C-reactive protein enhances murine antibody–mediated transfusion-related acute lung injury

Abstract

Key Points• CRP enhances antibodymediated lung damage when infused into TRALI-resistant mice.• CRP and TRALI-inducing antibodies generate a synergistic increase in MIP-2 production and pulmonary neutrophil accumulation in vivo.Transfusion-related acute lung injury (TRALI) is a syndrome of respiratory distress triggered by blood transfusions and is the leading cause of transfusion-related mortality. TRALI has primarily been attributed to passive infusion of HLA and/or human neutrophil antigen antibodies present in transfused blood products, and predisposing factors such as inflammation are known to be important for TRALI initiation. Because the acute-phase protein C-reactive protein (CRP) is highly upregulated during infections and inflammation and can also enhance antibody-mediated responses such as in vitro phagocytosis, respiratory burst, and in vivo thrombocytopenia, we investigated whether CRP affects murine antibody-mediated TRALI induced by the anti-major histocompatibility complex antibody 34-1-2s. We found that BALB/c mice injected with 34-1-2s or CRP alone were resistant to TRALI, however mice injected with 34-1-2s together with CRP had significantly enhanced lung damage and pulmonary edema. Mechanistically, 34-1-2s injection with CRP resulted in a significant synergistic increase in plasma levels of the neutrophil chemoattractant macrophage inflammatory protein-2 (MIP-2) and pulmonary neutrophil accumulation. Importantly, murine MIP-2 is the functional homolog of human interleukin-8, a known risk factor for human TRALI. These results suggest that elevated in vivo CRP levels, like those observed during infections, may significantly predispose recipients to antibodymediated TRALI reactions and support the notion that modulating CRP levels is an effective therapeutic strategy to reduce TRALI severity. (Blood. 2015;126(25):2747-2751 Introduction Transfusion-related acute lung injury (TRALI) is characterized by respiratory distress following blood transfusions and is the leading cause of transfusion-related mortality.1,2 Approximately 80% of TRALI cases are associated with HLA-or human neutrophil antigen-specific antibodies present in donor blood.3,4 A 2-hit model was hypothesized to underlie antibody-mediated TRALI where the first hit comprises patient predisposing factors, such as inflammation, and the second hit is due to antibodies in the transfused blood.1 The pathogenesis of antibody-mediated TRALI, however, is still poorly understood, and controversy has arisen using animal models. For example, several cell types have been implicated in inducing lung damage by the TRALI-inducing anti-major histocompatibility complex (MHC) class I antibody 34-1-2s.5 Neutrophils were originally thought to be stimulated by 34-1-2s to produce reactive oxygen species that damaged the pulmonary endothelium in an Fc-dependent manner.1,5-13 Strait et al, 14 however, showed that neutrophil involvement was limited and that activated endothelial cells and complement interactions were the primary events in TRALI induction. Furth...

Low levels of interleukin-10 in patients with transfusion-related acute lung injury

“…The first hit consists of a pre-disposing factor present in the recipient such as inflammation while the second hit is conveyed by factors present in the transfused blood product such as anti-leukocyte antibodies (3). For example, the acute phase protein C-reactive protein (CRP) which rapidly increases during infection and inflammation was shown to enhance antibody-mediated TRALI in mice (4) and in line with that data, CRP was found to be elevated in human TRALI patients (5) confirming its role as a first hit risk factor in human TRALI.…”

Gastrointestinal microbiota contributes to the development of murine transfusion-related acute lung injury

“…6,[10][11][12][13] Briefly, the right lung of each mouse was removed and weighed to determine the wet weight and then dried in an oven at 60°C for 48 hours. The dried samples were reweighed to obtain the dry weight.…”

“…2 Using animal models of antibodymediated TRALI, it has become clear that neutrophils (polymorphonuclear cells [PMNs]) are the major effector cells in TRALI. 6,[9][10][11][12][13] Moreover, using a novel C57BL/6 knockout (KO) model of antibodymediated TRALI, we recently demonstrated that PMN-reactive oxygen species are critically essential for inducing the acute lung injury in TRALI. 12 In addition, CD4 1 T regulatory cells and dendritic cells were identified as important suppressor cells of antibody-mediated TRALI and this protective response was associated with production of the anti-inflammatory cytokine IL-10.…”

“…2 The first hit is recipient-predisposing factors, such as systemic inflammation, which can manifest itself as increased interleukin (IL)-6, 3,4 IL-8 [3][4][5] or C-reactive protein (CRP) levels. 6,7 The second hit is subsequently conveyed by pathogenic antileukocyte antibodies or other biological response modifiers present in the transfused donor blood. 2,8 In the majority of the cases, human neutrophil antigen-or HLA-specific antibodies in the transfused blood are involved.…”

TRALI: hit by CRP

“…This study provides a novel and direct link between inflammation and TRALI, opening doors for possible new approaches in targeting TRALI. 1 T RALI is a syndrome characterized by acute respiratory distress resulting in acute lung injury within 6 hours upon blood transfusion. In the majority of the cases, antibodies against HLAs and/or human neutrophil antigen (HNA) present in the transfused product are thought to be responsible for initiating TRALI.…”