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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...

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. PPAR␥ agonists inhibit TGF-␤ induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex disease for which the pathogenesis is poorly understood. In this study, we identified lactic acid as a metabolite that is elevated in the lung tissue of patients with IPF. Objectives: This study examines the effect of lactic acid on myofibroblast differentiation and pulmonary fibrosis. Methods: We used metabolomic analysis to examine cellular metabolism in lung tissue from patients with IPF and determined the effects of lactic acid and lactate dehydrogenase-5 (LDH5) overexpression on myofibroblast differentiation and transforming growth factor (TGF)-b activation in vitro. Measurements and Main Results: Lactic acid concentrations from healthy and IPF lung tissue were determined by nuclear magnetic resonance spectroscopy; a-smooth muscle actin, calponin, and LDH5 expression were assessed by Western blot of cell culture lysates. Lactic acid and LDH5 were significantly elevated in IPF lung tissue compared with controls. Physiologic concentrations of lactic acid induced myofibroblast differentiation via activation of TGF-b. TGF-b induced expression of LDH5 via hypoxia-inducible factor 1a (HIF1a). Importantly, overexpression of both HIF1a and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low-dose TGF-b to induce differentiation. Furthermore, inhibition of both HIF1a and LDH5 inhibited TGF-b-induced myofibroblast differentiation. Conclusions: We have identified the metabolite lactic acid as an important mediator of myofibroblast differentiation via a pHdependent activation of TGF-b. We propose that the metabolic milieu of the lung, and potentially other tissues, is an important driving force behind myofibroblast differentiation and potentially the initiation and progression of fibrotic disorders.