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Evidence of CD40L/CD40 pathway involvement in experimental transfusion-related acute lung injury.

ABSTRACT: 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.

SUBMITTER: Tariket S

PROVIDER: S-EPMC6715651 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Evidence of CD40L/CD40 pathway involvement in experimental transfusion-related acute lung injury.

Tariket Sofiane S Hamzeh-Cognasse Hind H Laradi Sandrine S Arthaud Charles-Antoine CA Eyraud Marie-Ange MA Bourlet Thomas T Berthelot Philippe P Garraud Olivier O Cognasse Fabrice F

Scientific reports 20190829 1

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 ...[more]

PMID: 31467410

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Project description:Although respiratory distress is a common complication of severe malaria, little is known about the underlying molecular basis of lung dysfunction. Animal models have provided powerful insights into the pathogenesis of severe malaria syndromes such as cerebral malaria; however, no model of malaria-induced lung injury has been definitively established. This work used bronchoalveolar lavage (BAL), histopathology and gene expression analysis to examine the development of acute lung injury (ALI) in mice infected with Plasmodium berghei ANKA (PbA). BAL fluid of PbA-infected C57BL/6 mice revealed a significant increase in IgM and total protein prior to the development of cerebral malaria (CM), indicating disruption of the alveolar-capillary membrane barrier â the physiological hallmark of acute lung injury (ALI). In contrast to sepsis-induced ALI, BAL fluid cell counts remained constant with no infiltration of neutrophils. Histopathology showed septal inflammation without cellular transmigration into the alveolar spaces. Microarray analysis comparing malaria-induced ALI with sepsis-induced ALI identified several common gene ontology groups characterizing ALI in these models, including defense and immune response. Severity of malaria-induced ALI varied in a panel of inbred mouse strains, and development of ALI correlated with peripheral parasite burden but not CM susceptibility. CD36-/- mice, which have decreased parasite lung sequestration, were relatively protected from ALI. In summary, parasite burden and CD36-mediated sequestration in the lung are primary determinants of ALI in experimental murine malaria. Furthermore, differential susceptibility of mouse strains to malaria-induced ALI and CM indicate that distinct genetic determinants likely regulate susceptibility to these two important causes of malaria-associated morbidity and mortality. Keywords: Time course Lungs were excised immediately following euthanasia, snap-frozen in liquid nitrogen and stored at â80Â°C until use. Total RNA was extracted using Trizol reagent (Invitrogen) according to the manufacturerâs instructions, and mRNA was purified using an Oligo-dT cellulose column (NEB, Mississauga, ON) as described previously [54]. cDNA with incorporated 5-(3-aminoallyl)-2âdeoxyuridine-5â-triphosphate (AAdUTP; Sigma, Oakville ON) was reverse-transcribed from 1-2 Âµg mRNA. Purified cDNA was coupled with N-hydroxysuccinimide esters of Cy3 or Cy5 (GE Lifesciences, Baie d'Urfe QC). Cy3 and Cy5-labeled cDNA pairs and Agilent control spots were added to a final volume of 0.5ml hybridization buffer (1 M NaCl, 0.5% sodium sarcosine, 50 mM methyl ethane sulfonate (MES), pH 6.5, 33% formamide and 40Âµg salmon sperm DNA (Invitrogen)). Hybridizations were performed in Agilent hybridization (Agilent, Palo Alto CA) chambers at 42Â°C with rotation for 18-24 hours. Slides were washed in 6X SSPE, 0.005% sarcosine, followed by 0.06X SSPE, allowed to dry and scanned with a 4000A microarray scanner (Axon Instruments, Union City CA). TIFF images were quantified with GenePix (Axon Instruments). Variance stabilizing normalization [55] and loess smoothing were applied in Bioconductor [56] and the data were transformed to log2 scale. Each array was hybridized with cDNA transcribed from an RNA pool of 5 C57BL/6 mice per timepoint (Day 0 and 6) and technical replicates (dye-swap) experiments were performed for both time points.

Dataset Information

Evidence of CD40L/CD40 pathway involvement in experimental transfusion-related acute lung injury.

Publications

Evidence of CD40L/CD40 pathway involvement in experimental transfusion-related acute lung injury.

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