In the present study we demonstrate that PAR2 is highly expressed in airway epithelium of preterm infants who died of prolonged RDS or of BPD, and that the expression is significantly stronger in comparison with newborn infants without lung pathology. The level of PAR2 expression also showed a trend to increase with progression of RDS toward BPD. Moreover, in preterm infants with lung injury we found that trypsin-2, a potential activator of PAR2, is co-localized with PAR2 in the airway epithelium. PAR2 expression was also evident in bronchial and vascular smooth muscle, and in vascular endothelium in lungs of preterm infants with RDS or BPD and of term infants without lung pathology. This localization in infants is in accordance with earlier studies showing PAR2 expression in adult human lung tissue (6,7,27).

The endogenous activator(s) of PAR2 in the lung remains largely to be determined. In normal adult lung tissue, immunoreactivity for trypsin(ogen) was co-localized with PAR2 in the airway epithelium (7). Therefore, it has been suggested that trypsin, tightly regulated by protease inhibitors such as 1-antitrypsin, may be a physiologic activator of epithelial PAR2 in the lungs, and that epithelial PAR2 is involved in cytoprotection rather than inflammation (7,33). Like pancreatic trypsin, its isoenzyme trypsin-2 is a potent PAR2 activator (34). We have previously shown that trypsin-2 is strongly expressed in lungs of preterm infants with respiratory distress, and that during the first 2 postnatal weeks, high levels of pulmonary trypsinogen-2 are associated with subsequent development of BPD (21). In the present study we demonstrated that in preterm infants who died of prolonged RDS or BPD, trypsin-2 is co-localized with PAR2 in bronchial and alveolar epithelium. Furthermore, expression of trypsin-2 was also detected in the vascular endothelium of those preterm infants with prolonged RDS who presented with strong endothelial PAR2 expression. We hypothesize that activation of PAR2 in the lungs of preterm infants by high levels of trypsin-2 during the early postnatal period may play a role in persistent inflammatory pulmonary reaction associated with the development of BPD. This hypothesis is also supported by earlier studies showing deficiency in pulmonary 1-antitrypsin in preterm infants with RDS (35,36).

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To be capable of activating PAR2 in the lung, trypsinogen must be processed by specific enzymes. At present, it is unclear how trypsinogen is activated outside the intestine where it is activated by enteropeptidase. In vitro, it has been shown that incubation of activated leukocytes with trypsinogen can result in a conversion of trypsinogen to trypsin (37). This leukocyte-mediated mechanism could be one by which trypsinogen may be activated in the lungs of preterm infants with respiratory distress. Further studies on the mechanism of trypsin activation are important, since the trypsinogen to trypsin activators themselves might be a therapeutic target.

In conclusion, PAR2 and its potential activator trypsin-2 are co-localized in the lungs of preterm infants with prolonged RDS or BPD. We suggest that activation of PAR2 in the preterm lung by high levels of trypsin-2 may play a role in pulmonary inflammation and fibroproliferation associated with the development of BPD. Overall, our data point to both trypsin-2 and PAR2 as potential therapeutic targets in the setting of RDS and BPD in preterm infants. 589ccfa754

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