Blood. 2007 Sep 15;110(6):1989-96. Epub 2007 Jun 1.
Nardi MA, Gor Y, Feinmark SJ, Xu F, Karpatkin S.
Significance:
Patients with HIV related immunologic thrombocytopenia develop a unique Ab capable of oxidatively fragmenting platelets by the generation of ROS from platelet NADPH Oxidase and 12-lipoxygenase.
Yet the thrombocytopenia responds to steroid treatment in vivo. Thus steroids must be operating via a different mechanism than that of inhibition of opsonized platlets by phagocytosis.
In this paper we demonstrate that Dexasmethasone inhibits ROS production by inhibiting key enzymes involved in ROS generation: PLA2, 12 Lipoxygenase and NADPH Oxidase membrane translocation.
Abstract:
An HIV antibody (Ab) against platelet integrin GPIIIa49-66 induces complement-independent platelet particle formation by the elaboration of reactive oxygen species (ROS) downstream of the activation of the platelet NADPH oxidase by the 12-lipoxygenase (12-LO) product 12(S)-HETE.
To determine whether other inducers of platelet particle formation also function via the induction of ROS, we examined the effects of the Ca(2+) ionophore A23187 and phorbol myristate acetate (PMA). Both agents induced oxidative platelet particle formation in an identical fashion as Ab, requiring Ca(2+) flux and 12(S)-HETE production as well as intact NADPH oxidase and 12-LO pathways.
Since HIV-ITP patients with this Ab correct their platelet counts with dexamethasone (Dex), we examined the role of this steroid in this unique autoimmune disorder.
Dex at therapeutic concentrations inhibited Ab-, A23187-, or PMA-induced platelet particle formation by inhibiting platelet PLA(2), 12-LO, and NADPH oxidase. The operational requirement of translocation of PLA(2), 12-LO, and NADPH oxidase components (p67 phox) from cytosol to membrane for induction of ROS was both inhibited and partially reversed by Dex in platelets.
We conclude that (1) platelet particle formation can be induced by the generation of ROS; and (2) platelet PLA(2), 12-LO, NADPH oxidase, and cytosol membrane translocation, requirements for ROS production, are inhibited by Dex.
PMID: 17545506
