Inflammation and sepsis induce changes in the extracellular matrix (ECM). ECM degradation and deposition is tightly controlled by matrix metalloproteinases (MMP) and their inhibitors, tissue inhibitors of metalloproteinase (TIMP) respectively. TIMP are multifunctional, participating in anti-apoptotic activity, B cell differentiation, and IL-10 production. We hypothesize that differential expression of TIMP-1 and MMP-9 occurs in SIRS patients that remain uninfected compared to those who subsequently become infected and that these differences occur prior to onset of clinical sepsis.
Longitudinal blood samples were collected on critically ill non-infected SIRS patients and analyzed for MMP-9 and TIMP-1. SIRS patients who subsequently converted to sepsis (Pre-septic SIRS) were time matched to patients who remained uninfected (Non-septic SIRS). Comparisons between the 2 groups occurred at study entry, and at 60 hours prior (T-60), 36 hours prior (T-36), and 12 hours prior (T-12) to onset of microbiologically proven clinical sepsis. MMP-9 and TIMP-1 were measured by immunoassay. Data expressed as mean±SD.
50 Pre-septic SIRS patients and 47 Non-septic SIRS patients were compared at each time point (see table). TIMP-1 levels were significantly higher in the pre-septic SIRS patients. MMP-9 levels were similar in both groups until Pre-septic elevated at T-12. MMP-9/TIMP-1 ratios were lower in the Pre-septic patients initially but sequentially increased becoming significantly elevated at T-12 prior to clinical sepsis.
ECM undergoes dynamic modulation with changes in MMP-9/TIMP-1 ratio prior to conversion from SIRS to sepsis. Elevated TIMP-1 levels occur early, more than 60 hours before clinical sepsis. In addition, TIMP-1 appears dissociated from MMP-9 suggesting alternative activation and functions in SIRS patients who subsequently convert to sepsis.
Earlier diagnosis of sepsis in SIRS patients may be possible by evaluating modulators of the extracellular matrix.
Steven Johnson, Grant monies (from industry related sources) Research Grant Support from BD Diagnostics, Baltimore Maryland; Glaxo SmithKline; Wyeth; Consultant fee, speaker bureau, advisory committee, etc. GlaxoSmithKline; Wyeth; Lilly.