The reaction of Pt(dba) 2 with CO (1 atm) in toluene affords a brown precipitate which can be isolated and redissolved in CH 2 Cl 2 to give a colloidal solution of fcc platinum particles with a large size dispersity (10-20 Å, I). Redissolution of I in THF leads to stable 12 Å fcc platinum particles (II) which can be isolated and characterized by high-resolution electron microscopy (HREM) and wide-angle X-ray scattering (WAXS). The original reaction in THF leads to the direct formation of II. Addition of 0.2 equiv of PPh 3 to II yields a new colloid, III, of the same size but of icosahedral structure. III was characterized by HREM and spectroscopic techniques. In particular, 13 C and 31 P NMR spectroscopy demonstrates the absence of a Knight shift for these particles. Addition of excess triphenylphosphine leads to another species, IV, displaying broader size distribution with a maximum at 17 Å and an fcc structure. The reaction of I with more than 0.2 equiv of PPh 3 affords mixtures containing colloids, clusters (predominantly Pt 5 (CO) 6 (PPh 3 ) 4 ), and mononuclear complexes. Both the formation of the colloids and their transformation into molecular species is rapid at room temperature. It is suggested that such processes may be more frequent in organometallic chemistry than previously thought.
Sepsis is characterized by systemic inflammation with release of a large amount of inflammatory mediators. If sustained, this inflammatory response can lead to multiple organ failure and/or immunoparalysis. In the latter condition, the host may be susceptible to opportunistic infections or be unable to clear existing infections. Therefore, it is potentially beneficial to resolve inflammation by reducing inflammation without compromising host defense. We examined the effect of lipoxin A4 (LXA4), a compound with inflammatory resolution properties, in the cecal ligation and puncture (CLP) model of sepsis. Cecal ligation and puncture rats were given either saline or LXA4 (40 μg/kg, i.p.) 5 h after surgery. Lipoxin A4 administration increased 8-day survival of CLP rats, which lived longer than 48 h, and attenuated tissue injury after 8 days. Therefore, we investigated the effects of LXA4 on systemic inflammation and bacterial load 48 h after CLP sepsis. Plasma IL-6, monocyte chemotactic protein 1, and IL-10 levels were reduced in LXA4-treated rats compared with CLP rats given saline vehicle. Lipoxin A4 reduced phosphorylation of the p65 subunit of nuclear factor κB (NF-κB) at serines 536 and 468 in peritoneal macrophages, suggesting that LXA4 reduced production of proinflammatory mediators through an NF-κB-mediated mechanism. Lipoxin A4 reduced blood bacterial load and increased peritoneal macrophage number without affecting phagocytic ability, suggesting that LXA4 reduced blood bacterial load by enhancing macrophage recruitment. It also suggests that LXA4 reduced systemic inflammation and NF-κB activation without compromising host defense. Increased macrophage recruitment was in part due to a direct effect of LXA4 as LXA4 increased peritoneal macrophage recruitment in sham controls and partly due to reduced production of IL-10 as LXA4 decreased macrophage IL-10 release (a known inhibitor of macrophage migration) after CLP. The results suggest that LXA4 increased survival in sepsis by simultaneously reducing systemic inflammation as well as bacterial spread.
Macrophages are central in coordinating immune responses, tissue repair, and regeneration, with different subtypes being associated with inflammation-initiating and proresolving actions. We recently identified a family of macrophage-derived proresolving and tissue regenerative molecules coined maresin conjugates in tissue regeneration (MCTR). Herein, using lipid mediator profiling we identified MCTR in human serum, lymph nodes, and plasma and investigated MCTR biosynthetic pathways in human macrophages. With human recombinant enzymes, primary cells, and enantiomerically pure compounds we found that the synthetic maresin epoxide intermediate 13S,14S-eMaR (13S,14S-epoxy- 4Z,7Z,9E,11E,16Z,19Z-docosahexaenoic acid) was converted to MCTR1 (13R-glutathionyl, 14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid) by LTC4S and GSTM4. Incubation of human macrophages with LTC4S inhibitors blocked LTC4 and increased resolvins and lipoxins. The conversion of MCTR1 to MCTR2 (13R-cysteinylglycinyl, 14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid) was catalyzed by γ-glutamyl transferase (GGT) in human macrophages. Biosynthesis of MCTR3 was mediated by dipeptidases that cleaved the cysteinyl-glycinyl bond of MCTR2 to give 13R-cysteinyl, 14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid. Of note, both GSTM4 and GGT enzymes displayed higher affinity to 13S,14S-eMaR and MCTR1 compared with their classic substrates in the cysteinyl leukotriene metabolome. Together these results establish the MCTR biosynthetic pathway and provide mechanisms in tissue repair and regeneration.
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