RESUMO
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.
Assuntos
Lesão Pulmonar Aguda/genética , Fatores de Transcrição Kruppel-Like/genética , MicroRNAs/genética , Receptores de Interleucina-8A/genética , Fator de Transcrição RelA/genética , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/terapia , Animais , Armadilhas Extracelulares/genética , Humanos , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B/genética , Ativação Transcricional/genética , Lesão Pulmonar Aguda Relacionada à Transfusão/genética , Lesão Pulmonar Aguda Relacionada à Transfusão/patologia , Lesão Pulmonar Aguda Relacionada à Transfusão/terapiaRESUMO
Platelet transfusions can cause adverse reactions in their recipients, including transfusion-related acute lung injury (TRALI). The pathophysiology of TRALI depends on a number of signaling pathways and the inflammatory role played by blood platelets remains controversial. Platelets are important in inflammation, particularly via the immunomodulator complex CD40/CD40L. We studied the specific function of the CD40/CD40L interaction in regulating an experimental TRALI Two-hit model. A mouse model of immune TRALI was triggered by injection of LPS and an anti-MHC I antibody, and the effect of injection of a neutralizing anti-CD40L antibody before induction of TRALI investigated. The characteristics of TRALI were decreased body temperature, pulmonary lesions, and immune cell infiltration into the alveolar space. Pulmonary infiltration was evaluated by blood counts of specific immune cells and their detection in lung sections. Inhibition of the CD40/CD40L immunomodulator interaction significantly reduced communication between immune and/or endothelial cells and the development of pulmonary edema. Hence, our results indicate that targeting of the CD40/CD40L interaction could be an important method to prevent TRALI. While considering that our work concerned a mouse model, we postulate that improvement of the conditions under which platelet concentrates are prepared/stored would assist in alleviating the risk of TRALI.