Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, PC38
Sildenafil alleviates bronchopulmonary dyplasia by up-regulating Hypoxia inducible factor-1α
H. Park1, J. Park2,4, C. Choi3, H. Lee3, B. Kim3, Y. Chun1,4
1. Physiology, Seoul National University, Seoul, Korea, Republic of. 2. Pharmacology, Seoul National University, Seoul, Korea, Republic of. 3. Pediatrics, Seoul National University, Seoul, Korea, Republic of. 4. Ischemic/Hypoxic Disease Institute, Seoul National University, Seoul, Korea, Republic of.
Bronchopulmonary dysplasia (BPD) is a major cause of morbidity in premature babies with birth weights less than 1 kg. Recently, sildenafil has been clinically tested to improve the pulmonary function in BPD patients. With respect to its pharmacological mode of action, sildenafil inhibits phosphodiesterase-5, leading to cGMP elevation. However, little is known about the mechanism by which sildenafil releases the BPD symptom. We here examined the mechanism in respect to the HIF-mediated adaptation to hyperoxic injury. All animal procedures were performed in accord with the Seoul National University Laboratory Animal Maintenance Manual. To induce BPD, neonatal rats were kept with foster rats for 7 days in a Plexiglas hyperoxia chamber containing 85% oxygen. While opening the chamber once a day for one hour, we rotated fosters daily to keep nursing neonates, and injected (i.p.) sidenafil (0.1 mg/g per day) or vehicle (DMSO) into neonates. Experiments were divided into three groups; normoxia, hyperoxia, and hyperoxia+sildenafil. After being taken out of the chamber, neonates were kept in room air and injected daily with drugs for a further 7 days. After the treatments, lungs were excised from neonates, and subjected to histological study. The morphometric analyses were performed in H&E-stained lung sections. The alveolarization was measured by mean cord length and alveolar surface area. The alveolarization was severely impaired in neonatal rats exposed to hyperoxia, and sildenafil recovered the alveolarization in the BPD model. Furthermore, HIF-1α in the lungs of sildenafil-treated rats was expressed in a higher level than those of BPD rats. Immunoblotting of CD31 (vessel formation marker) and VEGF (an angiogenic factor regulated by HIF-1) revealed that sildenafil effectively promoted vascular formation. Mechanistically, cGMP was accumulated by sildenafil on account of interfering PDE5. Sildenafil stimulation activated HIF-1α and its down-stream genes at protein or mRNA levels in the human small airway epithelial cell line. We further confirmed that cGMP is a mediator of sildenafil-dependent HIF-1α activation. In conclusion, the therapeutic effect of sildenafil on neonatal BPD is likely to be attributed to HIF-1 activation.
Where applicable, experiments conform with Society ethical requirements