Proceedings of The Physiological Society

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCB342

Poster Communications

Hemin treatment decreases oxidative stress, vascular inflammation and remodelling in chronically hypoxic and pulmonary hypertensive newborn lambs

R. Ebensperger1, F. A. Beñaldo1, C. Araya-Quijada1, S. Castillo-Galan1, A. Gonzalez-Candia1, E. A. Herrera1,2, R. V. Reyes1,2, F. Moraga3, P. A. Diaz1, M. Diaz4, A. J. Llanos1,2, G. Ebensperger1

1. Programa de Fisiopatologia, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile. 2. International Center for Andean Studies, Universidad de Chile, Santiago, Chile. 3. Facultad de Medicina, Universidad Católica del Norte, Coquimbo, Chile. 4. Departamento de Promoción de la Salud de la Mujer y el Recién Nacido, Facultad de Medicina, Universidad de Chile, Santiago, Chile.

The neonatal lamb gestated and born at high-altitude (HA) chronic hypoxia shows increased pulmonary arterial pressure, vascular hyperreactivity and remodelling, a troika that characterizes the neonatal pulmonary hypertension. These changes are mainly the result of a lesser capacity of the enzyme to produce cGMP, by a reduced enzymatic function due to a sGC at low tissue concentration (1). Hemin is an heme oxygenase inductor, resulting in an elevated CO and cGMP production in HA neonatal lambs. Further, hemin administration could also enhance sGC protein expression and function, and decrease cellular processes such as inflammation and oxidative stress. Therefore, we proposed that hemin administration is able to augment cGMP and reduce the pulmonary vascular inflammation and oxidative stress. Twelve pulmonary hypertensive newborn sheep, born and raised at Putre Research Station, INCAS (3,600 m) were separated in two groups: 6 newborn sheep, were treated receiving daily a hemin dose (15 µg kg-1 day-1SC) during 10 days. Six newborn lambs were the controls receiving the vehicle. At 15 days old, the lambs were euthanized, lungs were dissected, weighed and collected for molecular determinations (cGMP content, 8-Isoprostane and catalase activity, TNF-a and PDGF isoforms expression), histologic studies (muscle layer measurement in small pulmonary arteries) and immunohistochemistry (proliferation marker Ki67, macrophage marker CD 163 and NFkB). All procedures were approved by the Bioethical Committee of the Faculty of Medicine, University of Chile (CBA #0561 FMUCH). Hemin-treatment increased sGC protein expression and cGMP content, decreased the muscle layer area, Ki67 and PDGFs isoforms (mitogenic agents), relative to high-altitude newborn controls. Further, hemin-treated lambs showed a reduction in oxidative stress markers, catalase activity, and NFkB immunohistochemistry measurement compare to controls. Finally, macrophages were decreased in pulmonary arteries of hemin group. We conclude that hemin improves cellular cGMP status, reduced the inflammation and oxidative stress in neonatal pulmonary circulation in high altitude lambs. Further, this treatment was able to decreased pathologic pulmonary remodelling in the pulmonary arteries.

Where applicable, experiments conform with Society ethical requirements