Elevated Plasma Levels of Matrix Metalloproteinase-3 and Tissue-Inhibitor of Matrix Metalloproteinases-1 Associate With Organ Dysfunction and Mortality in Sepsis

Abstract

Background: Matrix Metalloproteinases (MMP) respond to tissue damage during sepsis. Higher plasma concentrations of MMPs and the tissue-inhibitor of matrix metalloproteinases (TIMP) have been reported in sepsis compared with healthy controls. The objective of this study was to examine if plasma levels of MMP-3, MMP-9, and TIMP-1 associate with mortality and organ dysfunction during sepsis. Methods: We conducted a prospective cohort study of critically ill patients with sepsis adjudicated per Sepsis-3 criteria at a tertiary academic medical center. We measured plasma concentrations of MMP-3, MMP-9, and TIMP-1 on intensive care unit admission. We phenotyped the subjects for shock, acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), and mortality at 30 days. We used logistic regression to test the associations between the MMPs and TIMP-1 with shock, ARDS, AKI, and mortality. Results: Higher plasma TIMP-1 levels were associated with shock (odds ratio [OR] 1.51 per log increase [95% CI 1.25, 1.83]), ARDS (OR 1.24 [95% CI 1.05, 1.46]), AKI (OR 1.18 [95% CI 1.01, 1.38]), and mortality (OR 1.20 [95% CI 1.05, 1.46]. Higher plasma MMP-3 concentrations were associated with shock (OR 1.40 [95% CI 1.12, 1.75]) and mortality (OR 1.24 [95% CI 1.03, 1.48]) whereas MMP-9 levels were not associated with outcomes. Higher plasma TIMP-1 to MMP-3 ratios were associated with shock (OR 1.41 [95% CI 1.15, 1.72], P = 0.02). Conclusion: Elevated plasma concentrations of TIMP-1 associate with organ dysfunction and mortality in sepsis. Higher plasma levels of MMP-3 associate with shock and mortality. Plasma MMP and TIMP-1 may warrant further investigation as emerging sepsis theragnostic biomarkers.

Plasma TIMP-1 as a sex-specific biomarker for acute lung injury

“…In clinical cohorts, TIMP-1 systemic level was significantly higher in ARDS subjects than in other sub-groups of ventilated patients with respiratory failure, and it was independently associated with 90-day mortality and worse hypoxemia [28]. Likewise, higher plasma of TIMP-1 concentration was significantly associated with ARDS and 30-day mortality risk in critically ill patients admitted to the ICU [29]. These findings demonstrate the prognostic potential of circulating TIMP-1 in ARDS and encourage further biomarker studies to be conducted.…”

Integrated Analysis of Transcriptome in Interleukin-10 Treated Peripheral Blood Cell Reveal Conservative Differential Expressed Genes

“…The role of TIMP1 in sepsis has also been revealed. It is reported that compared with the healthy control group, the plasma concentration of TIMP1 in patients with sepsis is higher, which is a marker of acute renal injury and can be used to predict the prognosis [22] . It has also been reported that plasma TIMP1 concentration is associated with organ dysfunction in patients with sepsis [18] .…”

Multiplex quantification of C-terminal alpha-1-antitrypsin peptides provides a novel approach for characterizing systemic inflammation

“…2 ). This observation might be related to MMP activity since it has been shown that higher plasma levels of MMP-3 are associated with septic shock and mortality 68 . C22, C39, C43 and C45 seem to play only a minor, if any, role during systemic inflammation because they were not detected or below the LLOQ in septic patients (Fig.…”