Endotoxin induces expression of type II phospholipase A2 in macrophages during acute lung injury in guinea pigs: involvement of TNF-alpha in lipopolysaccharide-induced type II phospholipase A2 synthesis.
Elevated levels of secretory type II phospholipase A2 (sPLA2-II) have been associated with a poor clinical outcome in the acute respiratory distress syndrome. This study identifies the cell source(s) and the mechanisms of sPLA2-II synthesis in the guinea pig model of acute respiratory distress syndrome induced by intratracheal injection of LPS. Administration of LPS led to an increase in lung membrane-associated calcium-dependent sPLA2 activity, which was abrogated by LY311727, a selective inhibitor of sPLA2-II. No sPLA2 activity was detected in the vascular compartment of the lung. LPS administration induced a parallel accumulation of sPLA2-II mRNA in lung tissues. In situ hybridization showed that sPLA2-II transcripts were synthesized in interstitial and alveolar macrophages (AM). Incubation of AM with LPS enhanced the expression of sPLA2-II mRNA, leading to stimulation of sPLA2-II synthesis and secretion. This increase was prevented by the addition of anti-TNF-alpha and anti-p55 TNF receptor Abs. Furthermore, the addition to AM of cellfree bronchoalveolar fluid collected from LPS-treated guinea pigs increased sPLA2-II expression, which was abrogated by anti-TNF-alpha Ab. These findings demonstrate that 1) macrophages are in vivo the major cell source of sPLA2-II in LPS-induced acute lung injury; 2) in contrast to that in other cell systems, regulation of LPS-induced sPLA2-II synthesis in AM is TNF-alpha dependent; and 3) production of TNF-alpha in the air-lung interface is an important step for sPLA2-II synthesis in macrophages.
Arbibe
L
L
Unit of Cellular Pharmacology, Associate Unit of the Pasteur Institute/INSERM 285, Paris, France.
Vial
D
D
Rosinski-Chupin
I
I
Havet
N
N
Huerre
M
M
Vargaftig
B B
BB
Touqui
L
L
D000818:Animals; D006168:Guinea Pigs; D006801:Humans; D017403:In Situ Hybridization; D007231:Infant, Newborn; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D016676:Macrophages, Alveolar / Q000201:enzymology*; D008297:Male; D010741:Phospholipases A / Q000096:biosynthesis*; D054467:Phospholipases A2; D012127:Respiratory Distress Syndrome, Newborn / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D010741:Phospholipases A; D054467:Phospholipases A2