Dexamethasone treatment does not inhibit fibroproliferation in chronic lung disease of prematurity

Abstract

Pulmonary fibrosis results from excessive fibroblast proliferation and increased collagen deposition and occurs in chronic lung disease of prematurity (CLD). Platelet-derived growth factor (PDGF)-BB is mitogenic for fibroblasts and levels are increased in fibrotic lung disorders. Systemic dexamethasone (DEX) treatment improves pulmonary function and reduces inflammation in infants with or at risk of CLD. However, the effect of DEX treatment on fibroblast activity, PDGF-BB and collagen synthesis in the lungs of CLD patients is uncertain.Bronchoalveolar lavage (BAL) fluids, obtained from 15 infants at risk of CLD before and after DEX treatment, were analysed for fibroblast mitogenicity, PDGF-BB, N-terminal propeptide of collagen type III (PIIINP) and interleukin (IL)-1b levels and inflammatory cell numbers.After DEX treatment, the mitogenic activity of BAL fluid for fibroblasts was not reduced but increased. The change in mitogenicity correlated with a change in BAL fluid PDGF-BB levels. Furthermore, BAL fluid-induced fibroblast proliferation was blocked using an inhibitor of the PDGF receptor. DEX treatment did not influence PIIINP levels, but reduced IL-1b levels and inflammatory cell numbers in BAL fluid.This study suggests that dexamethasone treatment does not reduce fibroblast proliferation despite apparent downregulation of inflammation. The present findings do not support the use of dexamethasone for prevention of the fibrotic response in infants at risk of chronic lung disease of prematurity. Neonatal respiratory distress syndrome (RDS) is characterised by pulmonary inflammation with neutrophils and macrophages as the main cell types [1,2]. RDS can progress towards chronic lung disease (CLD) of prematurity, also known as bronchopulmonary dysplasia. Risk factors for the development of CLD include premature birth with concomitant lung immaturity, mechanical ventilator-induced lung injury, oxygen toxicity and pulmonary inflammation [3].Pulmonary fibrosis is characterised by excessive fibroblast proliferation and increased collagen deposition [4] and is a common feature in infants dying because of CLD [5]. Increased pulmonary levels of fibrogenic mediators, such as fibronectin and transforming growth factor-b 1 , which increase proliferation and collagen synthesis by fibroblasts, have been associated with CLD development [6,7].Treatment with systemic dexamethasone (DEX) is commonly used in infants with or at risk of CLD and improves pulmonary function, facilitates weaning from the ventilator and reduces pulmonary inflammation [8]. However, it has been suggested that DEX treatment may not inhibit the development of pulmonary fibrosis in CLD, since it does not decrease fibronectin concentrations in bronchoalveolar lavage (BAL) fluid [6]. Conversely, DEX treatment of CLD infants results in decreased urinary excretion of hydroxyproline, indicating suppressed collagen synthesis in these infants [9]. However, the specific effect of DEX treatment on lung collagen synthesis during CLD development remains unc...

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