Riboflavin and ultraviolet light treatment of platelets triggers p38MAPK signaling: inhibition significantly improves in vitro platelet quality after pathogen reduction treatment

Abstract

These findings support a model of one dominant underlying molecular signaling mechanism that is impacted by the riboflavin and UV (Mirasol) PRT process resulting in alterations in PLT quality. The identification of such a target should assist in the development of strategies to ameliorate this negative aspect of an otherwise beneficial and important safety development for transfusion medicine.

p38 mitogen‐activated protein kinase regulates mitochondrial function and microvesicle release in riboflavin‐ and ultraviolet light–treated apheresis platelet concentrates

“…1 Previously, we and others have demonstrated that inhibition of the stress kinase p38 improves PLT in vitro quality with or without RF/UV treatment during storage, showing a deceleration of apoptosis development. 15,25,29 Here we provide further insights into the mechanism of the impact of RF/UV treatment on PLT mitochondrial function and demonstrate that some of these activities are also modulated by p38 MAPK. Accumulating evidence demonstrates that PI-treated PLTs share highly similar behaviors with PLTs stimulated by physiologic activators, including PLT activation, degranulation, and development of apoptosis, leading to the conclusion that these processes have the same signaling mechanism.…”

“…1 These treatments aim to target the replication and/or proliferation mechanism of pathogens and to destroy residual white blood cells (WBCs) to improve the safety of blood 14,15,25 The aim of this study was to evaluate the effects of RF/UV treatment on PLT mitochondrial function and signaling, including the recently discovered release of MT by PLTs, and to determine whether p38 is involved in the modulation of these mechanisms.…”

“…Our previous studies have shown that RF/UV treatment triggers immediate phosphorylation of p38 in apheresis PCs with an increasing trend during storage. 15,25 Addition of the p38 inhibitor SB203580 before RF/UV treatment results in significantly improved ex vivo PLT quality, demonstrated by the down regulation of PLT activation, PS exposure, and apoptosis development. 15,25 In this study, we further show that this compound inhibits the mitochondrial translocation of Bax and Bid in RF/UVtreated PLTs and protects mitochondrial integrity by decreasing cyto c release and loss of DW m , effects that might explain the reduced PS exposure and caspase activities we previously reported when this inhibitor was used.…”

“…[11][12][13] Recently, we and other groups have demonstrated that apoptotic events including phosphatidylserine (PS) exposure, increased proapoptotic protein expression, and caspase activation are triggered by RF/UV treatment in stored PCs, further supporting the model that apoptosis is involved in development of the PLT storage lesion. 14,15 However, the detailed biochemical mechanism(s) triggered by RF/UV are still unclear. PLTs can generate reactive oxygen species (ROS), such as O -2 , OH -, and H 2 O 2 , which play critical roles in regulating PLT activity.…”

“…Inhibition of p38 activity before the PI treatment significantly improved the PLT quality and reduced PLT apoptosis development by the decrease of PS exposure, proapoptotic protein expression, and caspase activation. 14,15,25 The aim of this study was to evaluate the effects of RF/UV treatment on PLT mitochondrial function and signaling, including the recently discovered release of MT by PLTs, and to determine whether p38 is involved in the modulation of these mechanisms.…”