Lysophosphatidic acid generation by pulmonary NKT cell ENPP-2/autotaxin exacerbates hyperoxic lung injury.

Abstract

Hyperoxia is still broadly used in clinical practice in order to assure organ oxygenation in critically ill patients, albeit known toxic effects. In this present study, we hypothesize that lysophosphatidic acid (LPA) mediates NKT cell activation in a mouse model of hyperoxic lung injury. In vitro, pulmonary NKT cells were exposed to hyperoxia for 72 h, and the induction of the ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP-2) was examined and production of lysophosphatidic acid (LPA) was measured. In vivo, animals were exposed to 100 % oxygen for 72 h and lungs and serum were harvested. Pulmonary NKT cells were then incubated with the LPA antagonist Brp-LPA. Animals received BrP-LPA prior to oxygen exposure. Autotaxin (ATX, ENPP-2) was significantly up-regulated on pulmonary NKT cells after hyperoxia (p < 0.01) in vitro. LPA levels were increased in supernatants of hyperoxia-exposed pulmonary NKT cells. LPA levels were significantly reduced by incubating NKT cells with LPA-BrP during oxygen exposure (p < 0,05) in vitro. Hyperoxia-exposed animals showed significantly increased serum levels of LPA (p ≤ 0,05) as well as increased pulmonary NKT cell numbers in vivo. BrP-LPA injection significantly improved survival as well as significantly decreased lung injury and lowered pulmonary NKT cell numbers. We conclude that NKT cell-induced hyperoxic lung injury is mediated by pro-inflammatory LPA generation, at least in part, secondary to ENPP-2 up-regulation on pulmonary NKT cells. Being a potent LPA antagonist, BrP-LPA prevents hyperoxia-induced lung injury in vitro and in vivo.

• Authors: Martina Nowak-Machen, Martin Lange, Mark Exley, Sherry Wu, Anny Usheva, Simon C Robson
• Journal: Purinergic signalling (Purinergic Signal) Vol. 11 Issue 4 Pg. 455-61 (Dec 2015) ISSN: 1573-9546 [Electronic] Netherlands
• PMID: 26306905 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Brp-LPA
• Lysophosphatidylcholines
• Lysophospholipids
• Receptors, Purinergic P2X7
• Phosphoric Diester Hydrolases
• alkylglycerophosphoethanolamine phosphodiesterase
• lysophosphatidic acid
• Oxygen

Topics

• Acute Lung Injury (metabolism, pathology)
• Animals
• Cell Count
• Hyperoxia (metabolism, pathology)
• Inflammation (pathology)
• Lung (pathology)
• Lysophosphatidylcholines (metabolism)
• Lysophospholipids (antagonists & inhibitors, biosynthesis, pharmacology)
• Mice
• Mice, Inbred C57BL
• Natural Killer T-Cells (metabolism)
• Oxygen (toxicity)
• Phosphoric Diester Hydrolases (metabolism)
• Receptors, Purinergic P2X7 (biosynthesis, genetics)
• Up-Regulation (drug effects)