Impact of the adequacy of antibiotic therapy on the outcome of ventilator-associated pneumonia (original) (raw)

Impact of pro-domain stability of matrix metalloproteinase-8 on the outcome of sepsis

Critical Care, 2011

IntroductionAnimal studies suggest matrix metalloproteinase-8 (MMP8) (neutrophil collagenase) impairs neutrophil (PMN) recruitment in inflammation; in humans, MMP8 has been associated with inflammation. We hypothesized that septic patients with single nucleotide polymorphisms (SNPs) in the MMP8 promoter region will have a survival advantage, and this advantage is due to differences in MMP8 enzymatic activity and not MMP8 levels.MethodsWe examined data from patients with CAP-associated sepsis (GenIMS), analyzed three functional SNPs (rs3765620, rs1940475, rs11225395) in 1,567 Caucasians and tested associations with 60-day and 90-day mortality and severe sepsis incidence. We simulated functional MMP8 SNPs using anisotropic network modeling. Modeling suggested pro-domain structural stability affecting zymogen activation. Based upon the predictions, we then studied zymogen activation using bioluminescent resonance energy transfer (BRET). We generated recombinant pro-MMP8 with a pro-domain