title: Early elevation of matrix metalloproteinase-8 and -9 in pediatric ARDS is associated with an increased risk of prolonged mechanical ventilation.
abstract: BACKGROUND
  Matrix metalloproteinases (MMP) -8 and -9 may play key roles in the modulation of neutrophilic lung inflammation seen in pediatric Acute Respiratory Distress Syndrome (ARDS). We aimed to perform a comprehensive analysis of MMP-8 and MMP-9 activity in tracheal aspirates of pediatric ARDS patients compared with non-ARDS controls, testing whether increased MMP-8 and -9 activities were associated with clinical outcomes.
  
  
  METHODS
  Tracheal aspirates were collected from 33 pediatric ARDS patients and 21 non-ARDS controls at 48 hours of intubation, and serially for those who remained intubated greater than five days. MMPs, tissue inhibitor of metalloproteinases (TIMPs), human neutrophil elastase (HNE) and myeloperoxidase (MPO) activity were measured by ELISA, and correlated with clinical indicators of disease severity such as PRISM (Pediatric Risk of Mortality) scores, oxygen index (OI), multi-organ system failure (MOSF) and clinical outcome measures including length of intubation, ventilator-free days (VFDs) and mortality in the Pediatric Intensive Care Unit (PICU).
  
  
  RESULTS
  Active MMP-9 was elevated early in pediatric ARDS subjects compared to non-ARDS controls. Higher MMP-8 and active MMP-9 levels at 48 hours correlated with a longer course of mechanical ventilation (r = 0.41, p = 0.018 and r = 0.75, p<0.001; respectively) and fewer number of VFDs (r = -0.43, p = 0.013 and r = -0.76, p<0.001; respectively), independent of age, gender and severity of illness. Patients with the highest number of ventilator days had the highest levels of active MMP-9. MMP-9 and to a lesser extent MMP-8 activities in tracheal aspirates from ARDS subjects were sensitive to blockade by small molecule inhibitors.
  
  
  CONCLUSIONS
  Higher MMP-8 and active MMP-9 levels at 48 hours of disease onset are associated with a longer duration of mechanical ventilation and fewer ventilator-free days among pediatric patients with ARDS. Together, these results identify early biomarkers predictive of disease course and potential therapeutic targets for this life threatening disease.
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. mkong@peds.uab.edu
authors.forename: Michele Y F
authors.initials: MY
authors.lastname: Kong
authors.forename: Yao
authors.initials: Y
authors.lastname: Li
authors.forename: Robert
authors.initials: R
authors.lastname: Oster
authors.forename: Amit
authors.initials: A
authors.lastname: Gaggar
authors.forename: J P
authors.initials: JP
authors.lastname: Clancy
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D015415:Biomarkers / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007223:Infant; D019272:Leukocyte Elastase / Q000378:metabolism; D008171:Lung Diseases / Q000201:enzymology* / Q000473:pathology / Q000628:therapy*; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D009195:Peroxidase / Q000378:metabolism; D012121:Respiration, Artificial; D018570:Risk Assessment; D012307:Risk Factors; D013577:Syndrome; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014132:Trachea / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D009195:Peroxidase; D019272:Leukocyte Elastase; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9