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Human leukocyte antigen (HLA)-A2 antibody contributes to the pathogenesis of transfusion-related acute lung injury (TRALI) via polymorphonuclear neutrophil (PMN) activation, but the signaling pathways involved this process remain largely undefined. In this study, we sought to study the signaling pathways involved in the pathogenesis of HLA-A2-induced TRALI. Lipopolysaccharide (LPS), and the plasma from the HLA-A2 antibody-positive donors were utilized to establish a rat model of TRALI. Human pulmonary endothelial cells (HPMECs) were in vitro co-cultured with HLA-A2 antibody-treated PMNs and then treated with LPS to induce a cytotoxicity model. The effects of HLA-A2 antibody on HPMEC injury were evaluated in this model. Besides, dasatinib was used to block the Src phosphorylation to explore whether Src involved in the TRALI or HPMEC injury induced by HLA-A2 antibody. The HLA-A2 antibody plus LPS induced TRALI and stimulated PMN activation in rats. HLA-A2 antibody-induced TRALI could be attenuated via depletion of PMN. HLA-A2 antibody activated NF-κB and NLRP3 inflammasome. In addition, HLA-A2 antibody aggravated the HPMEC injuries and the release of PMN surfaces makers, but dasatinib treatment reversed this effect, indicating that HLA-A2 antibody activated PMNs and exacerbated TRALI by stimulating phosphorylation of Src followed by activation of NF-κB and NLRP3 inflammasome, which was validated in vivo. In summary, HLA-A2 induced PMNs by activating NF-κB/NLRP3 inflammasome via phosphorylated-Src elevation, thereby exacerbating TRALI. This study highlights promising target for the treatment of antibody-mediated TRALI., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Transfusion‐related acute lung injury (TRALI) is a clinical syndrome which is associated with the formation of neutrophil extracellular trap (NET). Recent studies have demonstrated the roles of microRNAs (miRNAs) in the pathophysiological process of TRALI. Here, the study focused on the role of miR‐144 and the molecular mechanisms in NET‐induced TRALI. Up‐regulated miR‐144 and under‐expressed KLF2 were determined in patients with TRALI. In the mouse model of a two‐event TRALI induced by intraperitoneal injections with lipopolysaccharide and anti‐H‐2Kd mAb, we determined expression patterns of miR‐144, Krüppel‐like factor 2 (KLF2), chemokine (C‐X‐C motif) receptor 1 (CXCR1) and nuclear factor kappa‐B (NF‐kappaB) p65. The results confirmed that miR‐144 was highly expressed, while KLF2 was poorly expressed in mice with TRALI. Dual‐luciferase reporter gene assay identified that miR‐144 could target KLF2. Using gain‐ and loss‐of‐function approaches, we analysed the effects of miR‐144 and its interaction with KLF2 on TRALI. Enforced expression of miR‐144 was found to aggravate NET‐induced TRALI by down‐regulating KLF2 and activating the NF‐kappaB/CXCR1 signalling pathway in TRALI mice. Collectively, miR‐144‐targeted inhibition of KLF2 and activation of NF‐kappaB/CXCR1 are possible mechanisms responsible for NET‐caused TRALI. These findings aid in the development of therapeutic modalities for the treatment of TRALI. [ABSTRACT FROM AUTHOR]