Bronchopulmonary dysplasia (BPD) is the most common chronic respiratory disease in premature newborns born before 32 weeks of gestation. BPD is characterized by lung growth arrest (hypoalveolarization), rarefaction of microvascularization (hypoangiogenesis) and inflammation. BPD can be complicated with pulmonary hypertension (PH) which increases the mortality rate (almost 50% of preterm infants die 2 years after diagnosis of BPD-PH). Thrombomodulin (TM), a glycoprotein expressed mostly on vascular endothelial cells, plays a central role in hemostasis but also in inflammation and angiogenesis. We thus explored the role of TM in experimental BPD-PH.

We used neonatal rats exposed to normoxia (21% O ₂ ) or hyperoxia (90% O ₂ ) during 14 days to mimic BPD-PH in vivo. Human umbilical artery endothelial cells (HUAECs) from premature newborns were also exposed to normoxia or hyperoxia (60% O ₂ during 6.24 and 48 h). To investigate TM expression and distribution, Western Blot and ELISA were performed on both models, whereas immunofluorescence was conducted on the animal model to visualize tissue-specific localization.

We showed that TM was (i) decreased in lung and arteries from newborn rat pups exposed to hyperoxia and (ii) correlated with an increase of soluble thrombomodulin (sTM) level in the plasma whereas in the heart, TM was unchanged. The observed increase in plasma sTM was associated with elevated plasma levels of proteases (MMP-9), whereas these proteases were decreased in lung tissues, likely driving the pronounced cleavage of TM into its soluble form. Moreover, in the lung, TM was located on both the vascular endothelial and epithelial alveolar cells. In HUAECs, TM expression was assessed in a hyperoxia time course at 6.24, and 48 hours, with the most significant decrease observed at 24 hours, associated to an increase of sTM level in the supernatant.

Based on these initial findings, targeting TM may be a promising therapeutic strategy for BPD-PH. Treatments that increase the expression and/or activity of TM, such as statins or recombinant human thrombomodulin (rhTM) could be considered.