Published ahead of print on January 18, 2007, doi:10.1164/rccm.200608-1103OC Am. J. Respir. Crit. Care Med., Volume 175, Number 6, March 2007, 595-603 A more recent version of this article appeared on March 15, 2007
Submitted on August 7, 2006 Selective NOD1 Agonists Cause Shock and Organ Injury/Dysfunction In vivoNeil Cartwright1,1 Department of Critical Care, National Heart and Lung Institute, Imperial College, London, United Kingdom, 2 The William Harvey Research Institute, Queen Mary-University of London, Barts and The London School of Medicine and Dentistry, London, United Kingdom, 3 Institute of Cell and Molecular Science, Barts and The London, London, United Kingdom, 4 CNRS, Transogenose Institute, Orleans, France * To whom correspondence should be addressed. E-mail: j.a.mitchell{at}ic.ac.uk.
Rationale: NLRs (nucleotide oligomerisation domain, NOD, proteins containing a leucine rich repeat) are cytosolic pattern recognition receptors. NOD1 senses diaminopimelic acid (DAP)-containing peptidoglycan present in Gram negative bacteria, whilst NOD2 senses the muramyl dipeptide(MDP) present in most organisms. Bacteria are the most common cause of septic shock, which is characterised clinically by hypotension resistant to vasopressor agents. In animal models, Gram negative septic shock is mimicked by lipopolysaccharide (LPS) which signals through Toll-like receptor (TLR) 4 and its adaptor MyD88. The role of NLRs in the pathophysiology of septic shock is not known. Objectives: To compare the effects of a selective NOD1 agonists with LPS in vivo. Methods. Vascular smooth muscle cells or whole aortae from wild type, or genetically modified mice were stimulated in vitro with agonists of NOD1 (FK565) or NOD2 (MDP). Vasoconstriction was measured using wire-myography. Nitric oxide (NO) formation was measured using Griess reaction and NO synthase (NOS)-II protein by Western blotting. In vivo, blood pressure, heart rate and urine output were measured in sham, LPS or FK565 treated animals. Biomarkers of end-organ injury, coagulation activation, NO and cytokines were measured in plasma. Main results: FK565, but not MDP, induced NOS-II protein/activity in vascular smooth muscle and vascular hyporeactivity to pressor agents. FK565 had no effect on vessels from NOD1 -/- mice, but was active in vessels from TLR4 -/- , TLR2 -/- or MyD88 -/-mice. FK565 induced hypotension, increased heart rate and caused multiple (renal, liver) injury and dysfunction in vivo. Conclusions: Activation of NOD1 induces shock and multiple organ injury/dysfunction. Key words: Peptidoglycan, Lipopolysaccharides, Receptors, Pattern Recognition, Vasodilation, Nitric oxide synthase
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
