Sphingosine kinase 1 deficiency confers protection against hyperoxia-induced bronchopulmonary dysplasia in a murine model: role of S1P signaling and Nox proteins.

Abstract

Bronchopulmonary dysplasia of the premature newborn is characterized by lung injury, resulting in alveolar simplification and reduced pulmonary function. Exposure of neonatal mice to hyperoxia enhanced sphingosine-1-phosphate (S1P) levels in lung tissues; however, the role of increased S1P in the pathobiological characteristics of bronchopulmonary dysplasia has not been investigated. We hypothesized that an altered S1P signaling axis, in part, is responsible for neonatal lung injury leading to bronchopulmonary dysplasia. To validate this hypothesis, newborn wild-type, sphingosine kinase1(-/-) (Sphk1(-/-)), sphingosine kinase 2(-/-) (Sphk2(-/-)), and S1P lyase(+/-) (Sgpl1(+/-)) mice were exposed to hyperoxia (75%) from postnatal day 1 to 7. Sphk1(-/-), but not Sphk2(-/-) or Sgpl1(+/-), mice offered protection against hyperoxia-induced lung injury, with improved alveolarization and alveolar integrity compared with wild type. Furthermore, SphK1 deficiency attenuated hyperoxia-induced accumulation of IL-6 in bronchoalveolar lavage fluids and NADPH oxidase (NOX) 2 and NOX4 protein expression in lung tissue. In vitro experiments using human lung microvascular endothelial cells showed that exogenous S1P stimulated intracellular reactive oxygen species (ROS) generation, whereas SphK1 siRNA, or inhibitor against SphK1, attenuated hyperoxia-induced S1P generation. Knockdown of NOX2 and NOX4, using specific siRNA, reduced both basal and S1P-induced ROS formation. These results suggest an important role for SphK1-mediated S1P signaling-regulated ROS in the development of hyperoxia-induced lung injury in a murine neonatal model of bronchopulmonary dysplasia.

• Authors: Anantha Harijith, Srikanth Pendyala, Narsa M Reddy, Tao Bai, Peter V Usatyuk, Evgeny Berdyshev, Irina Gorshkova, Long Shuang Huang, Vijay Mohan, Steve Garzon, Prasad Kanteti, Sekhar P Reddy, J Usha Raj, Viswanathan Natarajan
• Journal: The American journal of pathology (Am J Pathol) Vol. 183 Issue 4 Pg. 1169-1182 (Oct 2013) ISSN: 1525-2191 [Electronic] United States
• PMID: 23933064 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Lysophospholipids
• Membrane Glycoproteins
• Reactive Oxygen Species
• sphingosine 1-phosphate
• Cybb protein, mouse
• NADPH Oxidase 2
• NADPH Oxidase 4
• NADPH Oxidases
• Nox4 protein, mouse
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• rac1 GTP-Binding Protein
• Aldehyde-Lyases
• sphingosine 1-phosphate lyase (aldolase)
• Sphingosine

Topics

• Aldehyde-Lyases (deficiency, metabolism)
• Animals
• Animals, Newborn
• Bronchopulmonary Dysplasia (enzymology, etiology, pathology, prevention & control)
• Disease Models, Animal
• Down-Regulation (drug effects)
• Endothelial Cells (drug effects, enzymology, pathology)
• Humans
• Hyperoxia (complications, enzymology, pathology)
• Lysophospholipids (metabolism)
• Membrane Glycoproteins (metabolism)
• Mice
• Mice, Inbred C57BL
• NADPH Oxidase 2
• NADPH Oxidase 4
• NADPH Oxidases (metabolism)
• Phosphotransferases (Alcohol Group Acceptor) (deficiency, metabolism)
• Pneumonia (complications, pathology)
• Pulmonary Alveoli (enzymology, pathology)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Sphingosine (analogs & derivatives, metabolism)
• rac1 GTP-Binding Protein (metabolism)