Early Plasma Matrix Metalloproteinase Profiles. A Novel Pathway in Pediatric Acute Respiratory Distress Syndrome

Abstract

Rationale: MMPs (Matrix metalloproteinases) and their endogenous tissue inhibitors may contribute to lung injury through extracellular matrix degradation and modulation of inflammation and fibrosis.

Objectives: To test for an association between MMP pathway proteins and inflammation, endothelial dysfunction, and clinical outcomes.

Methods: We measured MMPs in plasma collected on acute respiratory distress syndrome (ARDS) Day 1 from 235 children at five hospitals between 2008 and 2017. We used latent class analysis to identify patients with distinct MMP profiles and then associated those profiles with markers of inflammation (IL-1RA, -6, -8, -10, and -18; macrophage inflammatory protein-1α and -1β; tumor necrosis factor-α and -R2), endothelial injury (angiopoietin-2, von Willebrand factor, soluble thrombomodulin), impaired oxygenation (Pa_O2/Fi_O2 [P/F] ratio, oxygenation index), morbidity, and mortality.

Measurements and main results: In geographically distinct derivation and validation cohorts, approximately one-third of patients demonstrated an MMP profile characterized by elevated MMP-1, -2, -3, -7, and -8 and tissue inhibitor of metalloproteinase-1 and -2; and depressed active and total MMP-9. This MMP profile was associated with multiple markers of inflammation, endothelial injury, and impaired oxygenation on Day 1 of ARDS, and conferred fourfold increased odds of mortality or severe morbidity independent of the P/F ratio and other confounders (95% confidence interval, 2.1-7.6; P < 0.001). Logistic regression using both the P/F ratio and MMP profiles was superior to the P/F ratio alone in prognosticating mortality or severe morbidity (area under the receiver operating characteristic curve, 0.75; 95% confidence interval, 0.68-0.82 vs. area under the receiver operating characteristic curve, 0.66; 95% confidence interval, 0.58-0.73; P = 0.009).

Conclusions: Pediatric patients with ARDS have specific plasma MMP profiles associated with inflammation, endothelial injury, morbidity, and mortality. MMPs may play a role in the pathobiology of children with ARDS.

Keywords: matrix metalloproteinases; pediatric acute lung injury; pediatric acute respiratory distress syndrome; pediatric intensive care unit; tissue inhibitor of metalloproteinases.

Figure 1.

MMP (matrix metalloproteinase) profiles in pediatric acute respiratory distress syndrome. Each bar represents the mean level for each log₁₀-transformed MMP protein, standardized to the cohort mean of 0 and SD of 1. In both the derivation (n = 126) and validation (n = 109) cohorts, patients separated into two profiles using MMP-1, -3, -7, -8, and -9, and TIMP-1 (tissue inhibitor of metalloproteinase-1) and -2 (MMP-2 and active MMP-9 were not used in latent class generation because of collinearity with TIMP-2 and total MMP-9, respectively). MMP profile 1 demonstrated elevated MMP-1, -2, -3, -7, and -8 and TIMP-1 and -2, and depressed active and total MMP-9 relative to MMP profile 2.

Figure 2.

Pediatric acute respiratory distress syndrome survival stratified by Day 1 plasma MMP (matrix metalloproteinase) profile. Kaplan-Meier survival estimates are plotted according to MMP profile. Survival estimates were compared using the log-rank test of equality of survivor functions. By hospital discharge, mortality rates for patients with MMP profile 1 exceeded those of patients with MMP profile 2 (derivation cohort: 26.7% vs. 12.7%, P = 0.047; validation cohort: 34.5% vs. 8.0%, P < 0.001). ARDS = acute respiratory distress syndrome.

Figure 3.

Prognostication of mortality or severe morbidity in pediatric acute respiratory distress syndrome. In the combined cohorts, logistic regression for the composite outcome of mortality or severe morbidity was performed with the Day 1 Pa_O2/Fi_O2 (P/F) ratio and then again with both the Day 1 P/F ratio and Day 1 plasma MMP (matrix metalloproteinase) profile. The model using both Day 1 P/F ratio and the Day 1 plasma MMP profile demonstrated greater area under the receiver operating characteristic curve (AUROC) than the model using Day 1 P/F ratio alone (AUROC, 0.75; 95% confidence interval [CI], 0.68–0.82 vs. AUROC, 0.66; 95% CI, 0.58–0.73; P = 0.009). Similar findings occurred when replacing the P/F ratio with the oxygenation index (AUROC, 0.78; 95% CI, 0.71–0.85 vs. AUROC, 0.69; 95% CI, 0.62–0.77; P = 0.019). OI = oxygenation index.