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Leukotriene A 4 hydrolase (LTA 4 H) catalyzes production of the proinflammatory lipid mediator, leukotriene (LT) B 4 , which is implicated in a number of inflammatory diseases. We have identified a potent and selective inhibitor of both the epoxide hydrolase and aminopeptidase activities of recombinant human LTA 4 H (IC 50 , approximately 10 nM). In a murine model of arachidonic acid-induced ear inflammation, the LTA 4 H inhibitor, JNJ-26993135 (1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidine-4-carboxylic acid), dose-dependently inhibited ex vivo LTB 4 production in blood, in parallel with dose-dependent inhibition of neutrophil influx (ED 50 , 1-3 mg/kg) and ear edema. In murine whole blood and in zymosan-induced peritonitis, JNJ-26993135 selectively inhibited LTB 4 production, without affecting cysteinyl leukotriene production, while maintaining or increasing production of the anti-inflammatory mediator, lipoxin (LX) A 4 . The 5-lipoxygenase (5-LO) inhibitor zileuton showed inhibition of LTB 4 , LTC 4 , and LXA 4 production. Although zileuton inhibited LTB 4 production in the peritonitis model more effectively than the LTA 4 H inhibitor, the influx of neutrophils into the peritoneum after 1 and 2 h was significantly higher in zileuton-versus JNJ-26993135-treated animals. This difference may have been mediated by the increased LXA 4 levels in the presence of the LTA 4 H inhibitor. The selective inhibition of LTB 4 production by JNJ-26993135, while increasing levels of the anti-inflammatory mediator, LXA 4 , may translate to superior therapeutic efficacy versus 5-LO or 5-LO-activating protein inhibitors in LTB 4 -mediated inflammatory diseases.

Most machine elements, such as gears and bearings, are operated in the mixed lubrication region. To evaluate lubrication performance for these tribological components, a contact model in mixed elastohydrodynamic lubrication is presented. This model deals with the EHL problem in the very thin film region where the film is not thick enough to separate the asperity contact of rough surface. The macro contact area is then divided into the lubricated area and the micro asperity contact areas by the contacted rough surfaces. In the case when asperity to asperity contact is present, Reynolds equation is only valid in the lubricated areas. Asperity contact pressure is determined by the interaction of two mating surfaces. The applied load is carried out by the lubricant film and the contacted asperities. FFT techniques are utilized to calculate the surface displacement (forward problem) by convolution and the asperity contact pressure (inverse problem) by deconvolution for non-periodic surfaces. With the successful implementation of FFT and multigrid methods, the lubricated contact problem can be solved within hours on a PC for the grids as large as one million nodes. This capability enables us to simulate random rough surfaces in a dense mesh. The load ratio, contact area ratio and average gap are introduced to characterize the performance of mixed lubrication with asperity contacts. Discussions are given regarding the asperity orientation as well as the effect of rolling-sliding condition. Numerical results of real rough topography are illustrated with effects of velocity parameter on load ratio, contact ratio, and average gap.

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