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

Abstract

Key Points• Gastrointestinal flora contributes to development of antibody-mediated murine TRALI.• Depletion of gastrointestinal flora prevents TRALI by inhibiting MIP-2 secretion and pulmonary neutrophil accumulation.Transfusion-related acute lung injury (TRALI) is a syndrome of respiratory distress upon blood transfusion and is the leading cause of transfusion-related fatalities. Whether the gut microbiota plays any role in the development of TRALI is currently unknown. We observed that untreated barrier-free (BF) mice suffered from severe antibody-mediated acute lung injury, whereas the more sterile housed specific pathogen-free (SPF) mice and gut flora-depleted BF mice were both protected from lung injury. The prevention of TRALI in the SPF mice and gut flora-depleted BF mice was associated with decreased plasma macrophage inflammatory protein-2 levels as well as decreased pulmonary neutrophil accumulation. DNA sequencing of amplicons of the 16S ribosomal RNA gene revealed a varying gastrointestinal bacterial composition between BF and SPF mice. BF fecal matter transferred into SPF mice significantly restored TRALI susceptibility in SPF mice. These data reveal a link between the gut flora composition and the development of antibody-mediated TRALI in mice. Assessment of gut microbial composition may help in TRALI risk assessment before transfusion.

The Pathogenic Involvement of Neutrophils in Acute Respiratory Distress Syndrome and Transfusion-Related Acute Lung Injury

“…Pulmonary PMN infiltration has been described to occur in multiple animal models of TRALI [11,13,47,48,49,50,51,52,53,54,55,56,57]. Additionally, the abundance of PMNs has been observed in pulmonary tissue of TRALI patients upon autopsy [58,59].…”

The Role of Complement in Transfusion-Related Acute Lung Injury

“…This may possibly include the manufacturing process used to generate the 34-1-2s antibody, which may have differed between studies, and this may consequently have differentially impacted the antibody-Fc glycosylation composition and thereby the interaction with Fc receptors or complement. Additionally, the controversy may possibly be due to the composition of the gastrointestinal microbiota [47], which can be influenced by changes in environmental animal housing conditions (specific pathogen-free vs barrierfree housing) [19,47]. Barrier-free mice were shown to be hypersusceptible to TRALI, whereas specific pathogen-free mice were resistant to TRALI (unless primed with LPS), and fecal transfer from barrier-free mice to specific pathogen-free mice could restore the susceptibility to TRALI [47], indicating a role for the gastrointestinal microbiota in TRALI.…”

“…Additionally, the controversy may possibly be due to the composition of the gastrointestinal microbiota [47], which can be influenced by changes in environmental animal housing conditions (specific pathogen-free vs barrierfree housing) [19,47]. Barrier-free mice were shown to be hypersusceptible to TRALI, whereas specific pathogen-free mice were resistant to TRALI (unless primed with LPS), and fecal transfer from barrier-free mice to specific pathogen-free mice could restore the susceptibility to TRALI [47], indicating a role for the gastrointestinal microbiota in TRALI. Overall, this reveals a need for systematic in-depth investigations into the potential contribution of various complement cascade components in inducing TRALI.…”

“…Differences between the study of Strait et al [45] and Looney et al [11] may be explained by the timing of experimental endpoints after 34-1-2s injection, which was 30 minutes in the study by Strait et al [45], whereas this was 2 hours in the study of Looney et al [11]. Additionally, the observed differences may be due to the nature of the animal housing which may affect the composition of the gastrointestinal microbiota and thereby the susceptibility to TRALI [19,47]. Furthermore, in a study by Sachs et al using an ex vivo rat model of anti-CD177-mediated TRALI, complement was not found to be required for TRALI induction (TRALI induction was more dependent on the density of the cognate antigen), as TRALI occurred in a complement-free environment [48].…”

Platelet‐derived extracellular vesicles convey mitochondrial DAMPs in platelet concentrates and their levels are associated with adverse reactions

“…However, sterile inflammation and organ injury in transfused recipients still occur in the absence of any apparent infectious agents . Transfusion‐related acute lung injury is the leading cause of transfusion‐related death and is initiated by soluble mediators in plasma, such as antibodies against the human leukocyte antigen on WBCs of the recipient or lysophospholipids, and may be modulated by regulatory T cells or the recipient gastrointestinal microbiota . Febrile nonhemolytic transfusion reactions (FNHTRs) are more frequent; they affect approximately 1% to 5% of total platelet transfusions and are experienced by 30% of multitransfused patients .…”