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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

Lack of FXIII results in a failure to resolve colonic damage after DSS exposure.(A) Colon lengths observed in cohorts of WT and FXIII−/− mice 7 days after withdrawal of DSS (n = 10 per cohort). Note that colons were significantly shorter in FXIII−/− mice (consistent with more severe lingering disease) in comparison to WT mice. (B) Representative H&E-stained section of colon tissue harvested from a WT mouse 7 days after DSS withdrawal demonstrated substantial resolution of DSS-induced colitis in this time frame. Note the generally intact mucosa with mild inflammation, and occasional crypt loss and crypt spacing (triangle). (C) In contrast, colons harvested from FXIII−/− mice typically had large areas of ulceration (arrowheads) and inflammatory submucosal edema (*). (D-E) Representative immunohistochemical analyses of fibrin(ogen) deposition (detected by brown staining) within colon tissue sections harvest from WT (D) and FXIII−/− mice (E) 7 days after withdrawal of the DSS challenge. Note that interstitial fibrin(ogen) was minimal in the well-resolved colonic mucosa of WT mice; indeed, the trace fibrin(ogen) detected was generally not appreciably different from that observed in unchallenged WT mice (F). In contrast, interstitial fibrin(ogen) deposits were readily observed in the colons of FXIII−/− mice a full week after withdrawal of DSS, and were particularly intense in the numerous areas of lingering severe mucosal damage. Size bars represent 50 μm. (G-I) Colons harvested from FXIII−/− mice (white bars) had more severe microscopic features of disease relative to WT mice (black bars) in the resolution phase 7 days after withdrawal of DSS challenge based on comparative analyses of histopathology scores evaluating key individual (G) and combined (H) disease scores (n = 10 per cohort). (I) Shown are results of direct microscopic measurement of mucosal ulceration as a percentage of colon length (n = 10 per cohort). * P < 0.01, all P values were generated with a Mann-Whitney U test.
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pone.0128113.g003: Lack of FXIII results in a failure to resolve colonic damage after DSS exposure.(A) Colon lengths observed in cohorts of WT and FXIII−/− mice 7 days after withdrawal of DSS (n = 10 per cohort). Note that colons were significantly shorter in FXIII−/− mice (consistent with more severe lingering disease) in comparison to WT mice. (B) Representative H&E-stained section of colon tissue harvested from a WT mouse 7 days after DSS withdrawal demonstrated substantial resolution of DSS-induced colitis in this time frame. Note the generally intact mucosa with mild inflammation, and occasional crypt loss and crypt spacing (triangle). (C) In contrast, colons harvested from FXIII−/− mice typically had large areas of ulceration (arrowheads) and inflammatory submucosal edema (*). (D-E) Representative immunohistochemical analyses of fibrin(ogen) deposition (detected by brown staining) within colon tissue sections harvest from WT (D) and FXIII−/− mice (E) 7 days after withdrawal of the DSS challenge. Note that interstitial fibrin(ogen) was minimal in the well-resolved colonic mucosa of WT mice; indeed, the trace fibrin(ogen) detected was generally not appreciably different from that observed in unchallenged WT mice (F). In contrast, interstitial fibrin(ogen) deposits were readily observed in the colons of FXIII−/− mice a full week after withdrawal of DSS, and were particularly intense in the numerous areas of lingering severe mucosal damage. Size bars represent 50 μm. (G-I) Colons harvested from FXIII−/− mice (white bars) had more severe microscopic features of disease relative to WT mice (black bars) in the resolution phase 7 days after withdrawal of DSS challenge based on comparative analyses of histopathology scores evaluating key individual (G) and combined (H) disease scores (n = 10 per cohort). (I) Shown are results of direct microscopic measurement of mucosal ulceration as a percentage of colon length (n = 10 per cohort). * P < 0.01, all P values were generated with a Mann-Whitney U test.

Mentions: In contrast to the similarities in overall disease severity observed immediately following 7 days of DSS exposure, significant FXIII-dependent differences in colonic tissue damage were observed in mice 7 days after the withdrawal of the DSS challenge, effectively in the colitis injury “resolution phase.” Here, colons harvested from FXIII−/− mice 7 days after DSS withdrawal were significantly shorter than those harvested from DSS-challenged WT mice (Fig 3A), suggesting more severe colitis in FXIII−/− cohorts. Histological analyses demonstrated significant areas of inflammation, crypt loss and ulceration in colons harvested from FXIII−/− mice 7 days after DSS withdrawal that were similar to those observed immediately after the 7 day DSS challenge. In contrast, the microscopic evidence of colitis apparent immediately following a 7 day DSS challenge had largely resolved in colons harvested from WT animals 7 days following DSS withdrawal. (Fig 3B & 3C). These results suggest that the persistent intestinal hemorrhage and continued weight loss observed in FXIII-/- mice after withdrawal of the DSS challenge and the return to normal drinking water was not simply the result of the bleeding tendency associated with FXIII deficiency, but also due to a failure to resolve DSS-induced mucosal damage.


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)

Lack of FXIII results in a failure to resolve colonic damage after DSS exposure.(A) Colon lengths observed in cohorts of WT and FXIII−/− mice 7 days after withdrawal of DSS (n = 10 per cohort). Note that colons were significantly shorter in FXIII−/− mice (consistent with more severe lingering disease) in comparison to WT mice. (B) Representative H&E-stained section of colon tissue harvested from a WT mouse 7 days after DSS withdrawal demonstrated substantial resolution of DSS-induced colitis in this time frame. Note the generally intact mucosa with mild inflammation, and occasional crypt loss and crypt spacing (triangle). (C) In contrast, colons harvested from FXIII−/− mice typically had large areas of ulceration (arrowheads) and inflammatory submucosal edema (*). (D-E) Representative immunohistochemical analyses of fibrin(ogen) deposition (detected by brown staining) within colon tissue sections harvest from WT (D) and FXIII−/− mice (E) 7 days after withdrawal of the DSS challenge. Note that interstitial fibrin(ogen) was minimal in the well-resolved colonic mucosa of WT mice; indeed, the trace fibrin(ogen) detected was generally not appreciably different from that observed in unchallenged WT mice (F). In contrast, interstitial fibrin(ogen) deposits were readily observed in the colons of FXIII−/− mice a full week after withdrawal of DSS, and were particularly intense in the numerous areas of lingering severe mucosal damage. Size bars represent 50 μm. (G-I) Colons harvested from FXIII−/− mice (white bars) had more severe microscopic features of disease relative to WT mice (black bars) in the resolution phase 7 days after withdrawal of DSS challenge based on comparative analyses of histopathology scores evaluating key individual (G) and combined (H) disease scores (n = 10 per cohort). (I) Shown are results of direct microscopic measurement of mucosal ulceration as a percentage of colon length (n = 10 per cohort). * P < 0.01, all P values were generated with a Mann-Whitney U test.
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Related In: Results  -  Collection

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

pone.0128113.g003: Lack of FXIII results in a failure to resolve colonic damage after DSS exposure.(A) Colon lengths observed in cohorts of WT and FXIII−/− mice 7 days after withdrawal of DSS (n = 10 per cohort). Note that colons were significantly shorter in FXIII−/− mice (consistent with more severe lingering disease) in comparison to WT mice. (B) Representative H&E-stained section of colon tissue harvested from a WT mouse 7 days after DSS withdrawal demonstrated substantial resolution of DSS-induced colitis in this time frame. Note the generally intact mucosa with mild inflammation, and occasional crypt loss and crypt spacing (triangle). (C) In contrast, colons harvested from FXIII−/− mice typically had large areas of ulceration (arrowheads) and inflammatory submucosal edema (*). (D-E) Representative immunohistochemical analyses of fibrin(ogen) deposition (detected by brown staining) within colon tissue sections harvest from WT (D) and FXIII−/− mice (E) 7 days after withdrawal of the DSS challenge. Note that interstitial fibrin(ogen) was minimal in the well-resolved colonic mucosa of WT mice; indeed, the trace fibrin(ogen) detected was generally not appreciably different from that observed in unchallenged WT mice (F). In contrast, interstitial fibrin(ogen) deposits were readily observed in the colons of FXIII−/− mice a full week after withdrawal of DSS, and were particularly intense in the numerous areas of lingering severe mucosal damage. Size bars represent 50 μm. (G-I) Colons harvested from FXIII−/− mice (white bars) had more severe microscopic features of disease relative to WT mice (black bars) in the resolution phase 7 days after withdrawal of DSS challenge based on comparative analyses of histopathology scores evaluating key individual (G) and combined (H) disease scores (n = 10 per cohort). (I) Shown are results of direct microscopic measurement of mucosal ulceration as a percentage of colon length (n = 10 per cohort). * P < 0.01, all P values were generated with a Mann-Whitney U test.
Mentions: In contrast to the similarities in overall disease severity observed immediately following 7 days of DSS exposure, significant FXIII-dependent differences in colonic tissue damage were observed in mice 7 days after the withdrawal of the DSS challenge, effectively in the colitis injury “resolution phase.” Here, colons harvested from FXIII−/− mice 7 days after DSS withdrawal were significantly shorter than those harvested from DSS-challenged WT mice (Fig 3A), suggesting more severe colitis in FXIII−/− cohorts. Histological analyses demonstrated significant areas of inflammation, crypt loss and ulceration in colons harvested from FXIII−/− mice 7 days after DSS withdrawal that were similar to those observed immediately after the 7 day DSS challenge. In contrast, the microscopic evidence of colitis apparent immediately following a 7 day DSS challenge had largely resolved in colons harvested from WT animals 7 days following DSS withdrawal. (Fig 3B & 3C). These results suggest that the persistent intestinal hemorrhage and continued weight loss observed in FXIII-/- mice after withdrawal of the DSS challenge and the return to normal drinking water was not simply the result of the bleeding tendency associated with FXIII deficiency, but also due to a failure to resolve DSS-induced mucosal damage.

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