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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

Plasma levels of FXIII are a sensitive biomarker of colitis in mice.(A) Plasma FXIII activity in unchallenged WT mice and DSS-challenged WT and FXIII−/− mice. Plasma samples were collected for analysis 7 days following withdrawal from an initial 7 day DSS-challenge. Note that FXIII activity was significantly lower in DSS-challenged WT mice than unchallenged controls, even well into the colitis resolution phase (* P < 0.0001, Mann Whitney U test). Predictably, no FXIII activity was detectable in plasma prepared from FXIII−/− mice. Data were normalized to the unchallenged WT cohort. (B) Plasma FXIII activity in WT mice 7 days after withdrawal of DSS inversely correlated with residual colitis activity as assessed by the histopathology score (R2 = 0.63, P < 0.05).
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pone.0128113.g004: Plasma levels of FXIII are a sensitive biomarker of colitis in mice.(A) Plasma FXIII activity in unchallenged WT mice and DSS-challenged WT and FXIII−/− mice. Plasma samples were collected for analysis 7 days following withdrawal from an initial 7 day DSS-challenge. Note that FXIII activity was significantly lower in DSS-challenged WT mice than unchallenged controls, even well into the colitis resolution phase (* P < 0.0001, Mann Whitney U test). Predictably, no FXIII activity was detectable in plasma prepared from FXIII−/− mice. Data were normalized to the unchallenged WT cohort. (B) Plasma FXIII activity in WT mice 7 days after withdrawal of DSS inversely correlated with residual colitis activity as assessed by the histopathology score (R2 = 0.63, P < 0.05).

Mentions: Previous studies have suggested that decreased plasma levels of FXIII may be a useful biomarker in patients with inflammatory bowel disease [26–29]. In order to determine if plasma FXIII activity in mice recovering from experimental colitis correlates with the presence of disease, FXIII activity in plasma from WT and FXIII−/− mice (included as a control) 7 days after DSS withdrawal was compared with values from unchallenged mice of both genotypes. As expected, there was no measurable FXIII activity in plasma harvested from either DSS-challenged or unchallenged FXIII−/− mice (Fig 4A and data not shown). Plasma FXIII activity was significantly decreased in DSS-challenged WT mice relative to unchallenged WT animals (Fig 4A). Moreover, FXIII levels in the DSS-challenged WT mice inversely correlated with disease severity as assessed by histological parameters (Fig 4B). Lower plasma FXIII levels appeared to be particularly predictive of the presence of mucosal ulceration. Only 1 of 4 DSS challenged WT mice with plasma FXIII activity levels > 60% had any histological evidence of ulceration, whereas all of the mice with plasma FXIII activity levels of <60% (5 of 5) manifested some degrees of mucosal ulceration (P < 0.05, Fisher’s exact test, two tailed). The inverse correlation of FXIII levels with residual mucosal damage in DSS-challenged mice suggests that increasing FXIII activity could improve mucosal healing in experimental colitis.


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)

Plasma levels of FXIII are a sensitive biomarker of colitis in mice.(A) Plasma FXIII activity in unchallenged WT mice and DSS-challenged WT and FXIII−/− mice. Plasma samples were collected for analysis 7 days following withdrawal from an initial 7 day DSS-challenge. Note that FXIII activity was significantly lower in DSS-challenged WT mice than unchallenged controls, even well into the colitis resolution phase (* P < 0.0001, Mann Whitney U test). Predictably, no FXIII activity was detectable in plasma prepared from FXIII−/− mice. Data were normalized to the unchallenged WT cohort. (B) Plasma FXIII activity in WT mice 7 days after withdrawal of DSS inversely correlated with residual colitis activity as assessed by the histopathology score (R2 = 0.63, P < 0.05).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0128113.g004: Plasma levels of FXIII are a sensitive biomarker of colitis in mice.(A) Plasma FXIII activity in unchallenged WT mice and DSS-challenged WT and FXIII−/− mice. Plasma samples were collected for analysis 7 days following withdrawal from an initial 7 day DSS-challenge. Note that FXIII activity was significantly lower in DSS-challenged WT mice than unchallenged controls, even well into the colitis resolution phase (* P < 0.0001, Mann Whitney U test). Predictably, no FXIII activity was detectable in plasma prepared from FXIII−/− mice. Data were normalized to the unchallenged WT cohort. (B) Plasma FXIII activity in WT mice 7 days after withdrawal of DSS inversely correlated with residual colitis activity as assessed by the histopathology score (R2 = 0.63, P < 0.05).
Mentions: Previous studies have suggested that decreased plasma levels of FXIII may be a useful biomarker in patients with inflammatory bowel disease [26–29]. In order to determine if plasma FXIII activity in mice recovering from experimental colitis correlates with the presence of disease, FXIII activity in plasma from WT and FXIII−/− mice (included as a control) 7 days after DSS withdrawal was compared with values from unchallenged mice of both genotypes. As expected, there was no measurable FXIII activity in plasma harvested from either DSS-challenged or unchallenged FXIII−/− mice (Fig 4A and data not shown). Plasma FXIII activity was significantly decreased in DSS-challenged WT mice relative to unchallenged WT animals (Fig 4A). Moreover, FXIII levels in the DSS-challenged WT mice inversely correlated with disease severity as assessed by histological parameters (Fig 4B). Lower plasma FXIII levels appeared to be particularly predictive of the presence of mucosal ulceration. Only 1 of 4 DSS challenged WT mice with plasma FXIII activity levels > 60% had any histological evidence of ulceration, whereas all of the mice with plasma FXIII activity levels of <60% (5 of 5) manifested some degrees of mucosal ulceration (P < 0.05, Fisher’s exact test, two tailed). The inverse correlation of FXIII levels with residual mucosal damage in DSS-challenged mice suggests that increasing FXIII activity could improve mucosal healing in experimental colitis.

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