title: Thrombospondin-1 contributes to mortality in murine sepsis through effects on innate immunity.
abstract: BACKGROUND
  Thrombospondin-1 (TSP-1) is involved in many biological processes, including immune and tissue injury response, but its role in sepsis is unknown. Cell surface expression of TSP-1 on platelets is increased in sepsis and could activate the anti-inflammatory cytokine transforming growth factor beta (TGFβ1) affecting outcome. Because of these observations we sought to determine the importance of TSP-1 in sepsis.
  
  
  RESULTS
  We performed studies on TSP-1 null and wild type (WT) C57BL/6J mice to determine the importance of TSP-1 in sepsis. We utilized the cecal ligation puncture (CLP) and intraperitoneal E. coli injection (i.p. E. coli) models of peritoneal sepsis. Additionally, bone-marrow-derived macrophages (BMMs) were used to determine phagocytic activity. TSP-1-/- animals experienced lower mortality than WT mice after CLP. Tissue and peritoneal lavage TGFβ1 levels were unchanged between animals of each genotype. In addition, there is no difference between the levels of major innate cytokines between the two groups of animals. PLF from WT mice contained a greater bacterial load than TSP-1-/- mice after CLP. The survival advantage for TSP-1-/- animals persisted when i.p. E. coli injections were performed. TSP-1-/- BMMs had increased phagocytic capacity compared to WT.
  
  
  CONCLUSIONS
  TSP-1 deficiency was protective in two murine models of peritoneal sepsis, independent of TGFβ1 activation. Our studies suggest TSP-1 expression is associated with decreased phagocytosis and possibly bacterial clearance, leading to increased peritoneal inflammation and mortality in WT mice. These data support the contention that TSP-1 should be more fully explored in the human condition.
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Dorothy M. Davis Heart and Lung Research Institute, Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Sara
authors.initials: S
authors.lastname: McMaken
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Exline
authors.forename: Payal
authors.initials: P
authors.lastname: Mehta
authors.forename: Melissa
authors.initials: M
authors.lastname: Piper
authors.forename: Yijie
authors.initials: Y
authors.lastname: Wang
authors.forename: Sara N
authors.initials: SN
authors.lastname: Fischer
authors.forename: Christie A
authors.initials: CA
authors.lastname: Newland
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Schrader
authors.forename: Shannon R
authors.initials: SR
authors.lastname: Balser
authors.forename: Anasuya
authors.initials: A
authors.lastname: Sarkar
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Baran
authors.forename: Clay B
authors.initials: CB
authors.lastname: Marsh
authors.forename: Charles H
authors.initials: CH
authors.lastname: Cook
authors.forename: Gary S
authors.initials: GS
authors.lastname: Phillips
authors.forename: Naeem A
authors.initials: NA
authors.lastname: Ali
mesh_terms: D000818:Animals; D058491:Bacterial Load / Q000276:immunology; D002432:Cecum / Q000382:microbiology / Q000473:pathology; D002452:Cell Count; D016207:Cytokines / Q000097:blood; D019610:Cytoprotection; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D008026:Ligation; D008264:Macrophages / Q000166:cytology; D051379:Mice; D010533:Peritoneal Lavage; D010537:Peritoneum / Q000382:microbiology / Q000473:pathology; D010587:Phagocytosis; D011677:Punctures; D018805:Sepsis / Q000097:blood / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D016019:Survival Analysis; D019700:Thrombospondin 1 / Q000172:deficiency / Q000378:metabolism*; D014945:Wound Healing
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D019700:Thrombospondin 1