Limits...
Factor XIII Transglutaminase Supports the Resolution of Mucosal Damage in Experimental Colitis.

Andersson C, Kvist PH, McElhinney K, Baylis R, Gram LK, Pelzer H, Lauritzen B, Holm TL, Hogan S, Wu D, Turpin B, Miller W, Palumbo JS - PLoS ONE (2015)

Bottom Line: The thrombin-activated transglutaminase factor XIII (FXIII) that covalently crosslinks and stablizes provisional fibrin matrices is also thought to support endothelial and epithelial barrier function and to control inflammatory processes.The most striking differences were seen in the resolution of mucosal ulceration, the most severe histopathological manifestation of DSS-induced colitis.These findings directly demonstrate that FXIII is a significant determinant of mucosal healing and clinical outcome following inflammatory colitis induced mucosal injury and provide a proof-of-principle that clinical interventions supporting FXIII activity may be a means to limit colitis pathology and improve resolution of mucosal damage.

View Article: PubMed Central - PubMed

Affiliation: Novo Nordisk A/S, Biopharmaceutical Research Unit, Copenhagen, Denmark.

ABSTRACT
The thrombin-activated transglutaminase factor XIII (FXIII) that covalently crosslinks and stablizes provisional fibrin matrices is also thought to support endothelial and epithelial barrier function and to control inflammatory processes. Here, gene-targeted mice lacking the FXIII catalytic A subunit were employed to directly test the hypothesis that FXIII limits colonic pathologies associated with experimental colitis. Wildtype (WT) and FXIII-/- mice were found to be comparable in their initial development of mucosal damage following exposure to dextran sulfate sodium (DSS) challenge. However, unlike FXIII-sufficient mice, FXIII-deficient cohorts failed to efficiently resolve colonic inflammatory pathologies and mucosal damage following withdrawal of DSS. Consistent with prior evidence of ongoing coagulation factor activation and consumption in individuals with active colitis, plasma FXIII levels were markedly decreased in colitis-challenged WT mice. Treatment of colitis-challenged mice with recombinant human FXIII-A zymogen significantly mitigated weight loss, intestinal bleeding, and diarrhea, regardless of whether cohorts were FXIII-sufficient or were genetically devoid of FXIII. Similarly, both qualitative and quantitative microscopic analyses of colonic tissues revealed that exogenous FXIII improved the resolution of multiple colitis disease parameters in both FXIII-/- and WT mice. The most striking differences were seen in the resolution of mucosal ulceration, the most severe histopathological manifestation of DSS-induced colitis. These findings directly demonstrate that FXIII is a significant determinant of mucosal healing and clinical outcome following inflammatory colitis induced mucosal injury and provide a proof-of-principle that clinical interventions supporting FXIII activity may be a means to limit colitis pathology and improve resolution of mucosal damage.

No MeSH data available.


Related in: MedlinePlus

Genetic elimination of FXIII prolongs colitis symptoms.FXIII−/− mice (◯) challenged with DSS develop significantly worse clinical signs of disease relative to WT mice (●) based on a multiparameter Disease Activity Index score (A) and weight loss (B). Note that body mass continued to decline in FXIII−/− mice even after DSS was withdrawn, whereas body mass stabilized and improved in WT animals during this period. P values were generated with a 2 way ANOVA, n = 10 mice per cohort.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4476663&req=5

pone.0128113.g001: Genetic elimination of FXIII prolongs colitis symptoms.FXIII−/− mice (◯) challenged with DSS develop significantly worse clinical signs of disease relative to WT mice (●) based on a multiparameter Disease Activity Index score (A) and weight loss (B). Note that body mass continued to decline in FXIII−/− mice even after DSS was withdrawn, whereas body mass stabilized and improved in WT animals during this period. P values were generated with a 2 way ANOVA, n = 10 mice per cohort.

Mentions: In order to directly determine if FXIII plays a role in the development and resolution of experimental colitis in vivo, FXIII-A deficient (FXIII−/−) and WT littermate control mice were enrolled in colitis studies initiated by dextran sulfate sodium (DSS)-induced mucosal damage. The animals were monitored closely throughout the study period using a clinical scoring system based on weight loss, fecal consistency and blood in feces, generating a total disease activity index (DAI, see Methods for details). A worsening in clinical disease characteristics (increase in DAI) was apparent in FXIII−/− mice relative to WT mice by the end of the 7 day DSS challenge period, which was driven primarily by differences in intestinal bleeding (Fig 1A). Dissecting the DAI looking only at intestinal bleeding it was evident that by day 5 of the study, 7 of 10 FXIII−/− mice exhibited intestinal hemorrhage (5 with occult blood in stool and 2 with overtly bloody stools). In contrast, none of the 10 WT mice challenged in parallel exhibited evidence of intestinal bleeding at this early time point (P < 0.001, Fisher’s exact test). There was also a trend toward more weight loss in the FXIII−/− cohort within the window of DSS challenge, but this did not reach statistical significance within this 7 day timeframe (Fig 1B). However, FXIII−/− mice showed persistent intestinal hemorrhage as well as continued weight loss after withdrawal of the DSS challenge and the return to normal drinking water (Fig 1B). This resulted in a persistently high overall DAI score following the withdrawal of DSS in FXIII−/− mice (Fig 1A). In contrast, WT mice quickly showed a cessation of intestinal bleeding, diarrhea and weight loss when transitioned to normal water, resulting in both a significantly lower and an ultimately declining DAI score following DSS withdrawal compared to FXIII−/− mice. These experiments were completed twice with similar results.


Factor XIII Transglutaminase Supports the Resolution of Mucosal Damage in Experimental Colitis.

Andersson C, Kvist PH, McElhinney K, Baylis R, Gram LK, Pelzer H, Lauritzen B, Holm TL, Hogan S, Wu D, Turpin B, Miller W, Palumbo JS - PLoS ONE (2015)

Genetic elimination of FXIII prolongs colitis symptoms.FXIII−/− mice (◯) challenged with DSS develop significantly worse clinical signs of disease relative to WT mice (●) based on a multiparameter Disease Activity Index score (A) and weight loss (B). Note that body mass continued to decline in FXIII−/− mice even after DSS was withdrawn, whereas body mass stabilized and improved in WT animals during this period. P values were generated with a 2 way ANOVA, n = 10 mice per cohort.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476663&req=5

pone.0128113.g001: Genetic elimination of FXIII prolongs colitis symptoms.FXIII−/− mice (◯) challenged with DSS develop significantly worse clinical signs of disease relative to WT mice (●) based on a multiparameter Disease Activity Index score (A) and weight loss (B). Note that body mass continued to decline in FXIII−/− mice even after DSS was withdrawn, whereas body mass stabilized and improved in WT animals during this period. P values were generated with a 2 way ANOVA, n = 10 mice per cohort.
Mentions: In order to directly determine if FXIII plays a role in the development and resolution of experimental colitis in vivo, FXIII-A deficient (FXIII−/−) and WT littermate control mice were enrolled in colitis studies initiated by dextran sulfate sodium (DSS)-induced mucosal damage. The animals were monitored closely throughout the study period using a clinical scoring system based on weight loss, fecal consistency and blood in feces, generating a total disease activity index (DAI, see Methods for details). A worsening in clinical disease characteristics (increase in DAI) was apparent in FXIII−/− mice relative to WT mice by the end of the 7 day DSS challenge period, which was driven primarily by differences in intestinal bleeding (Fig 1A). Dissecting the DAI looking only at intestinal bleeding it was evident that by day 5 of the study, 7 of 10 FXIII−/− mice exhibited intestinal hemorrhage (5 with occult blood in stool and 2 with overtly bloody stools). In contrast, none of the 10 WT mice challenged in parallel exhibited evidence of intestinal bleeding at this early time point (P < 0.001, Fisher’s exact test). There was also a trend toward more weight loss in the FXIII−/− cohort within the window of DSS challenge, but this did not reach statistical significance within this 7 day timeframe (Fig 1B). However, FXIII−/− mice showed persistent intestinal hemorrhage as well as continued weight loss after withdrawal of the DSS challenge and the return to normal drinking water (Fig 1B). This resulted in a persistently high overall DAI score following the withdrawal of DSS in FXIII−/− mice (Fig 1A). In contrast, WT mice quickly showed a cessation of intestinal bleeding, diarrhea and weight loss when transitioned to normal water, resulting in both a significantly lower and an ultimately declining DAI score following DSS withdrawal compared to FXIII−/− mice. These experiments were completed twice with similar results.

Bottom Line: The thrombin-activated transglutaminase factor XIII (FXIII) that covalently crosslinks and stablizes provisional fibrin matrices is also thought to support endothelial and epithelial barrier function and to control inflammatory processes.The most striking differences were seen in the resolution of mucosal ulceration, the most severe histopathological manifestation of DSS-induced colitis.These findings directly demonstrate that FXIII is a significant determinant of mucosal healing and clinical outcome following inflammatory colitis induced mucosal injury and provide a proof-of-principle that clinical interventions supporting FXIII activity may be a means to limit colitis pathology and improve resolution of mucosal damage.

View Article: PubMed Central - PubMed

Affiliation: Novo Nordisk A/S, Biopharmaceutical Research Unit, Copenhagen, Denmark.

ABSTRACT
The thrombin-activated transglutaminase factor XIII (FXIII) that covalently crosslinks and stablizes provisional fibrin matrices is also thought to support endothelial and epithelial barrier function and to control inflammatory processes. Here, gene-targeted mice lacking the FXIII catalytic A subunit were employed to directly test the hypothesis that FXIII limits colonic pathologies associated with experimental colitis. Wildtype (WT) and FXIII-/- mice were found to be comparable in their initial development of mucosal damage following exposure to dextran sulfate sodium (DSS) challenge. However, unlike FXIII-sufficient mice, FXIII-deficient cohorts failed to efficiently resolve colonic inflammatory pathologies and mucosal damage following withdrawal of DSS. Consistent with prior evidence of ongoing coagulation factor activation and consumption in individuals with active colitis, plasma FXIII levels were markedly decreased in colitis-challenged WT mice. Treatment of colitis-challenged mice with recombinant human FXIII-A zymogen significantly mitigated weight loss, intestinal bleeding, and diarrhea, regardless of whether cohorts were FXIII-sufficient or were genetically devoid of FXIII. Similarly, both qualitative and quantitative microscopic analyses of colonic tissues revealed that exogenous FXIII improved the resolution of multiple colitis disease parameters in both FXIII-/- and WT mice. The most striking differences were seen in the resolution of mucosal ulceration, the most severe histopathological manifestation of DSS-induced colitis. These findings directly demonstrate that FXIII is a significant determinant of mucosal healing and clinical outcome following inflammatory colitis induced mucosal injury and provide a proof-of-principle that clinical interventions supporting FXIII activity may be a means to limit colitis pathology and improve resolution of mucosal damage.

No MeSH data available.


Related in: MedlinePlus