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The role of surfactant phospholipids in the modulation of tumour necrosis factor-α production by monocytes

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Author
Morris, Keith
Date
2001
Type
Thesis
Publisher
Cardiff Metropolitan University
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Abstract
The release of the cytokine Tumour Necrosis Factor-α (TNF-α) by alveolar macrophages, is central to the inflammatory response within the lung. The Alveolar macrophage is derived from peripheral blood monocytes. This study investigated how pulmonary surfactant (composed of approximately 90% phospholipids and lipids and 10% surfactant proteins) modulates the lipopolysaccharide (LPS) induced production of TNF- α in the human monocytic cell line MonoMac-6 (MM6). The artificial surfactants Curosurf™, Survantar™ and Exosurf™, were all shown to significantly inhibit TNF- α (p<0.05). The major lipid components of surfactant, phosphatidylcholine and cholesterol, were both also seen to modulate TNF-a release in these cells but the effect of cholesterol was not seen at physiological concentrations. Further incubation with 1,2 dipalmitoylphosphatidylcholine (DPPC), the major disaturated species of phosphatidylcholine present in surfactant also significantly reduced TNF- α. In contrast 1- palmitoyl-2-arachidonoyl phosphatidylcholine, (PAPC) an unsaturated species of phosphatidylcholine, did not significantly modulate TNF- α release in MM6 cells. DPPC was also seen to down-regulate TNF- α release in human peripheral blood monocytes. DPPC was also able to significantly reduce membrane fluidity (p<0.05) and also reduce TNF- α mRNA production. Transmission electron microscopy demonstrated that incubation with DPPC altered the monocyte membrane ultrastructure. Chromatography also demonstrated increased concentrations of DPPC in the cells after incubation with DPPC. The LPS induced release of another inflammatory cytokine IL-β and the regulatory cytokine IL-10 were unaffected by incubating MM6 cells with DPPC. The LPS induced expression of the monocyte LPS receptor CDl4, was also reduced by DPPC. LPS induced release of prostaglandin E2 (PGE2), an important regulator of TNF- α, was significantly (P<0.05) increased in DPPC treated cells. Inhibition of PGE2 production by aspirin and the specific COX-2 inhibitor NS-398, reversed the modulation of LPS induced TNF- α release by DPPC. COX-2 the enzyme responsible for PGE2 synthesis, was seen to be directly upregulated by DPPC whereas PPAR-y, an important ligand for polyunsaturated fatty acids and regulator of COX-2 expression, was reduced by DPPC. Taken together these results suggest an important role for the disaturated phosphatidylcholine species and important surfactant phospholipid DPPC, in regulating the TNF- α, in a mechanism that involves upregulation of PGE2 down-regulation of PPAR-y, and increased production of COX-2.
URI
http://hdl.handle.net/10369/6495
Description
PhD
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  • PhD theses \ Traethodau PhD [469]

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