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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 and immunohistochemistry of day 7 DSS-treated wild-type and HAS3  rectal sections. Cross-section images from Figures 6 and 7 were enlarged to show detail with the following tissue regions marked as follows: (E) epithelium, (Lp) lamina propria, (Mm) muscularis mucosae, (Sm) submucosae, (V) blood vessels, (Me) muscularis externa, and (L) leukocytes. The luminal muscularis mucosa and submucosae boundary are marked in yellow dashed line.
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fig8: Histology and immunohistochemistry of day 7 DSS-treated wild-type and HAS3 rectal sections. Cross-section images from Figures 6 and 7 were enlarged to show detail with the following tissue regions marked as follows: (E) epithelium, (Lp) lamina propria, (Mm) muscularis mucosae, (Sm) submucosae, (V) blood vessels, (Me) muscularis externa, and (L) leukocytes. The luminal muscularis mucosa and submucosae boundary are marked in yellow dashed line.

Mentions: Enlargements of the images from 7-day DSS treatment of wild-type and HAS3 mice are presented in Figure 8 and they display strikingly different tissue structure. Firstly, observing from the intestinal lumen downward, the lamina propria (Lp) of wild-type animals has lost all epithelium (E) as well as crypt architecture, and infiltrating leukocytes are prevalent in this tissue area (Figure 8(a)). In the HAS3 section (Figure 8(c)), the epithelium and crypt architecture are largely maintained in the lamina propria, and very little increase in the population of infiltrating leukocytes is noted. Secondly, while the muscularis mucosa (Mm) is slightly expanded in the HAS3 animals, it does not achieve the overall thickness observed in the wild-type group. Thirdly, the submucosa (Sm) of the wild-type mouse colon is vastly expanded compared to the HAS3 tissue and contains many more and thicker walled blood vessels (V). Strikingly, there is also a much greater presence of infiltrating leukocytes (L) in the submucosal space of the wild-type mouse colon than in the HAS3 tissue (Figure 8(a) versus Figure 8(c)). HA deposition within the inflamed and highly vascularized submucosa region of the wild-type sections is tremendously increased compared to either day 7 treated HAS3 section (Figure 8(b) versus Figure 8(d)) or the untreated wild-type control (Figure 7). The absence of numerous expanded blood vessels and reduced hyaluronan deposition in the HAS3 submucosa may explain why a leukocyte infiltrate is minor in these mice at day 7.


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 and immunohistochemistry of day 7 DSS-treated wild-type and HAS3  rectal sections. Cross-section images from Figures 6 and 7 were enlarged to show detail with the following tissue regions marked as follows: (E) epithelium, (Lp) lamina propria, (Mm) muscularis mucosae, (Sm) submucosae, (V) blood vessels, (Me) muscularis externa, and (L) leukocytes. The luminal muscularis mucosa and submucosae boundary are marked in yellow dashed line.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig8: Histology and immunohistochemistry of day 7 DSS-treated wild-type and HAS3 rectal sections. Cross-section images from Figures 6 and 7 were enlarged to show detail with the following tissue regions marked as follows: (E) epithelium, (Lp) lamina propria, (Mm) muscularis mucosae, (Sm) submucosae, (V) blood vessels, (Me) muscularis externa, and (L) leukocytes. The luminal muscularis mucosa and submucosae boundary are marked in yellow dashed line.
Mentions: Enlargements of the images from 7-day DSS treatment of wild-type and HAS3 mice are presented in Figure 8 and they display strikingly different tissue structure. Firstly, observing from the intestinal lumen downward, the lamina propria (Lp) of wild-type animals has lost all epithelium (E) as well as crypt architecture, and infiltrating leukocytes are prevalent in this tissue area (Figure 8(a)). In the HAS3 section (Figure 8(c)), the epithelium and crypt architecture are largely maintained in the lamina propria, and very little increase in the population of infiltrating leukocytes is noted. Secondly, while the muscularis mucosa (Mm) is slightly expanded in the HAS3 animals, it does not achieve the overall thickness observed in the wild-type group. Thirdly, the submucosa (Sm) of the wild-type mouse colon is vastly expanded compared to the HAS3 tissue and contains many more and thicker walled blood vessels (V). Strikingly, there is also a much greater presence of infiltrating leukocytes (L) in the submucosal space of the wild-type mouse colon than in the HAS3 tissue (Figure 8(a) versus Figure 8(c)). HA deposition within the inflamed and highly vascularized submucosa region of the wild-type sections is tremendously increased compared to either day 7 treated HAS3 section (Figure 8(b) versus Figure 8(d)) or the untreated wild-type control (Figure 7). The absence of numerous expanded blood vessels and reduced hyaluronan deposition in the HAS3 submucosa may explain why a leukocyte infiltrate is minor in these mice at day 7.

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