Sphingosine kinase 1 deficiency confers protection against hyperoxia-induced bronchopulmonary dysplasia in a murine model: role of S1P signaling and Nox proteins.
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.
Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois; Department of Medicine, University of Illinois at Chicago, Chicago, Illinois. Electronic address: harijith@uic.edu.
Anantha
A
Harijith
Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois.
Srikanth
S
Pendyala
Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois.
Narsa M
NM
Reddy
Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois.
Tao
T
Bai
Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois.
Peter V
PV
Usatyuk
Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois.
Evgeny
E
Berdyshev
Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois.
Irina
I
Gorshkova
Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois.
Long Shuang
LS
Huang
Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois.
Vijay
V
Mohan
Department of Pathology, University of Illinois at Chicago, Chicago, Illinois.
Steve
S
Garzon
Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois.
Prasad
P
Kanteti
Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois.
Sekhar P
SP
Reddy
Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois.
J Usha
JU
Raj
Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois.
Viswanathan
V
Natarajan
D000446:Aldehyde-Lyases / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000201:enzymology* / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D018496:Hyperoxia / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency* / Q000378:metabolism; D011014:Pneumonia / Q000150:complications / Q000473:pathology; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000099157:Sphingosine Kinase
D000446:Aldehyde-Lyases; D008246:Lysophospholipids; D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017382:Reactive Oxygen Species; D013110:Sphingosine; D020830:rac1 GTP-Binding Protein; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C488842:Cybb protein, mouse; C422943:Nox4 protein, mouse; C022649:sphingosine 1-phosphate lyase (aldolase)