title: BRCA1 gene therapy reduces systemic inflammatory response and multiple organ failure and improves survival in experimental sepsis.
abstract: Sepsis-related complications and mortality remain a major clinical problem. Increased cell death and unresolved cellular repair have been implicated as key upstream mediators of sepsis-induced organ dysfunction and death. We hypothesised that gene therapy with BRCA1, a critical regulator of DNA damage repair and cell survival, would attenuate the sequelae of sepsis and peritonitis in mice subjected to caecal ligation and perforation (CLP) and thioglycollate stimulation. C57Bl/6J mice underwent sham or CLP surgery 3 days following treatment with either human BRCA1 adenovirus (AdBRCA1) or the adeno-CMV-null vector (Adnull). The 24-h post-CLP mortality was 2.8% vs 17.9% (P<0.001) and the median post-CLP survival was 50.5 vs 33 h (P<0.05) for AdBRCA1- vs Adnull-treated mice, respectively. AdBRCA1 therapy blunted CLP-associated cardiac, pulmonary, hepatic and renal dysfunction and also reduced CLP-elicited double strand breaks and apoptosis in the liver. BRCA1 gene therapy was associated with lower CLP-evoked cardiac and hepatic superoxide generation that in the liver was in part due to improved reactive oxygen species removal. CLP also elevated mesenteric arteriolar and serum intercellular adhesion molecule-1, both of which were partially abrogated with AdBRCA1 administration. Thioglycollate-challenged AdBRCA1-treated mice displayed reduced peritoneal neutrophil recruitment and dampened cytokine elaboration relative to their Adnull-treated counterparts. Taken together, we report a novel role of BRCA1 gene therapy in limiting systemic inflammation, multiple-organ failure and mortality in experimental sepsis.
authors.affiliation: Division of Cardiac Surgery, St Michael's Hospital, Toronto, ON, Canada. teohh@smh.ca
authors.forename: H
authors.initials: H
authors.lastname: Teoh
authors.forename: A
authors.initials: A
authors.lastname: Quan
authors.forename: A K
authors.initials: AK
authors.lastname: Creighton
authors.forename: K W
authors.initials: KW
authors.lastname: Annie Bang
authors.forename: K K
authors.initials: KK
authors.lastname: Singh
authors.forename: P C
authors.initials: PC
authors.lastname: Shukla
authors.forename: N
authors.initials: N
authors.lastname: Gupta
authors.forename: Y
authors.initials: Y
authors.lastname: Pan
authors.forename: F
authors.initials: F
authors.lastname: Lovren
authors.forename: H
authors.initials: H
authors.lastname: Leong-Poi
authors.forename: M
authors.initials: M
authors.lastname: Al-Omran
authors.forename: S
authors.initials: S
authors.lastname: Verma
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D019313:BRCA1 Protein / Q000235:genetics*; D016207:Cytokines / Q000032:analysis; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000628:therapy*; D018805:Sepsis / Q000378:metabolism / Q000628:therapy*; D013481:Superoxides / Q000032:analysis
chemical_list: D019313:BRCA1 Protein; D016207:Cytokines; D013481:Superoxides; D018799:Intercellular Adhesion Molecule-1