Plasma from stored packed red blood cells and MHC class I antibodies causes acute lung injury in a 2-event in vivo rat model

Abstract

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion death. We hypothesize that TRALI requires 2 events: (1) the clinical condition of the patient and (2) the infusion of antibodies against MHC class I antigens or the plasma from stored blood. A 2-event rat model was developed with saline (NS) or endotoxin (LPS) as the first event and the infusion of plasma from packed red blood cells (PRBCs) or antibodies (OX18 and OX27) against MHC class I antigens as the second event. ALI was determined by Evans blue dye leak from the plasma to the bronchoalveolar lavage fluid (BALF), protein and CINC-1 concentrations in the BALF, and the lung histology. NS-treated rats did not evidence ALI with any second events, and LPS did not cause ALI. LPS-treated animals demonstrated ALI in response to plasma from stored PRBCs, both prestorage leukoreduced and unmodified, and to OX18 and OX27, all in a concentration-dependent fashion. ALI was neutrophil (PMN) dependent, and OX18/OX27 localized to the PMN surface in vivo and primed the oxidase of rat PMNs. We conclude that TRALI is the result of 2 events with the second events consisting of the plasma from stored blood and antibodies that prime PMNs. IntroductionTransfusion-related acute lung injury (TRALI) is the leading cause of transfusion mortality in the United States. 1,2 TRALI is the acute onset of noncardiogenic pulmonary edema as documented by chest radiograph and profound hypoxemia, in accordance with the definition of acute lung injury (ALI), that occurs within 6 hours of transfusion. 3,4 TRALI may occur with or without conditions that predispose the patient to ALI, and may be the worsening of pulmonary function in patients with preexisting ALI. 3,4 All blood products have been implicated in TRALI, but components that contain large amounts of plasma are mainly responsible. 5,6 The current incidence of TRALI has been estimated as 1/7900 to 1/1330 in the United Kingdom and the United States with lesser incidences in Europe. [5][6][7][8] Current mortality rates vary from 5% to 35% with the lesser mortality rates predominating. [5][6][7][8] The pathophysiology of TRALI has not been elucidated despite numerous studies. [9][10][11][12][13][14] The first mechanism proposed was the infusion of donor antibodies directed against the HLA class I or granulocyte-specific antigens on the recipient's leukocytes with animal models composed of an in vivo murine model and an isolated, perfused rabbit lung that provided physiologic relevance. [9][10][11][12]14 In addition, the neutrophil (PMN) was proposed to be the effector cell, identical to other forms of ALI and the acute respiratory distress syndrome (ARDS). [9][10][11][12]14 However, look-back studies of donors with specific antibodies directed against HLA or granulocyte antigens demonstrated that the infusion of donor antibodies into a recipient that expressed the cognate antigen resulted in TRALI in a minority of these patients, implying that the clinical condition of the recipient may be important for the d...

The incidence, risk factors, and outcome of transfusion-related acute lung injury in a cohort of cardiac surgery patients: a prospective nested case-control study

“…A threshold model has been proposed, 19 in which the presence of a strong "first event" may require only a weak second event before TRALI occurs. [44][45][46] In accordance, in a mouse model of TRALI, the presence of an inflammatory reaction resulted in onset of TRALI after a lower dose of antibodies compared with healthy controls. 47,48 Our data suggest that patients with an expected prolonged time on the cardiopulmonary bypass may benefit from HLA/HNA antibody-free blood products.…”

“…30,31 The mechanism by which stored blood causes lung injury may be through passive infusion of lysoPCs, which accumulate during storage of RBCs and PLTs. 22,44 In this study, we show an association between the number of transfused RBC products stored for more than 14 days and the onset of TRALI. This association disappeared after adjusting for patient risk factors.…”

Experimental prestorage filtration removes antibodies and decreases lipids in RBC supernatants mitigating TRALI in vivo

“…6 Briefly, rats were injected intraperitoneally with 2 mg/kg lipopolysaccharide (LPS, Salmonella enteritides), incubated for 2 hours, and anesthetized with 60 mg/kg pentobarbital, and the femoral vessels were cannulated. 6 Blood was removed (10 minutes) equal to 10% of the total blood volume 31 followed by infusion of an identical volume of heat-treated (56°C for 30 minutes to obviate the effects of fibrinogen and complement) cell-free plasma with 50 mg/mL of OX27 6 filtration or heat-treated supernatant from day 1 or day 42 RBC units that underwent experimental filtration or standard LR. These second events were infused at 4 mL/h followed by 30 mg/kg of Evans blue dye (EBD).…”

“…[21][22][23] These antibodies, lipids, or sCD40L activate neutrophils (PMNs), allowing for PMN-mediated endothelial damage, capillary leak, and acute lung injury (ALI). [6][7][8]13,24 We hypothesize that a prestorage filter that removes antibodies, leukocytes, and platelets and decreases lipid bioactivity would significantly decrease the presence of donor HLA antibodies and the accumulation of biologically active lipids and sCD40L and would abrogate TRALI in a 2-event animal model.…”

“…1,2,4,5 TRALI has been reported to be the result of at least 2 events: the first pertaining to the clinical condition of the patient, and the second to the infusion of antibodies that recognize human lymphocyte antigen (HLA) class I, class II, or granulocyte antigens or the infusion of biological response modifiers, which include both biologically active lipids and soluble CD40 ligand (sCD40L). [6][7][8][9][10][11][12][13][14][15] Standard prestorage leukoreduction (LR) was reported to have decreased TRALI reactions at 1 medical center; however, LR has not affected TRALI incidence in the United States or worldwide. 16,17 To date, there are few RBC mitigation strategies for TRALI.…”