Lipoxins, aspirin-triggered epi-lipoxins, lipoxin stable analogues, and the resolution of inflammation: stimulation of macrophage phagocytosis of apoptotic neutrophils in vivo
| Autor: | John Savill, David C. Cottell, Catherine Godson, Giovanni Berlasconi, Killeen Harvey, Lars Peter Erwig, Andrew J. Rees, Hugh R. Brady, Graham L. Thomas, Keira Reville, Nicos A. Petasis, Siobhan Mitchell |
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| Rok vydání: | 2002 |
| Předmět: |
medicine.medical_specialty
Jumonji Domain-Containing Histone Demethylases Neutrophils Phagocytosis Anti-Inflammatory Agents Inflammation Apoptosis Receptors Cell Surface Pharmacology Granulocyte Biology chemistry.chemical_compound Drug Stability In vivo Bone Marrow Internal medicine medicine Cyclic AMP Humans Receptor Cells Cultured Lipoxin Aspirin Macrophages General Medicine Lipid signaling Lipids Enzymes medicine.anatomical_structure Endocrinology Phenotype chemistry Nephrology Eicosanoids medicine.symptom Peptides |
| Zdroj: | Journal of the American Society of Nephrology : JASN. 13(10) |
| ISSN: | 1046-6673 |
| Popis: | Lipoxins (LX) are eicosanoids with antiinflammatory activity in glomerulonephritis (GN) and inflammatory diseases, hypersensitivity, and ischemia reperfusion injury. It has been demonstrated that LXA(4) stimulates non-phlogistic phagocytosis of apoptotic polymorphonuclear neutrophils (PMN) by monocyte-derived macrophages (Mphi) in vitro, suggesting a role for LX as endogenous pro-resolution lipid mediators. It is here reported that LXA(4), LXB(4), the aspirin-triggered LX (ATL) epimer, 15-epi-LXB(4), and a stable synthetic analogue 15(R/S)-methyl-LXA(4) stimulate phagocytosis of exogenously administered excess apoptotic PMN by macrophages (M phi) in vivo in a classic model of acute inflammation, namely thioglycollate-induced peritonitis. Significant enhancement of phagocytosis in vivo was observed with 15-min exposure to LX and with intraperitoneal doses of LXA(4), LXB(4), 15(R/S)-methyl-LXA(4), and 15-epi-LXB(4) of 2.5 to 10 micro g/kg. Non-phlogistic LX-stimulated phagocytosis by M phi was sensitive to inhibition of PKC and PI 3-kinase and associated with increased production of transforming growth factor-beta(1) (TGF-beta(1)). LX-stimulated phagocytosis was not inhibited by phosphatidylserine receptor (PSR) antisera and was abolished by prior exposure of M phi to beta 1,3-glucan, suggesting a novel M phi-PMN recognition mechanism. Interestingly, the recently described peptide agonists of the LXA(4) receptor (MYFINITL and LESIFRSLLFRVM) stimulated phagocytosis through a process associated with increased TGF-beta(1) release. These data provide the first demonstration that LXA(4), LXB(4), ATL, and LX stable analogues rapidly promote M phi phagocytosis of PMN in vivo and support a role for LX as rapidly acting, pro-resolution signals in inflammation. Engagement of the LXR by LX generated during cell-cell interactions in inflammation and by endogenous LXR peptide agonists released from distressed cells may be an important stimulus for clearance of apoptotic cells and may be amenable to pharmacologic mimicry for therapeutic gain. |
| Databáze: | OpenAIRE |
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