PURPOSE: Although implicated in adult ARDS, the role of matrix metalloproteinase (MMP) -8 and -9 in pediatric ARDS remains ill defined. We performed 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. 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 scores, oxygen index, multi-organ system failure and clinical outcome measures including length of intubation (LOI), ventilator-free days (VFDs) and mortality in our Pediatric Intensive Care Unit.
RESULTS: Robust MMP-8 and MMP-9 activity was found in the ARDS group when compared to non-ARDS controls. In the ARDS cohort, higher MMP-8 and active MMP-9 levels at 48 hours of intubation and ARDS onset 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, disease etiology and severity of illness. Patients with the highest number of ventilator days had the highest levels of active MMP-9. No significant correlations were identified between total MMP-9, MMP-9:TIMP-1 ratios, TIMP-1, HNE and MPO levels with LOI and VFDs in the ARDS subjects. In the control non-ARDS group, no correlation was observed between all the measured biomarkers and clinical markers of disease severity and outcome measures. 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 VFDs among children with ARDS.
CLINICAL IMPLICATIONS: Together, these results identify early biomarkers predictive of ARDS disease course and potential therapeutic targets for this life threatening disease.
DISCLOSURE: The following authors have nothing to disclose: Michele Kong, Yao Li, Robert Oster, Amit Gaggar, John Paul Clancy
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