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Critical Care and Emergency Medicine


Thrombospondin-1 Contributes to Mortality in Murine Sepsis through Effects on Innate Immunity
Published: Monday, May 09, 2011
Author: Sara McMaken et al.

by Sara McMaken, Matthew C. Exline, Payal Mehta, Melissa Piper, Yijie Wang, Sara N. Fischer, Christie A. Newland, Carrie A. Schrader, Shannon R. Balser, Anasuya Sarkar, Christopher P. Baran, Clay B. Marsh, Charles H. Cook, Gary S. Phillips, Naeem A. Ali

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 (TGFß1) affecting outcome. Because of these observations we sought to determine the importance of TSP-1 in sepsis.

Methodology/Principal Findings

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 (IP 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 TGFß1 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 IP 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 TGFß1 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.

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