Role of plasma matrix-metalloproteases (MMPs) and their polymorphisms (SNPs) in sepsis development and outcome in ICU patients

Abstract

Matrix-metalloproteases (MMPs) and their tissue-inhibitors (TIMPs), modulated by different single nucleotide polymorphisms (SNPs), are critical in sepsis development. Ninety ICU severely septic and 91 ICU uninfected patients were prospectively studied. MMP-1 (−1607 1G/2G), MMP-3 (−1612 5A/6A), MMP-8 (−799 C/T), MMP-9 (−1562 C/T), and MMP-13 (−77A/G) SNPs were genotyped. Plasma MMPs (-1, -2, -3, -8, -9, -10, -13) and TIMPs (-1,-2,-4) were measured. AA homozygotes and A allele carriers of MMP-13 (−77 A/G) and 1G2G carriers of the MMP-1 (−1607 1G/2G) SNPs frequencies were different between septic and uninfected patients (p < 0.05), as well as plasma MMP-3, -8, -9 -10 and TIMP-2 levels (p < 0.04). No differences in MMPs levels among MMP-13 or MMP-1 SNPs genotypes carriers were observed. The area under the ROC curve for MMP-8 in the diagnosis of sepsis was 0.87 (95% CI 0.82–0.92), and that of CRP was 0.98 (0.94–0.998), whereas the area of MMP-9 in the detection of non-septic state was 0.73 (0.65–0.80), p < 0.0001 for all curves. Sepsis associated with increased MMP-8 and decreased MMP-9 levels in multivariate analysis (p < 0.0002). We report for the first time an association between MMP-13 and MMP-1 SNPs and sepsis. An independent association of MMP-8 and MMP-9 levels with sepsis was also observed.

Doxycycline Attenuates Lipopolysaccharide-Induced Microvascular Endothelial Cell Derangements

“…Some studies have shown higher MMP-9 levels correlate with improved survival in severe sepsis (18)(19)(20), whereas other reports illustrate decreased survival with increased MMP-9 levels (21) or increased MMP-9 levels in septic patients without any clear effect on mortality (22). Recent attempts to clarify these discrepancies have compared the levels of various MMPs in septic patients with those of other intensive care unit patients admitted for noninfectious reasons such as stroke or trauma: results showed lower levels of MMP-9 in septic patients than trauma and stroke controls and no difference between septic survivors and nonsurvivors (23). While this data did not quell the controversy surrounding MMP-9 levels and septic prognosis, it did highlight the need for further exploration of the role and mechanisms through which MMPs contribute to the pathophysiology of sepsis and septic shock.…”

Diagnostic Value of Matrix Metalloproteinase-9 and Tissue Inhibitor of Matrix Metalloproteinase-1 in Sepsis-Associated Acute Kidney Injury

“…We did not perform any power analysis due to missing pre-study data. The sample of 53 septic patients was assessed to be adequate based on previous MMP-9 and TIMP1studies in other septic patient populations (Muhl et al 2011;YazdanAshoori et al 2011;Martin et al 2014). The normality of data was assessed with Kolmogorov-Smirnov test.…”

Matrix Metalloproteinase-9 −1562C/T Gene Polymorphism Is Associated with Diabetic Nephropathy

“…The effects of a number of SNPs have been described for a number of MMPs [12]. A recent paper reported SNP in the MMP9 gene promoter that reduces the risk of diabetic microvascular complications [13], but there is no study specifically examining MMP9 SNPs in DN.…”