Abstract

Cytokines, IL-1beta, IL-6, IL-8, and TNFalpha, and lipids, lysophosphatidy1cholines (lyso-PCs), are generated during blood storage and may cause deleterious effects in the transfused host. One of these life-threatening complications is transfusion related acute lung injury (TRALI). Previous work has shown that lipids generated during routine blood storage are involved in the pathogenesis of TRALI. Lyso-PCs rapidly prime neutrophils (PMNs) in vitro for maximal cytotoxic potential and increased adherence to vascular endothelium (EC). Moreover, IL-6, IL-8 and TNFalpha also prime PMNs in vitro. Therefore, lipids and cytokines produced during blood storage may prime the PMNs of transfused hosts predisposing them to TRALI. PMN priming involves augmentation of both degranulation and the respiratory burst in response to a second agonist as well as increased adhesion of PMNs to EC, which results in the indiscriminate adherence to EC of PMNs with maximal cytotoxic potential. Priming agents cause acute lung injury in animal models; however, two agents must be administered. Furthermore, many of the agents used in these animal models also activate EC causing upregulation of adhesion molecules. We have hypothesized that a similar two event model exists for TRALI with each patient having an underlying clinical condition, which could act as the first event, followed by the infusion of lipids and cytokines in stored blood components representing the second event. We will test this hypothesis in by completing the following specific aims.
Specific Aim 1 : we have developed an animal model of TRALI to investigate the role of cytokines and lipids from stored blood as the second, of the two insults required in the pathogenesis of TRALI.
Specific Aim 2 will examine the clinical entities associated with the first event of this two event model including recent surgery, massive transfusion and cytokine therapy. In addition, the ability of the mediators involved with these clinical entities to activate pulmonary endothelium and to alter the PMN:EC physiology will be tested. Completion of these specific aims will provide information to target areas for clinical intervention to make transfusions safer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059355-03
Application #
6389785
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Barbosa, Luiz H
Project Start
1999-04-01
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
3
Fiscal Year
2001
Total Cost
$180,531
Indirect Cost

  Institution

Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045

  Publications

Loi, Michele M; Kelher, Marguerite; Dzieciatkowska, Monika et al. (2018) A comparison of different methods of red blood cell leukoreduction and additive solutions on the accumulation of neutrophil-priming activity during storage. Transfusion 58:2003-2012
Silliman, Christopher C; Kelher, Marguerite R; Khan, Samina Y et al. (2017) Supernatants and lipids from stored red blood cells activate pulmonary microvascular endothelium through the BLT2 receptor and protein kinase C activation. Transfusion 57:2690-2700
Kelher, Marguerite R; McLaughlin, Nathan J D; Banerjee, Anirban et al. (2017) LysoPCs induce Hck- and PKC?-mediated activation of PKC? causing p47phox phosphorylation and membrane translocation in neutrophils. J Leukoc Biol 101:261-273
Schofield, Thomas J; Conger, Rand D; Gonzales, Joseph E et al. (2016) Harsh parenting, physical health, and the protective role of positive parent-adolescent relationships. Soc Sci Med 157:18-26
Kelher, Marguerite R; Banerjee, Anirban; Gamboni, Fabia et al. (2016) Antibodies to major histocompatibility complex class II antigens directly prime neutrophils and cause acute lung injury in a two-event in vivo rat model. Transfusion 56:3004-3011
D'Alessandro, Angelo; Nemkov, Travis; Kelher, Marguerite et al. (2015) Routine storage of red blood cell (RBC) units in additive solution-3: a comprehensive investigation of the RBC metabolome. Transfusion 55:1155-68
Silliman, Christopher C; Kelher, Marguerite R; Khan, Samina Y et al. (2014) Experimental prestorage filtration removes antibodies and decreases lipids in RBC supernatants mitigating TRALI in vivo. Blood 123:3488-95
Ball, J Bradley; Khan, Samina Y; McLaughlin, Nathan J D et al. (2012) A two-event in vitro model of acute chest syndrome: the role of secretory phospholipase A2 and neutrophils. Pediatr Blood Cancer 58:399-405
Silliman, Christopher C; Moore, Ernest E; Kelher, Marguerite R et al. (2011) Identification of lipids that accumulate during the routine storage of prestorage leukoreduced red blood cells and cause acute lung injury. Transfusion 51:2549-54
Silliman, Christopher C; Kelher, Marguerite R; Gamboni-Robertson, Fabia et al. (2010) Tumor necrosis factor-alpha causes release of cytosolic interleukin-18 from human neutrophils. Am J Physiol Cell Physiol 298:C714-24

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