This application addresses broad Challenge Area (04) Clinical Research, and the specific Challenge Topic 04-HL-103 Assess the role of leukocyte interaction with platelets, erythrocytes, and endothelium in the pathogenesis of heart, lung, and blood diseases. Transfusion-related acute lung injury (TRALI), the main cause of transfusion-related morbidity and mortality reported to the FDA, is a clinical syndrome in which acute lung injury occurs within 6 hours of a blood transfusion. Although its pathophysiology remains unclear, antibodies and/or bioactive lipids activating polymorphonuclear neutrophils (PMNs) have been suggested to initiate the syndrome in patients with a predisposing pro-inflammatory event. Our preliminary studies suggest that platelet-leukocyte interactions play a key role in the disease. More specifically, endothelial signals emerging from the engagement of E- selectin with E-selectin ligand-1 (ESL-1) expressed on PMNs, induced the activation of the integrin Mac-1 at the leading edge of crawling PMNs, allowing the capture of platelets which, in turn, led to injury through the production of reactive oxygen species (ROS). The present challenge is to conduct pre-clinical studies and develop novel methods to assay this type of delayed PMN activation. The proposed translational studies will lead to a clinical trial testing the safety and efficacy of novel antagonists against adhesion molecules involved in TRALI.
In Specific Aim 1, we evaluate the efficacy of GMI-1070, novel selectin antagonist, in an established mouse model of TRALI.
In Specific Aim 2, we will develop a humanized model of TRALI in which mice harbor circulating human PMNs by transplantation of cord blood-derived hematopoietic stem and progenitor cells in immunodeficient NOD/SCID mice deficient in the IL-2r common gamma chain. We will induce TRALI by injection of an anti-HNA-2a, which was previously shown to produce lung injury in a rat ex vivo model. We will evaluate using multichannel fluorescence intravital microcopy (MFIM) whether the administration of this antibody induces platelet-leukocyte interactions and ROS generation. We will determine the effect of GMI-1070 administration on lung injury, and platelet-leukocyte interactions by MFIM.
In Specific Aim 3, we will develop a clinically relevant biological marker of the secondary wave of PMN activation using flow-based imaging of platelet complexes with the polarized leading edge of PMNs. This assay will provide a novel biological end-point to assess PMN activation and the efficacy of anti-inflammatory drugs in clinical trials.
Preliminary studies suggest that platelet-leukocyte interactions play a key role in the pathogenesis of TRALI. In this proposal, we will perform translational studies and develop new tools in preparation of a clinical trial to treat and/or prevent TRALI.
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| Jang, Jung-Eun; Hidalgo, Andrés; Frenette, Paul S (2012) Intravenous immunoglobulins modulate neutrophil activation and vascular injury through Fc?RIII and SHP-1. Circ Res 110:1057-66 |
| Jang, Jung-Eun; Hod, Eldad A; Spitalnik, Steven L et al. (2011) CXCL1 and its receptor, CXCR2, mediate murine sickle cell vaso-occlusion during hemolytic transfusion reactions. J Clin Invest 121:1397-401 |
