title: Cardiac fibroblasts: contributory role in septic cardiac dysfunction.
abstract: BACKGROUND
  Cardiac dysfunction is a frequent and severe complication of septic shock and contributes to the high mortality of sepsis. Although several mechanisms have been suspected to be responsible for sepsis-associated cardiac dysfunction, the precise cause(s) remains unclear to date.
  
  
  METHODS
  We tested the hypothesis that cardiac fibroblasts may play a critical role as a disease modifier involved in sepsis-associated cardiac dysfunction. Human cardiac fibroblasts (HCFs) cultured in vitro were exposed to lipopolysaccharide (LPS). Changes in cardiac morphology and function were assessed in mice with cecal ligation and puncture-induced sepsis.
  
  
  RESULTS
  In LPS-stimulated HCFs, messenger RNA and protein levels of proinflammatory molecules, including tumor necrosis factor-α, interleukin-1β, interleukin-6, and monocyte chemoattractant protein-1, were strikingly upregulated. LPS also increased expression and activity of matrix metalloproteinase (MMP)-9, but not MMP-2. LPS-induced expression of α-smooth muscle actin, a classical marker for myoblast differentiation, which was abrogated when MMP-9 small interfering RNA was transfected into HCFs. High gene expression levels of proinflammatory cytokines and MMP-9 were observed in the heart tissues of cecal ligation and puncture-induced septic mice. Histology sections of the hearts from septic mice showed perivascular and interstitial cardiac fibrosis, and echocardiography demonstrated that septic mice had profound cardiac dysfunction. The broad-spectrum MMP inhibitor ONO-4817 significantly alleviated these histologic and functional changes during the acute phase.
  
  
  CONCLUSIONS
  We suggest that cardiac fibroblasts are of pathogenetic importance in inflammation and fibrosis in the heart during sepsis, leading to cardiac dysfunction that would affect the outcome of sepsis syndrome.
authors.affiliation: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Tomita
authors.affiliation: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Mitchinori
authors.initials: M
authors.lastname: Takashina
authors.affiliation: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Mizuno
authors.affiliation: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Kimimasa
authors.initials: K
authors.lastname: Sakata
authors.affiliation: Department of Anesthesiology and Pain Relief Center, University of Tokyo Hospital, Tokyo, Japan.
authors.forename: Kohshi
authors.initials: K
authors.lastname: Hattori
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Joji
authors.initials: J
authors.lastname: Imura
authors.affiliation: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Wakana
authors.initials: W
authors.lastname: Ohashi
authors.affiliation: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. Electronic address: yhattori@med.u-toyama.ac.jp.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hattori
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology*; D005355:Fibrosis; D006321:Heart / Q000503:physiopathology*; D049690:History, Ancient; D006801:Humans; D008070:Lipopolysaccharides; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010647:Phenyl Ethers; D012772:Shock, Septic / Q000473:pathology / Q000503:physiopathology*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D016207:Cytokines; D008070:Lipopolysaccharides; C414368:N-hydroxy-5-ethoxymethyloxy-2-methyl-4-(4-phenoxybenzoyl)aminopentanamide; D016328:NF-kappa B; D010647:Phenyl Ethers; D020782:Matrix Metalloproteinases
keywords: Cardiac dysfunction; Cardiac fibroblast; Cardiac fibrosis; Inflammation; Polymicrobial sepsis