title: Factor XIII Transglutaminase Supports the Resolution of Mucosal Damage in Experimental Colitis.
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.
authors.affiliation: Novo Nordisk A/S, Biopharmaceutical Research Unit, Copenhagen, Denmark.
authors.forename: Christina
authors.initials: C
authors.lastname: Andersson
authors.affiliation: Novo Nordisk A/S, Biopharmaceutical Research Unit, Copenhagen, Denmark.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Kvist
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: Kathryn
authors.initials: K
authors.lastname: McElhinney
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Baylis
authors.affiliation: Novo Nordisk A/S, Biopharmaceutical Research Unit, Copenhagen, Denmark.
authors.forename: Luise K
authors.initials: LK
authors.lastname: Gram
authors.affiliation: Novo Nordisk A/S, Biopharmaceutical Research Unit, Copenhagen, Denmark.
authors.forename: Hermann
authors.initials: H
authors.lastname: Pelzer
authors.affiliation: Novo Nordisk A/S, Biopharmaceutical Research Unit, Copenhagen, Denmark.
authors.forename: Brian
authors.initials: B
authors.lastname: Lauritzen
authors.affiliation: Novo Nordisk A/S, Biopharmaceutical Research Unit, Copenhagen, Denmark.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Holm
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: Simon
authors.initials: S
authors.lastname: Hogan
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Wu
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: Brian
authors.initials: B
authors.lastname: Turpin
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: Whitney
authors.initials: W
authors.lastname: Miller
authors.affiliation: Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Palumbo
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D003092:Colitis / Q000139:chemically induced / Q000473:pathology*; D003106:Colon / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005176:Factor XIII / Q000235:genetics* / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000494:pharmacology; D014945:Wound Healing / Q000235:genetics*
chemical_list: D015415:Biomarkers; D011994:Recombinant Proteins; C064015:factor XIII subunit A; D005176:Factor XIII; D016264:Dextran Sulfate