Article abstract
Nature Immunology 8, 1303 - 1312 (2007)
Published online: 28 October 2007 | doi:10.1038/ni1525
'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage
Nicole C Kaneider1, Andrew J Leger1, Anika Agarwal1, Nga Nguyen1, George Perides2, Claudia Derian3, Lidija Covic1 & Athan Kuliopulos1
Abstract
Sepsis is a deadly disease characterized by considerable derangement of the proinflammatory, anti-inflammatory and coagulation responses. Protease-activated receptor 1 (PAR1), an important regulator of endothelial barrier function and blood coagulation, has been proposed to be involved in the lethal sequelae of sepsis, but it is unknown whether activation of PAR1 is beneficial or harmful. Using a cell-penetrating peptide (pepducin) approach, we provide evidence that PAR1 switched from being a vascular-disruptive receptor to a vascular-protective receptor during the progression of sepsis in mice. Unexpectedly, we found that the protective effects of PAR1 required transactivation of PAR2 signaling pathways. Our results suggest therapeutics that selectively activate PAR1-PAR2 complexes may be beneficial in the treatment of sepsis.
- Departments of Medicine and Biochemistry, Molecular Oncology Research Institute, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
- Department of Surgery, Tufts–New England Medical Center, Boston, Massachusetts 02111, USA.
- Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477, USA.
Correspondence to: Athan Kuliopulos1 e-mail: athan.kuliopulos@tufts.edu
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