储存的红细胞输血会导致贫血小鼠新生儿出现全身炎症反应综合征。

IF 4.8 3区 医学 Q2 CELL BIOLOGY Inflammation Research Pub Date : 2024-11-01 Epub Date: 2024-09-05 DOI:10.1007/s00011-024-01936-y
Balamurugan Ramatchandirin, Marie Amalie Balamurugan, Suneetha Desiraju, Yerin Chung, Boguslaw S Wojczyk, Krishnan MohanKumar
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引用次数: 0

摘要

目的:输注红细胞(RBCT)是早产儿和重症婴儿的救命疗法。然而,该过程与新生儿全身炎症反应综合征(SIRS)和潜在的多器官功能障碍综合征(MODS)的发生有关。本研究旨在探讨严重贫血的小鼠新生儿发生与 RBCT 相关的 SIRS 的机制:方法:将 C57BL/6(WT)、TLR4-/- 和髓系特异性触发髓系受体-1(trem1)-/- 小鼠幼崽分为 4 组(每组 n = 6)进行研究:(1)天真对照组;(2)输血对照组;(3)贫血组(血细胞比容 20-24%);(4)使用我们已建立的小鼠抽血诱发贫血(PIA)和输注 RBC 的贫血组。使用 Luminex 检测法测量血浆中的炎症细胞因子(IFN-γ、IL-1β、TNF-α、IL-6、MIP-1α、MIP-1β、MIP2 和 LIX)。体外研究包括:(i) 将细胞暴露于低浓度的脂多糖(LPS;500 ng/ml),使细胞致敏;(ii) 转染 trem1-siRNA,同时转染/不转染储存的 RBC 的血浆上清,通过 qRT-PCR 和免疫印迹来评估通过 trem1 引起的急性炎症反应:与接受储存的 RBCT 的非贫血小鼠("输血对照组")相比,贫血小鼠幼崽在接受储存的 RBC 后 2 小时内出现细胞因子风暴,这种风暴一直持续到输血后 6 小时,与 TLR4 无关。尽管如此,严重贫血幼鼠的循环内毒素水平升高,从而使循环单核细胞敏感,预先合成促炎细胞因子(IFN-γ、IL-1β、TNF-α、IL-6、MIP-1α、MIP-1β、MIP2、LIX)并表达 trem1。抑制 Raw264.7 细胞中 trem1 的表达可减轻内毒素相关的促炎细胞因子的预合成和 RBCT 诱导的炎性细胞因子的释放。事实上,髓系特异性 trem1-/- 小鼠幼崽在 RBCT 后出现 SIRS 的证据明显减少:结论:与严重贫血相关的低度炎症会使单核细胞变得敏感,从而促进促炎细胞因子和 trem1 的合成。在这种情况下,RBCT 会进一步激活这些单核细胞,从而诱发 SIRS。抑制包括单核细胞在内的骨髓细胞中的 trem1 可减轻小鼠新生儿因贫血和 RBCTs 的共同作用而产生的炎症反应。
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Stored RBC transfusions leads to the systemic inflammatory response syndrome in anemic murine neonates.

Objective: RBC transfusions (RBCT) are life-saving treatment for premature and critically ill infants. However, the procedure has been associated with the development of systemic inflammatory response syndrome (SIRS) and potentially multiple organ dysfunction syndrome (MODS) in neonates. The present study aimed to investigate the mechanisms of RBCT-related SIRS in severely anemic murine neonates.

Methods: C57BL/6 (WT), TLR4-/- and myeloid-specific triggered myeloid receptor-1 (trem1)-/- mouse pups were studied in 4 groups (n = 6 each): (1) naïve controls, (2) transfused control, (3) anemic (hematocrit 20-24%) and (4) anemic with RBC transfused using our established murine model of phlebotomy-induced anemia (PIA) and RBC transfusion. Plasma was measured for quantifying inflammatory cytokines (IFN-γ, IL-1β, TNF-α, IL-6, MIP-1α, MIP-1β, MIP2 and LIX) using a Luminex assay. In vitro studies included (i) sensitization by exposing the cells to a low level of lipopolysaccharide (LPS; 500 ng/ml) and (ii) trem1-siRNA transfection with/without plasma supernatant from stored RBC to assess the acute inflammatory response through trem1 by qRT-PCR and immunoblotting.

Results: Anemic murine pups developed cytokine storm within 2 h of receiving stored RBCs, which increased until 6 h post-transfusion, as compared to non-anemic mice receiving stored RBCTs ("transfusion controls"), in a TLR4-independent fashion. Nonetheless, severely anemic pups had elevated circulating endotoxin levels, thereby sensitizing circulating monocytes to presynthesize proinflammatory cytokines (IFN-γ, IL-1β, TNF-α, IL-6, MIP-1α, MIP-1β, MIP2, LIX) and express trem1. Silencing trem1 expression in Raw264.7 cells mitigated both endotoxin-associated presynthesis of proinflammatory cytokines and the RBCT-induced release of inflammatory cytokines. Indeed, myeloid-specific trem1-/- murine pups had significantly reduced evidence of SIRS following RBCTs.

Conclusion: Severe anemia-associated low-grade inflammation sensitizes monocytes to enhance the synthesis of proinflammatory cytokines and trem1. In this setting, RBCTs further activate these monocytes, thereby inducing SIRS. Inhibiting trem1 in myeloid cells, including monocytes, alleviates the inflammatory response associated with the combined effects of anemia and RBCTs in murine neonates.

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来源期刊
Inflammation Research
Inflammation Research 医学-免疫学
CiteScore
9.90
自引率
1.50%
发文量
134
审稿时长
3-8 weeks
期刊介绍: Inflammation Research (IR) publishes peer-reviewed papers on all aspects of inflammation and related fields including histopathology, immunological mechanisms, gene expression, mediators, experimental models, clinical investigations and the effect of drugs. Related fields are broadly defined and include for instance, allergy and asthma, shock, pain, joint damage, skin disease as well as clinical trials of relevant drugs.
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