosae hyperplasia, and increased angiogenesis using the point system described in the methods. Representative tissue sections are presented in Figure 6. As the length of time mice exposed to DSS increased, the average colitis scores for all genotype groups also increased (Figure 5(a)). However, a distinct and dramatic separation occurs when comparing the HAS3 group (colitis score 10.5) to wild-type mice (colitis score 16.5) at day 7 (P < 0.005), while there is no difference in the mean score comparison between wild-type and HAS1 mice at day 7 (Figure 5(b)). The HAS1/3 group score is lower than the wild-type group score and approaches but does not fully meet statistical significance at this day 7 time point. At day 10 time point, the difference is even more pronounced and demonstrates the decrease in colitis severity when the HAS3 enzyme is absent, both in the HAS3 and the HAS1/3 groups (Figure 5(a)).


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)

Histology of rectal sections from DSS-treated mice. (a) Representative rectal images of hematoxylin and eosin stained cross-sections from mice of each genotype sacrificed on the indicated DSS treatment time point at 10x magnification (scale bar = 200 um). Images captured with a Leica digital brightfield microscope and the Leica application software (LAS). (b) Submucosal swelling of the rectal longitudinal folds (dashed line) in the images presented in panel (a) was measured (area μm2) using ImageProPlus software. The untreated wild-type rectal section illustrates the region measured (yellow).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig6: Histology of rectal sections from DSS-treated mice. (a) Representative rectal images of hematoxylin and eosin stained cross-sections from mice of each genotype sacrificed on the indicated DSS treatment time point at 10x magnification (scale bar = 200 um). Images captured with a Leica digital brightfield microscope and the Leica application software (LAS). (b) Submucosal swelling of the rectal longitudinal folds (dashed line) in the images presented in panel (a) was measured (area μm2) using ImageProPlus software. The untreated wild-type rectal section illustrates the region measured (yellow).
Mentions: Histological analysis, utilizing a scoring system described previously [22, 23], is a valuable tool to semi-quantitatively assess the damage in the colon tissue during experimentally induced colitis events as it is to assess the extent of tissue injury observed in tissues surgically removed from IBD patients. Hematoxylin and eosin (H&E) stained rectal sections (the site where colitis begins in this model) from mice sacrificed at each time point were observed and scored for epithelial erosion/crypt damage, submucosal swelling, leukocyte infiltration, muscularis mucosae hyperplasia, and increased angiogenesis using the point system described in the methods. Representative tissue sections are presented in Figure 6. As the length of time mice exposed to DSS increased, the average colitis scores for all genotype groups also increased (Figure 5(a)). However, a distinct and dramatic separation occurs when comparing the HAS3 group (colitis score 10.5) to wild-type mice (colitis score 16.5) at day 7 (P < 0.005), while there is no difference in the mean score comparison between wild-type and HAS1 mice at day 7 (Figure 5(b)). The HAS1/3 group score is lower than the wild-type group score and approaches but does not fully meet statistical significance at this day 7 time point. At day 10 time point, the difference is even more pronounced and demonstrates the decrease in colitis severity when the HAS3 enzyme is absent, both in the HAS3 and the HAS1/3 groups (Figure 5(a)).

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