Resolvin D1 controls inflammation initiated by glutathione-lipid conjugates formed during oxidative stress.

BACKGROUND AND PURPOSE: Inflammation is associated with oxidative stress and local generation of lipid peroxidation-derived aldehydes, such as 4-hydroxy-trans-2-nonenal (HNE). In most tissues, HNE is readily conjugated with glutathione and presently it is unknown whether glutathionyl-HNE (GS-HNE) plays a functional role in inflammation. Here, we sought to determine whether GS-HNE is a mediator of oxidative stress-initiated inflammation and if its actions can be regulated by the anti-inflammatory and pro-resolving lipid mediator, resolvin D1 (RvD1). EXPERIMENTAL APPROACH: GS-HNE was administered intraperitoneally to mice and peritoneal lavages were assessed for leukocyte infiltration and lipid mediators were targeted by mediator-lipidomics. RvD1 was administered to mice treated with GS-HNE and leukocyte infiltration was assessed in the peritoneum. Superoxide production and CD11b modulation were measured in isolated human polymorphonuclear leukocytes incubated with GS-HNE. KEY RESULTS: GS-HNE (1-10 microg) evoked infiltration of Gr-1(+) leukocytes into the peritoneum to form an inflammatory exudate. With isolated human polymorphonuclear leukocytes, GS-HNE stimulated both superoxide generation and CD11b expression. Among the lipid mediators, both cyclooxygenase- and lipoxygenase-derived pro-inflammatory eicosanoids, including prostaglandin E(2), leukotriene B(4) and cysteinyl leukotrienes, were generated in exudates of mice injected intraperitoneally with GS-HNE. RvD1, given i.v. in doses as low as 0.01-10.0 ng, sharply reduced GS-HNE-stimulated leukocyte infiltration ( approximately 30-70%). CONCLUSIONS AND IMPLICATIONS: Glutathione conjugates of HNE, derived during oxidative stress, are pro-inflammatory in vivo. RvD1 protects against this oxidative stress-initiated inflammation.

Measurement of stellar age from uranium decay.

The ages of the oldest stars in the Galaxy indicate when star formation began, and provide a minimum age for the Universe. Radioactive dating of meteoritic material and stars relies on comparing the present abundance ratios of radioactive and stable nuclear species to the theoretically predicted ratios of their production. The radioisotope 232Th (half-life 14 Gyr) has been used to date Galactic stars, but it decays by only a factor of two over the lifetime of the Universe. 238U (half-life 4.5 Gyr) is in principle a more precise age indicator, but even its strongest spectral line, from singly ionized uranium at a wavelength of 385.957 nm, has previously not been detected in stars. Here we report a measurement of this line in the very metal-poor star CS31082-001, a star which is strongly overabundant in its heavy elements. The derived uranium abundance, log(U/H) = -13.7 +/- 0.14 +/- 0.12 yields an age of 12.5 +/- 3 Gyr, though this is still model dependent. The observation of this cosmochronometer gives the most direct age determination of the Galaxy. Also, with improved theoretical and laboratory data, it will provide a highly precise lower limit to the age of the Universe.