Thrombin contributes to bronchoalveolar lavage fluid mitogenicity in lung disease of the premature infant

• Published in: Pediatric pulmonology 2003-01, Vol.35 (1), p.34-41
• Main Authors: Dik, Willem A., Zimmermann, Luc J.I., Naber, Brigitta A., Janssen, Daphne J., van Kaam, Anton H.L.C., Versnel, Marjan A.
• Format: Article
• Language: English
• Subjects: Activin Receptors, Type I - metabolism; Antithrombin III - metabolism; BAL fluid; Biological and medical sciences; Bronchoalveolar Lavage Fluid - cytology; Cell Division; chronic lung disease of prematurity; Chronic obstructive pulmonary disease, asthma; fibroblast proliferation; Fibroblasts - pathology; fibrosis; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases - pathology; Medical sciences; Peptide Hydrolases - metabolism; Pneumology; Protein-Serine-Threonine Kinases; Pulmonary Fibrosis - etiology; Pulmonary Fibrosis - pathology; Receptors, Transforming Growth Factor beta - metabolism; Respiration, Artificial; Respiratory Distress Syndrome, Newborn - complications; Respiratory Distress Syndrome, Newborn - pathology; thrombin; Thrombin - metabolism
• ISSN: 8755-6863; 1099-0496
• DOI: 10.1002/ppul.10219

Chronic lung disease of prematurity (CLD) is a common consequence of neonatal respiratory distress syndrome (RDS) and is characterized by pulmonary fibrosis. Increased thrombin activity in the alveolar compartment is associated with pulmonary fibrosis in adults and animals, and contributes to bronchoalveolar lavage (BAL) fluid mitogenicity for fibroblasts. We hypothesized that BAL fluid from infants who develop CLD contains increased mitogenic activity for lung fibroblasts compared to BAL fluid from resolving RDS, and that increased thrombin levels contribute to this activity. Sequential BAL (postnatal days 2–14) was obtained from 37 premature infants who were ventilated for RDS. Twenty‐six infants developed CLD, whereas 11 resolved. BAL fluid mitogenic activity was determined in a proliferation assay, using human fetal lung fibroblasts. The contribution of thrombin to mitogenic activity was determined using the thrombin inhibitor PPACK. Furthermore, thrombin levels in BAL fluid were measured using a specific substrate to detect thrombin activity and by measuring thrombin‐antithrombin III complex (TATIII). BAL fluid mitogenic activity was comparable between CLD and RDS (CLD, 33% proliferation on day 2 to 41% on day 14; RDS, 21% on day 2 to 54% on day 7). Thrombin inactivation by PPACK completely inhibited mitogenic activity in BAL samples obtained on days 2 and 4 (CLD, P