Transfusion-related acute lung injury (TRALI) is a form of posttransfusion acute pulmonary insufficiency that has been linked to the infusion of biologic response modifiers (BRMs), including antileukocyte antibodies and lipids. Soluble CD40 ligand (sCD40L) is a platelet-derived proinflammatory mediator that accumulates during platelet storage. We hypothesized that human polymorphonuclear leukocytes (PMNs) express CD40, CD40 ligation rapidly primes PMNs, and sCD40L induces PMN-mediated cytotoxicity of human pulmonary microvascular endothelial cells (HMVECs). Levels of sCD40Lwere measured in blood components and in platelet concentrates (PCs) implicated in TRALI or control PCs that did not elicit a transfusion reaction. All blood components contained higher levels of sCD40L than fresh plasma, with apheresis PCs evidencing the highest concentration of sCD40L followed by PCs from whole blood, whole blood, and packed red blood cells (PRBCs). PCs implicated in TRALI reactions contained significantly higher sCD40L levels than control PCs. PMNs express functional CD40 on the plasma membrane, and recombinant sCD40L (10 ng/mL-1 g/mL) rapidly (5 minutes) primed the PMN oxidase. Soluble CD40L promoted PMN-mediated cytotoxicity of HMVECs as the second event in a 2-event in vitro model of TRALI. We concluded that sCD40L, which accumulates during blood component storage, has the capacity to activate adherent PMNs, causing endothelial damage and possibly TRALI in predisposed patients. IntroductionCD40 is a 48-kDa transmembrane glycoprotein and a member of the tumor necrosis factor (TNF) receptor family expressed on endothelial and epithelial cells, monocytes, and macrophages. 1 CD40 ligand (CD40L [CD154]) is a primarily platelet-derived pro-inflammatory mediator found in soluble (sCD40L) and cellassociated forms in transfused blood. 2,3 Soluble CD40L activates macrophages and elicits the production and release of multiple proinflammatory cytokines. 4 Furthermore, inhibition of the CD40-CD40L system in animal models reduces acute lung injury (ALI) caused by endotoxin (lipopolysaccharide [LPS]) or oxygen toxicity. [5][6][7] In addition, sCD40L is present in platelet concentrates and accumulates over routine 3-to 5-day storage times. 3 Polymorphonuclear leukocytes (PMNs) are critical in host defense against pathogens and exert their major microbicidal function in the tissues. 8,9 PMN priming is initiated by the attraction and adhesion of PMNs to activated vascular endothelium and continues until the pathogens are phagocytosed and destroyed. 6,[10][11][12] PMN-mediated acute lung injury (ALI) requires at least 2 separate events: endothelial activation, which includes the synthesis and release of chemokines and the increased surface expression of adhesion molecules that elicit PMN adhesion, and activation of adherent PMNs, which causes the release of their microbicidal arsenal and results in endothelial damage, capillary leak, and ALI. 10,11,[13][14][15][16] Such a 2-event model has been proposed for ALI, especially for transfusion...
Peroxisome proliferator-activated receptor ␥ (PPAR␥) is a ligand-activated transcription factor important in lipid metabolism, diabetes, and inflammation. We evaluated whether human platelets and megakaryocytes express PPAR␥ and whether PPAR␥ agonists influence platelet release of bioactive mediators. Although PPAR␥ is mainly considered a nuclear receptor, we show that enucleate platelets highly express PPAR␥ protein as shown by Western blotting, flow cytometry, and immunocytochemistry. Meg-01 megakaryocyte cells and human bone marrow megakaryocytes also express PPAR␥. Platelet and Meg-01 PPAR␥ bound the PPAR␥ DNA consensus sequence, and this was enhanced by PPAR␥ agonists. Platelets are essential not only for clotting, but have an emerging role in inflammation in part due to their release or production of the proinflammatory and proatherogenic mediators CD40 ligand (CD40L) and thromboxanes (TXs). Platelet incubation with a natural PPAR␥ agonist, 15d-PGJ 2 , or with a potent synthetic PPAR␥ ligand, rosiglitazone, prevented thrombin-induced CD40L surface expression and release of CD40L and thromboxane B 2 (TXB 2 ). 15d-PGJ 2 also inhibited platelet aggregation and adenosine triphosphate ( IntroductionPeroxisome proliferator-activated receptors (PPARs) are members of a nuclear hormone receptor superfamily of ligandactivated transcription factors. There are 3 PPAR subtypes: PPAR␣, PPAR/␦, and PPAR␥. The genes encoding the PPAR subtypes each reside on different chromosomes and have distinct tissue expression patterns. 1 While many reports focus on PPAR expression in the nucleus, PPAR␥, in particular, is also found in the cytoplasm. 2,3 PPAR␥ is highly expressed in white adipose tissue and was initially described as important for regulating gene expression in metabolism, insulin responsiveness, and adipocyte differentiation. 4,5 While PPAR␥ was originally thought to be found mainly in fat tissue, it is in fact widely expressed by many types of cells including macrophages, B and T lymphocytes, epithelial, endothelial, smooth muscle, and fibroblastic cells. 2,[6][7][8][9][10][11] PPAR␥ has also come to prominence as PPAR␥ agonists play an important role in immune function by dampening inflammation, attenuating macrophage/monocyte synthesis of proinflammatory cytokines, and inducing apoptosis in B lymphocytes. 2,6,12,13 PPAR␥ has also emerged as a key target for malignant cells as PPAR␥ agonists have shown therapeutic potential for B lymphoma and various epithelialderived cancers. 2,14,15 Megakaryocytes are the biggest cell of the bone marrow and the parent cell of platelets. Platelets are derived from the cytoplasm of megakaryocytes and are released to the bloodstream under the effects of cytokines such as interleukin-6 (IL-6) and 17 Platelets are enuclear cells that have a plasma membrane, surface-connected canalicular and tubular system, mitochondria, granules, lysosomes, and peroxisomes. 18 Recent studies demonstrate that platelets and many of their products are important not only in hemostasis, but have now emerg...
These are the first data demonstrating that a PLT-derived mediator, sCD40L, is associated with adverse transfusion events. Existing clinical factors, for example, inflammation or leukopenia, may influence whether infused mediators cause reactions.
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