TY - JOUR
T1 - Early plasma matrix metalloproteinase profiles a novel pathway in pediatric acute respiratory distress syndrome
AU - Zinter, Matt S.
AU - Delucchi, Kevin L.
AU - Kong, Michele Y.
AU - Orwoll, Benjamin E.
AU - Spicer, Aaron S.
AU - Lim, Michelle J.
AU - Alkhouli, Mustafa F.
AU - Ratiu, Anna E.
AU - McKenzie, Anne V.
AU - McQuillen, Patrick S.
AU - Dvorak, Christopher C.
AU - Calfee, Carolyn S.
AU - Matthay, Michael A.
AU - Sapru, Anil
N1 - Funding Information:
Supported by the NIH National Institute of Child Health and Human Development (K12HD000850, M.S.Z.; 5K12HD047349 and 5K08HL119359-02, M.Y.K.) and the NIH NHLBI (K23HL085526 and R01HL114484, A.S.; R37HL51856, M.A.M.; R35HL140026, C.S.C.).
Publisher Copyright:
Copyright © 2019 by the American Thoracic Society.
PY - 2019/1/15
Y1 - 2019/1/15
N2 - 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-1a and -1b; tumor necrosis factor-a 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.
AB - 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-1a and -1b; tumor necrosis factor-a 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.
KW - Matrix metalloproteinases
KW - Pediatric acute lung injury
KW - Pediatric acute respiratory distress syndrome
KW - Pediatric intensive care unit
KW - Tissue inhibitor of metalloproteinases
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U2 - 10.1164/rccm.201804-0678OC
DO - 10.1164/rccm.201804-0678OC
M3 - Article
C2 - 30114376
AN - SCOPUS:85060056373
SN - 1073-449X
VL - 199
SP - 181
EP - 189
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 2
ER -