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 (sPLA(2)-II) hav e been associated with a poor clinical outcome in the acute respirator y distress syndrome, This study identifies the cell source(s) and the mechanisms of sPLA(2)-II synthesis in the guinea pig model of acute re spiratory distress syndrome induced by intratracheal injection of LPS. Administration of LPS led to an increase in lung membrane-associated calcium-dependent sPLA(2) activity, which was abrogated by LY311727, a selective inhibitor of sPLA(2)-II, No sPLA(2) activity was detected i n the vascular compartment of the lung, LPS administration induced a p arallel accumulation of sPLA(2)-II mRNA in lung tissues, In situ hybri dization showed that sPLA(2)-II transcripts were synthesized in inters titial and alveolar macrophages (AM), Incubation of AM with LPS enhanc ed the expression of sPLA(2)-II mRNA, leading to stimulation of sPLA(2 )-II synthesis and secretion, This increase was prevented by the addit ion of anti-TNF-alpha and anti-p55 TNF receptor Abs, Furthermore, the addition to AM of cellfree bronchoalveolar fluid collected from LPS-tr eated guinea pigs increased sPLA(2)-II expression, which was abrogated by anti-TNF-alpha Ab, These findings demonstrate that 1) macrophages are in vivo the major cell source of sPLA(2)-II in LPS-induced acute l ung injury; 2) in contrast to that in other cell systems, regulation o f LPS-induced sPLA(2)-II synthesis in AM is TNF-alpha dependent; and 3 ) production of TNF-alpha in the air-lung interface is an important st ep for sPLA(2)-II synthesis in macrophages.