Lung disease of the preterm infant: mediators involved in fibroproliferation and fibrogenesis

To save life. prematurely born infants with neonatal respiratory distress syndrome (RDS) are artificially ventilated. RDS can resolve within days after birth (uncomplicated RDS) or progress towards a chronic lung disease called bronchopulmonary dysplasia (BPD). The lung pathology of BPD is associated with varying degrees of fibrosis that develops within days to weeks after mechanical ventilation treatment for RDS. The development of pulmonary fibrosis generally follows an inflammatory phase and is characterized by an increase in pulmonary fibroblast numbers and increased deposition of extracellular matrix components (especially collagen) in the lung interstitium. Numerous studies have focussed on inflammatory mediators in the pathogenesis of BPD. but only a few reports are available on the presence of fibrogenic mediators in the lungs during BPD development. The studies described in this thesis focussed mainly on mediators known to be involved in fibroproliferation (fibroblast proliferation) and fibrogenesis (collagen deposition) and are. therefore, of interest in understanding the pathogenesis of BPD. When sequential BAL fluids were examined from infants with resolving RDS and from infants developing BPD for their ntitogenic activity for human fetal lung fibroblasts (HFL-1) no differences were observed. This suggests that the mitogenic activity in the lungs of prematurely born infants is associated with RDS resolution and contributes to (or reflects) repair of the injured lung structures. The infants that developed BPD. experienced more severe RDS than the resolving infants. This suggests that the infants with BPD development had more severe lung tissue damage than infants with resolving RDS. At postnatal days 2 to 7. the ntitogenic activity of BAL fluids was comparable between RDS and BPD. in contrast to the expectation that the BAL fluid mitogenic activity would correlate with the severity of the initial damage. Therefore. the ntitogenic activity of BAL fluid from postnatal days 2 to 7 from infants developing BPD may be inadequate to initiate a proper repair response. When infants progressed to BPD. the ntitogenic activity of BAL fluid remained at the same level for at least 2 weeks after birth. This suggests that prolonged fibroproliferation occurs in the lungs of infants developing BPD. It can be postulated that an initially inadequate repair response followed by prolonged pulmonary fibroproliferation contributes to the development of the fibrosis in the lungs of these infants. The coagulation cascade serine protease thrombin was identified as an important fibroblast ntitogen in the BAL fluids. especially during the first four postnatal days in both resolving RDS and BPD. Furthermore, it became evident that from postnatal day 7 on factors other than thrombin also contributed to the mitogenic activity of the BAL fluid.

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