Gelatinase activities in the airways of premature infants and development of bronchopulmonary dysplasia

Abstract

2002.-Matrix-degrading metalloproteinases may play a role in the pathophysiology of bronchopulmonary dysplasia (BDP). We, therefore, evaluated correlations between gelatinase activities [metalloproteinase (MMP)-2 and MMP-9] or tissue inhibitor of metalloproteinase (TIMP)-1 levels present in the airways during the initial phase of hyaline membrane disease and the onset of BPD. Tracheal aspirates were obtained within 6 h of birth (day 0) from 64 intubated neonates with a gestational age Յ30 wk. Forty-five neonates were resampled on day 3 or 5. Total MMP-2 level measured by zymography fell with time, whereas total MMP-9 level and TIMP-1 levels, assayed by ELISA, increased; the MMP-9 increase correlated with the increase in airway inflammatory cell numbers. Among the parameters measured on day 0, 3, or 5, lower total MMP-2 level, lower birth weight, and higher fraction of inspired oxygen on day 0 were significantly and independently associated with the development of BPD. In conclusion, MMP-9 level and TIMP-1 levels increased after birth but are not linked to BPD outcome. In contrast, low MMP-2 level at birth is strongly associated with the development of BPD. metalloproteinase; lung development; newborn; extracellular matrix PREMATURE NEONATES WITH HYALINE membrane disease are at risk of developing bronchopulmonary dysplasia (BPD), as a sequel of both the disease and its treatment. The pathogenesis is unclear, but BPD is thought to result from damage to an immature lung. Mechanical ventilation, oxygen therapy, and airway inflammatory responses have all been implicated in the development of BPD (19). These insults appear to interfere with normal lung maturation, which is incomplete at birth. In particular, they appear to alter alveolar formation, on the basis of morphometric studies of severe BPD (3, 24). Alveolar formation is characterized by the multiplication of alveolar septa and the thinning of interalveolar walls, both of which require intense remodeling of the pulmonary extracellular matrix (4). Changes in matrix turnover have been experimentally linked to abnormal alveolar formation (20). The proteinase-antiproteinase balance in the lung is a key factor in harmonious matrix turnover. In particular, matrix metalloproteinases (MMPs), which can synergistically digest the major macromolecules of connective tissue matrices, have been implicated in physiological regulation of lung growth. The MMP gelatinase A (MMP-2) has been shown to play a role in the major collagen turnover that occurs during early postnatal rat lung growth (1, 2). We postulated that MMP-2 might also participate in human lung development and that inadequate MMP-2 levels in premature lungs exposed to insults could contribute to impaired lung growth and thus to BPD. We also postulated that MMPs may be secreted in excess during the inflammatory response associated with hyaline membrane disease and may, therefore, lead to tissue degradation. Gelatinase B (MMP-9) is the main MMP released by inflammatory cells such as neutrophils and alveolar macroph...

Role of Matrix Metalloproteinase-2 in Newborn Mouse Lungs under Hypoxic Conditions

“…Low MMP-2 in preterm infant airways is associated with subsequent BPD (38), and our study suggests that reductions in MMP-2 are not just a prognostic marker but may also be a contributor to the pathogenesis of BPD. Limitations of our study include the use of a newborn mouse model, which may not closely resemble the human equivalent, and the analysis of whole lung homogenates, which does not identify the cells responsible for the abnormalities in arterial and alveolar development.…”

Matrix Metalloproteinases in Lung: Multiple, Multifarious, and Multifaceted

“…Thus the increase in airway MMPs may present an association rather than the cause in this case (63). Another study found that among preterm infants, amount of MMP2 at birth successfully predicted the outcome of BPD; however, this was confounded by the finding that birth weight was significantly correlated with amount of MMP2, again suggesting that the biggest factor in whether an infant develops BPD or CLD is the stage of development at birth (55).…”

“…A hallmark of this lung injury is reepithelialization of denuded alveoli followed by the increased presence of fibroblasts and major areas of fibrosis. The cause of BPD is thought to be both the hyaline membrane disease and possible lung injury related to prolonged treatment with oxygen and mechanical ventilation (55).…”

KL4-Surfactant (Lucinactant) Protects Human Airway Epithelium from Hyperoxia

“…MMPs released by injured cells contribute to greater microvascular permeability and release matrix components that function as proinflammatory mediators or growth factors to further inflammation and remodeling (12). MMP activity in the lung and airways has been associated with fibrotic lung diseases, including BPD (13,14).…”