Matt S Zinter1, Kevin L Delucchi2, Michele Y Kong3, Benjamin E Orwoll1, Aaron S Spicer1, Michelle J Lim4, Mustafa F Alkhouli1, Anna E Ratiu4, Anne V McKenzie1, Patrick S McQuillen1, Christopher C Dvorak5, Carolyn S Calfee6,7, Michael A Matthay6,7, Anil Sapru1,4. 1. 1 Division of Critical Care and. 2. 2 Department of Psychiatry, and. 3. 3 Division of Critical Care Medicine, Department of Pediatrics, University of Alabama School of Medicine, Birmingham, Alabama; and. 4. 4 Division of Critical Care, Department of Pediatrics, Mattel Children's Hospital, University of California Los Angeles Geffen School of Medicine, Los Angeles, California. 5. 5 Division of Allergy, Immunology, and Blood & Marrow Transplantation, Department of Pediatrics, Benioff Children's Hospital. 6. 6 Department of Anesthesia and. 7. 7 Department of Medicine, Cardiovascular Research Institute, University of California San Francisco School of Medicine, San Francisco, California.
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 (PaO2/FiO2 [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.
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 (PaO2/FiO2 [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.
Entities:
Keywords:
matrix metalloproteinases; pediatric acute lung injury; pediatric acute respiratory distress syndrome; pediatric intensive care unit; tissue inhibitor of metalloproteinases
Authors: Matt S Zinter; Steven G DuBois; Aaron Spicer; Katherine Matthay; Anil Sapru Journal: Intensive Care Med Date: 2014-07-15 Impact factor: 17.440
Authors: Matt S Zinter; Aaron Spicer; Benjamin O Orwoll; Mustafa Alkhouli; Christopher C Dvorak; Carolyn S Calfee; Michael A Matthay; Anil Sapru Journal: Am J Physiol Lung Cell Mol Physiol Date: 2015-12-11 Impact factor: 5.464
Authors: Matt S Zinter; Benjamin E Orwoll; Aaron C Spicer; Mustafa F Alkhouli; Carolyn S Calfee; Michael A Matthay; Anil Sapru Journal: Crit Care Med Date: 2017-05 Impact factor: 9.296
Authors: Michelle J Lim; Matt S Zinter; Lucia Chen; Kayley Man Yee Wong; Anoopindar Bhalla; Kinisha Gala; Mona Guglielmo; Mustafa Alkhouli; Leanna L Huard; Mark R Hanudel; Sitaram Vangala; Andreas Schwingshackl; Michael Matthay; Anil Sapru Journal: Crit Care Med Date: 2021-10-25 Impact factor: 9.296
Authors: Matt S Zinter; Brent R Logan; Caitrin Fretham; Anil Sapru; Allistair Abraham; Mahmoud D Aljurf; Staci D Arnold; Andrew Artz; Jeffery J Auletta; Saurabh Chhabra; Edward Copelan; Christine Duncan; Robert P Gale; Eva Guinan; Peiman Hematti; Amy K Keating; David I Marks; Richard Olsson; Bipin N Savani; Celalettin Ustun; Kirsten M Williams; Marcelo C Pasquini; Christopher C Dvorak Journal: Biol Blood Marrow Transplant Date: 2019-09-26 Impact factor: 5.742
Authors: Nadir Yehya; Brian M Varisco; Neal J Thomas; Hector R Wong; Jason D Christie; Rui Feng Journal: Crit Care Date: 2020-12-07 Impact factor: 9.097
Authors: Tatiana Zyrianova; Benjamin Lopez; Riccardo Olcese; John Belperio; Christopher M Waters; Leanne Wong; Victoria Nguyen; Sriharsha Talapaneni; Andreas Schwingshackl Journal: Sci Rep Date: 2020-12-15 Impact factor: 4.379
Authors: Pratik Sinha; Kevin L Delucchi; Yue Chen; Hanjing Zhuo; Jason Abbott; Chunxue Wang; Nancy Wickersham; J Brennan McNeil; Alejandra Jauregui; Serena Ke; Kathryn Vessel; Antonio Gomez; Carolyn M Hendrickson; Kirsten N Kangelaris; Aartik Sarma; Aleksandra Leligdowicz; Kathleen D Liu; Michael A Matthay; Lorraine B Ware; Carolyn S Calfee Journal: Thorax Date: 2021-07-12 Impact factor: 9.139