Riociguat prevents hyperoxia-induced lung injury and pulmonary hypertension in neonatal rats without effects on long bone growth

Keyur Donda, Ronald Zambrano, Younghye Moon, Justin Percival, Ruben Vaidya, Fredrick Dapaah-Siakwan, Shihua Luo, Matthew R. Duncan, Yong Bao, Luqing Wang, Ling Qin, Merline Benny, Karen Young, Shu Wu

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Bronchopulmonary dysplasia (BPD) remains the most common and serious chronic lung disease of premature infants. Severe BPD complicated with pulmonary hypertension (PH) increases the mortality of these infants. Riociguat is an allosteric soluble guanylate cyclase stimulator and is approved by the FDA for treating PH in adults. However, it has not been approved for use in neonates due to concern for adverse effects on long bone growth. To address this concern we investigated if administration of riociguat is beneficial in preventing hyperoxia-induced lung injury and PH without side effects on long bone growth in newborn rats. Newborn rats were randomized to normoxia (21% O2) or hyperoxia (85% O2) exposure groups within 24 hours of birth, and received riociguat or placebo by once daily intraperitoneal injections during continuous normoxia or hyperoxia exposure for 9 days. In the hyperoxia control group, radial alveolar count, mean linear intercept and vascular density were significantly decreased, the pathological hallmarks of BPD, and these were accompanied by an increased inflammatory response. There was also significantly elevated vascular muscularization of peripheral pulmonary vessels, right ventricular systolic pressure and right ventricular hypertrophy indicating PH. However, administration of riociguat significantly decreased lung inflammation, improved alveolar and vascular development, and decreased PH during hyperoxia by inducing cGMP production. Additionally, riociguat did not affect long bone growth or structure. These data indicate that riociguat is beneficial in preventing hyperoxia-induced lung injury and PH without affecting long bone growth and structure and hence, suggests riociguat may be a potential novel agent for preventing BPD and PH in neonates.

Original languageEnglish (US)
Article numbere0199927
JournalPLoS One
Volume13
Issue number7
DOIs
StatePublished - Jul 1 2018

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hyperoxia
Hyperoxia
Bone Development
Lung Injury
Pulmonary Hypertension
hypertension
Rats
Bone
neonates
lungs
bones
Bronchopulmonary Dysplasia
bronchopulmonary dysplasia
Blood Vessels
blood vessels
normoxia
Right Ventricular Hypertrophy
Pulmonary diseases
Guanylate Cyclase
Infant Mortality

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Riociguat prevents hyperoxia-induced lung injury and pulmonary hypertension in neonatal rats without effects on long bone growth. / Donda, Keyur; Zambrano, Ronald; Moon, Younghye; Percival, Justin; Vaidya, Ruben; Dapaah-Siakwan, Fredrick; Luo, Shihua; Duncan, Matthew R.; Bao, Yong; Wang, Luqing; Qin, Ling; Benny, Merline; Young, Karen; Wu, Shu.

In: PLoS One, Vol. 13, No. 7, e0199927, 01.07.2018.

Research output: Contribution to journalArticle

Donda, K, Zambrano, R, Moon, Y, Percival, J, Vaidya, R, Dapaah-Siakwan, F, Luo, S, Duncan, MR, Bao, Y, Wang, L, Qin, L, Benny, M, Young, K & Wu, S 2018, 'Riociguat prevents hyperoxia-induced lung injury and pulmonary hypertension in neonatal rats without effects on long bone growth', PLoS One, vol. 13, no. 7, e0199927. https://doi.org/10.1371/journal.pone.0199927
Donda, Keyur ; Zambrano, Ronald ; Moon, Younghye ; Percival, Justin ; Vaidya, Ruben ; Dapaah-Siakwan, Fredrick ; Luo, Shihua ; Duncan, Matthew R. ; Bao, Yong ; Wang, Luqing ; Qin, Ling ; Benny, Merline ; Young, Karen ; Wu, Shu. / Riociguat prevents hyperoxia-induced lung injury and pulmonary hypertension in neonatal rats without effects on long bone growth. In: PLoS One. 2018 ; Vol. 13, No. 7.
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