Generation of lyso-phospholipids from surfactant in acute lung injury is mediated by type-II phospholipase A2 and inhibited by a direct surfactant protein A-phospholipase A2 protein interaction.
Lyso-phospholipids exert a major injurious effect on lung cell membranes during Acute Respiratory Distress Syndrome (ARDS), but the mechanisms leading to their in vivo generation are still unknown. Intratracheal administration of LPS to guinea pigs induced the secretion of type II secretory phospholipase A2 (sPLA2-II) accompanied by a marked increase in fatty acid and lyso-phosphatidylcholine (lyso-PC) levels in the bronchoalveolar lavage fluid (BALF). Administration of LY311727, a specific sPLA2-II inhibitor, reduced by 60% the mass of free fatty acid and lyso-PC content in BALF. Gas chromatography/mass spectrometry analysis revealed that palmitic acid and palmitoyl-2-lyso-PC were the predominant lipid derivatives released in BALF. A similar pattern was observed after the intratracheal administration of recombinant guinea pig (r-GP) sPLA2-II and was accompanied by a 50-60% loss of surfactant phospholipid content, suggesting that surfactant is a major lung target of sPLA2-II. In confirmation, r-GP sPLA2-II was able to hydrolyze surfactant phospholipids in vitro. This hydrolysis was inhibited by surfactant protein A (SP-A) through a direct and selective protein-protein interaction between SP-A and sPLA2-II. Hence, our study reports an in vivo direct causal relationship between sPLA2-II and early surfactant degradation and a new process of regulation for sPLA2-II activity. Anti-sPLA2-II strategy may represent a novel therapeutic approach in lung injury, such as ARDS.
Arbibe
L
L
Unité de Pharmacologie Cellulaire-Unité Associée Pasteur/INSERM U 485, Institut Pasteur, Paris, France.
Koumanov
K
K
Vial
D
D
Rougeot
C
C
Faure
G
G
Havet
N
N
Longacre
S
S
Vargaftig
B B
BB
Béréziat
G
G
Voelker
D R
DR
Wolf
C
C
Touqui
L
L
D000208:Acute Disease; D000818:Animals; D015374:Biosensing Techniques; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D005227:Fatty Acids / Q000378:metabolism; D054501:Group II Phospholipases A2; D006168:Guinea Pigs; D006868:Hydrolysis; D007211:Indoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008171:Lung Diseases / Q000503:physiopathology*; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D008297:Male; D019308:Palmitic Acid / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D011485:Protein Binding; D011510:Proteolipids / Q000378:metabolism*; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000378:metabolism*
D005227:Fatty Acids; D007211:Indoles; C095553:LY 311727; D008070:Lipopolysaccharides; D008244:Lysophosphatidylcholines; D011510:Proteolipids; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; C006065:We 201; D019308:Palmitic Acid; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2