E. colihemolysin-induced lipid mediator metabolism in alveolar macrophages: impact of eicosapentaenoic acid

Abstract

Escherichia coli hemolysin (HlyA) is a prototype of a large family of pore-forming proteinaceous exotoxins that have been implicated in the pathogenetic sequelae of severe infection and sepsis, including development of acute lung injury. In the present study in rabbit alveolar macrophages (AMs), subcytolytic concentrations of purified HlyA evoked rapid synthesis of platelet-activating factor, with quantities approaching those in response to maximum calcium ionophore challenge. In parallel, large quantities of leukotriene (LT) B(4) and 5-, 8-, 9-, 12-, and 15-hydroxyeicosatetraenoic acid (HETE) were liberated from HlyA-exposed AMs depending on exogenous arachidonic acid (AA) supply. Coadministration of eicosapentaenoic acid (EPA) dose dependently suppressed generation of the proinflammatory lipoxygenase products LTB(4) and 5-, 8-, 9-, and 12-HETE in parallel with the appearance of the corresponding EPA-derived metabolites LTB(5) and 5-, 8-, 9-, and 12-hydroxyeicosapentaenoic acid (HEPE). At equimolar concentrations, EPA turned out to be the preferred substrate over AA for these AM lipoxygenase pathways, with the sum of LTB(5) and 5-, 8-, 9-, and 12-HEPE surpassing the sum of LTB(4) and 5-, 8-, 9-, and 12-HETE by >80-fold. In contrast, coadminstration of EPA did not significantly reduce HlyA-elicited generation of the anti-inflammatory AA lipoxygenase product 15-HETE. We conclude that AMs are sensitive target cells for HlyA attack, resulting in marked proinflammatory lipid mediator synthesis. In the presence of EPA, lipoxygenase product formation is shifted from a pro- to an anti-inflammatory profile.

Epoxyeicosatrienoates are the dominant eicosanoids in human lungs upon microbial challenge

“…This may be explained by an additional amplification of the increase in LT generation due to exogenously supplied AA by multiple transcellular cooperative biosynthesis mechanisms typical for LTs, comprising a broad array of cell types, as described in the following. 1) The monitored LT profiles are compatible with the finding that even after extensive rinsing with buffer fluid, lungs harbour large, ''resident'' intracapillary pools of different leukocytes, but virtually no platelets [14,15], and that the various resting pulmonary leukocyte populations (intravascular, interstitial and alveolar macrophages [44,45]; lung mast cells [46]; intravascular granulocytes [3,18]; monocytes [47]; and lymphocytes [48]) are known to be involved in the biosynthesis of LOX-derived lipid mediators.…”

Hydroxyeicosapentaenoic acids from the Pacific krill show high ligand activities for PPARs

“…This report and the present results show that hydroxylation at the C-8 position is properties of HEPEs, including 8-HEPE. It was shown that Escherichia coli hemolysin induced production of 8-HEPE in rabbit macrophages ( 48 ). However, no enzyme with the capability of transforming EPA into 8-HEPE has been identifi ed to date.…”

“…The lipoxygenase pathway transforms PUFAs into lipoxins, leukotrienes, and monohydroxy fatty acids, whereas the cyclooxygenase pathway produces prostaglandins and thromboxanes. Production of HEPEs has been observed in platelets ( 47 ), macrophages ( 48,49 ), and lung cells ( 50 ); and Tomio et al ( 51 ) showed that 12-HEPE and 15-HEPE are decreased in 12/15-lipoxygenase knockout mice. In general, the physiological effects of HEPEs are unclear; however, it has been suggested that 12-HEPE and 15-HEPE have a suppressive effect on the development of endometriotic lesions ( 51 ).…”

Selective Activation of Human Intestinal Mast Cells by Escherichia coli Hemolysin

“…It has been shown that E. coli Hly mediates degranulation and production of eicosanoids, NO, respiratory burst, and different cytokines such as IL-1␤, IL-6, and CXCL8. Various cells including human neutrophils, basophils, macrophages, and endothelial cells can be targeted by Hly (22,(37)(38)(39)(40)(41). Studies performed in the 1980s suggested that Hly ϩ E. coli provoke histamine release in rat MCs (38,39).…”