trypsinogen and Bronchopulmonary-Dysplasia

Proteinase-activated receptor 2 (PAR(2)), a G-protein-coupled receptor activated by serine proteinases such as trypsin, has been suggested to play an important role in inflammatory and fibroproliferative processes. In preterm infants, the development of bronchopulmonary dysplasia (BPD) is characterized by early pulmonary inflammation and subsequent interstitial fibrosis. High pulmonary trypsin-2 has been shown to be associated with the development of BPD. We studied the expression and distribution of PAR(2) and trypsin-2 by immunohistochemistry in autopsy lung specimens of fetuses (n = 10), of preterm infants who died of acute or prolonged respiratory distress syndrome (RDS) (n = 8 and n = 7, respectively) or BPD (n = 6), and of newborn infants without lung disease (n = 5) who served as controls. In prolonged RDS and BPD, PAR(2) immunoreactivity was significantly higher in bronchial epithelium when compared with infants without pulmonary pathology (p < 0.05 and p < 0.005, respectively). In alveolar epithelium, expression of PAR(2) was elevated in prolonged RDS when compared with newborn infants without pulmonary pathology (p < 0.05). Moreover, strong expression of PAR(2) was detected in myofibroblasts of thickened and fibrotic alveolar walls in prolonged RDS or BPD. Trypsin-2 was co-localized with PAR(2) in bronchoalveolar epithelium. These findings suggest that PAR(2), possibly activated by trypsin-2, may participate in inflammation and fibroproliferation associated with progression of RDS toward BPD in preterm infants.

Topics: Acute Disease; Bronchopulmonary Dysplasia; Case-Control Studies; Chronic Disease; Fetus; Humans; Immunohistochemistry; Infant, Newborn; Infant, Premature; Pulmonary Alveoli; Receptor, PAR-2; Respiratory Distress Syndrome, Newborn; Trypsin; Trypsinogen

In the preterm infant, lung injury can lead to irreversible tissue destruction and abnormal lung development. We examined whether pulmonary trypsin, a potent matrix-degrading serine proteinase and proteinase-cascade activator, is associated with the development of bronchopulmonary dysplasia (BPD) in preterm infants.. Samples of tracheal aspirate fluid were collected from 32 intubated preterm infants during their first 2 postnatal weeks. The presence and molecular forms of trypsin in tracheal aspirate fluid samples were analyzed by zymography and Western blotting. The concentrations of trypsinogen-1 and -2 and tumor-associated trypsin inhibitor were measured by immunofluorometry. For examining the expression of trypsin-2 in lung tissue, immunohistochemistry was performed on autopsy specimens of fetuses, of preterm infants who died from respiratory distress syndrome or BPD, and of term infants without lung injury.. In infants who subsequently developed BPD (n = 18), we detected significantly higher concentrations of trypsinogen-2 during postnatal days 5 to 10 compared with those who survived without it. There was no difference in trypsinogen-1 concentrations. Tumor-associated trypsin inhibitor concentrations were significantly lower in infants who needed mechanical ventilation for >1 week. Immunohistochemistry demonstrated that trypsin-2 was predominantly expressed in bronchial and bronchiolar epithelium. In 2 preterm infants who died from prolonged respiratory distress syndrome, trypsin-2 was also expressed in vascular endothelium.. The levels of trypsinogen-2 are higher during postnatal days 5 to 10 in infants who subsequently develop BPD. The results suggest that high levels of pulmonary trypsin-2 may be associated with the development of BPD. This raises the possibility that therapy with exogenous proteinase inhibitors might prevent the development of BPD in preterm infants with respiratory distress.

Topics: Body Fluids; Bronchopulmonary Dysplasia; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Male; Pregnancy; Suction; Trachea; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen