Dexamethasone treatment suppresses collagen synthesis in infants with bronchopulmonary dysplasia

Abstract

Collagen is an essential component of connective tissue and is present in the pulmonary interstitium. Collagen deposition is known to increase in many acquired chronic diseases, including bronchopulmonary dysplasia (BPD). Urinary excretion of hydroxyproline has been used as a specific index of collagen synthesis. Many studies have demonstrated that dexamethasone therapy is associated with respiratory improvement in infants with BDP but the mechanism of this effect is not well understood. We postulated that in infants with BDP who receive dexamethasone, suppression of collagen synthesis may cause respiratory improvement. Therefore, we studied the effect of dexamethasone on respiratory status and urinary excretion of hydroxyproline in 14 ventilator-dependent infants with BDP. Infants received 0.5 mg/kg/day dexamethasone, tapered by half every 3 days to complete a 12 day course. Eleven of the 14 infants were extubated at a mean +/- SD of 8.7 +/- 4.9 days after starting dexamethasone. Mean urinary hydroxyproline/creatinine ratios at 3, 6, 9, and 12 days of dexamethasone therapy were significantly lower than the mean pretreatment value, but after discontinuation rapidly rose toward baseline values. Decreased urinary excretion of hydroxyproline indicates that dexamethasone suppressed collagen synthesis in these infants. We speculate that suppression of collagen synthesis reduced pulmonary inflammation and fibrosis, resulting in respiratory improvement.

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

“…In line with this, DEX treatment has been demonstrated to decrease total body collagen synthesis in infants with CLD [9,32]. However, no difference was observed in PIIINP levels before and after DEX treatment, indicating that DEX treatment does not influence collagen synthesis in the lungs of infants developing CLD, and, therefore, may not inhibit the development of pulmonary fibrosis in these infants.…”

“…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 unclear, as urinary excretion of hydroxyproline reflects total body collagen synthesis.…”

Markers and mediators of inflammation in neonatal lung disease

“…88,89 In addition, different studies have noted striking increases in plasma concentration of most amino acids and a decrease in urinary hydroxyproline (an amino acid found exclusively in collagen) in infants treated with systemic dexamethasone for BPD. [90][91][92][93] These findings suggest that systemic dexamethasone alters protein composition either by suppressing protein/collagen synthesis or increased proteolysis. However, long-term detrimental effects of dexamethasone treatment related to impairment of protein or collagen synthesis on lung growth and development in human infants are still unknown.…”

Pharmacometabolomics of Respiratory Phenotypic Response to Dexamethasone in Preterm Infants at Risk for Bronchopulmonary Dysplasia

“…Trans‐4‐hydroxyproline is elevated in patients with idiopathic pulmonary fibrosis . In 14 ventilator‐dependent infants with BPD, high‐dose dexamethasone treatment was associated with decreased urinary trans‐4‐hydroxyproline at days 3, 6, 9, and 12 of treatment, indicating suppressed collagen synthesis . In rats, sepsis‐associated lung injury is associated with increased pulmonary fibrosis and hydroxyproline content.…”