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PEDIATRICS Vol. 113 No. 6 June 2004, pp. 1709-1714

Low Levels of Tissue Inhibitors of Metalloproteinases With a High Matrix Metalloproteinase-9/Tissue Inhibitor of Metalloproteinase-1 Ratio Are Present in Tracheal Aspirate Fluids of Infants Who Develop Chronic Lung Disease

Ikechukwu I. Ekekezie, MD*, Donald W. Thibeault, MD*, Stephen D. Simon, PhD{ddagger}, Michael Norberg*, Jeffrey D. Merrill, MD§, Roberta A. Ballard, MD§, Philip L. Ballard, MD, PhD§ and William E. Truog, MD*

* Children’s Mercy Hospitals and Clinics, University of Missouri-Kansas City, School of Medicine, Department of Pediatrics, Section of Neonatal-Perinatal Medicine, Kansas City, Missouri
{ddagger} Office of Medical Research, Section of Biostatistics, Kansas City, Missouri
§ Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Department of Pediatrics, Section of Neonatology, Philadelphia, Pennsylvania

Objective. The pathogenesis of chronic lung disease (CLD) involves inflammation with proteolytic damage to lung extracellular matrix. Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that, acting in concert with their tissue inhibitors, tightly orchestrate extracellular matrix morphogenesis and repair after injury. Imbalances in their levels relative to that of their inhibitors have been implicated in diseases characterized by matrix disruption and remodeling. We investigated the possibility that imbalances in MMP-9 and MMP-2 relative to their tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2, respectively, in tracheal aspirates of preterm infants may be involved in the development of CLD.

Methods. Serial tracheal aspirates collected from birth until extubation in 49 ventilated preterm infants (24-32 weeks’ gestations) were analyzed for MMP-2, MMP-9, TIMP-1, and TIMP-2. Data normalized by TA values of free secretory component of immunoglobulin A were compared for CLD (n = 22) versus no CLD (n = 27). Also, known clinical predictors of CLD (gestational age, birth weight, and sex) were assessed for both groups. Association of predictors with the outcome CLD was assessed by logistic regression.

Results. Mean gestational age was lower in CLD infants, but birth weight and gender were comparable for both groups. CLD infants had significantly lower TIMP-1 level with higher MMP-9/TIMP-1 ratio during the first 2 weeks of life and low TIMP-2 and MMP-2 levels during the first 3 days of life compared with no-CLD infants. Logistic regression analysis indicated that the findings are predictive of CLD.

Conclusions. We conclude that low tracheal aspirate levels of TIMPs, with a high MMP-9/TIMP-1 ratio early in life, are associated with subsequent development of CLD.

Key Words: MMPs • TIMPs • chronic lung disease

Abbreviations: CLD, chronic lung disease • MMP, matrix metalloproteinase • TIMP, tissue inhibitor of metalloproteinase • RDS, respiratory distress syndrome • TAF, tracheal aspirate fluid • EIA, enzyme immunoassay

Received for publication Mar 10, 2003; Accepted Sep 15, 2003.




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