Fgf10 overexpression prevents lung injury in a BPD model

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm infants. It is most common in children born before 28th week of gestational age with low birth weight and prolonged oxygen supplementation. BPD is characterised by arrested lung growth, with decreased alveolarisation and a dysmorphic vascular structure, leading to reduced surface area for gas exchange. We hypothesized that Fgf10 plays an important role in alveogenesis in BPD. We established a mouse model of BPD by exposing the pups (control and experimental groups) to 85% oxygen (hyperoxia) or normoxia for 28 days.

In the experimental group, we used double transgenic animals (SPC-rtTA;tet(O)Fgf10) exposed to doxycycline treatment (food from P0) to induce expression of Fgf10. The control group was composed of double transgenic animals not exposed to doxycycline. Using real-time PCR we found a significant decrease in Fgfr2b and Fgf10 expression in the hyperoxia control group at days 21 and day 28. Compared to the normoxia control group, the lung histology of pups in the hyperoxia control group showed a simplification of alveoli after 14 days. In contrast Fgf10 overexpression in the hyperoxia experimental group prevented alveoli simplification but led also to hypercellularity of the septa as well as erythrocytes in the alveolar spaces. These findings were confirmed by mean linear intercept (MLI) and radial alveolar count (RAC) analysis (MLI: Control normoxia 34, Experimental hyperoxia 75, Control hyperoxia 87. RAC: Control normoxia 50, Experimental hyperoxia 35, Control hyperoxia 24).

We conclude that Fgf10 may be helpful in the treatment of BPD to maintain and/or promote secondary septa formation in alveogenesis. However, potential side effects on vascular development need to be considered.

In the future, we will examine the precise role of Fgf10 signaling in secondary septa formation using specific loss-of-function approach (Rosa26-CreERT2;Fgf10 flox/flox) and gain-of-function approaches (Rosa26-rtTA;tet(O)Fgf10). Further morphological and functional data achieved by design-based stereology and lung function analysis will allow a better understanding of the lung regeneration process.