Riociguat can ameliorate bronchopulmonary dysplasia in the SU5416 induced rat experimental model

Abstract

Background

Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature neonates. Classical BPD is caused by hyperoxia and high-pressure mechanical ventilation, whereas BPD in recent era is caused by impaired pulmonary angiogenesis and alveolarization in extreme prematurity. Although sildenafil was reported to be effective in a hyperoxia-induced rat BPD model, several clinical trials could not demonstrate any significant improvement in the respiratory statuses of BPD infants. Riociguat is a soluble guanylate cyclase stimulator that increases cyclic guanosine monophosphate activity in a nitric oxide independent manner. However, a beneficial effect in BPD has not been established yet.

Methods and Results

We established BPD model in rats by injection of SU5416 on day 1 followed by maintenance under normoxia, which resulted in oversimplified alveoli, sparse pulmonary capillary vessels, severe pulmonary hypertension, and growth retardation, which mimicked the features observed in recent clinical management of BPD. We administered riociguat from day 10, when BPD rats exhibited growth retardation. Histological analyses demonstrated that riociguat treatment significantly but partially ameliorated lung alveolarization, vascularization, and pulmonary hypertension. However, the survival rate was not significantly improved by riociguat treatment.

Conclusions

Riociguat could ameliorate pulmonary alveolarization, vascularization, and hypertension in the SU5416 induced BPD rat model, but could not improve the overall survival.

Keywords:

• Bronchopulmonary dysplasia
• riociguat
• alveolarization
• pulmonary vascularization
• pulmonary hypertension

Disclosure statement

No potential conflict of interest was reported by the authors.

Sources of funding

This work was supported by grants from the Ministry of Education, Science, Sports, and Culture of Japan (no. 17K16260).

Author contributions

S.K. performed all rat experiments. H.S., H.T., W.R., C.Y., and A.U. analyzed the histological data. H.I., J.N., R.I., S.K., C.Y., A.U., and K.O. managed all the experiments and discussed the results. S.K. and H.I. wrote the manuscript. All authors have accepted the final version of the manuscript.