Hemorrhagic shock and resuscitation are associated with peripheral blood mononuclear cell mitochondrial dysfunction and immunosuppression

Villarroel, Jose Paul Perales; Guan, Yuxia; Werlin, Evan; Selak, Mary; Becker, Lance B.; Sims, Carrie A.

doi:10.1097/ta.0b013e3182988b1f

Cited by 39 publications

(40 citation statements)

References 38 publications

(62 reference statements)

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“…Since then, improvements in hospital hygiene have reduced combat deaths from infectious disease, but an equivalent phenomenon persists [2,3]. Sterile trauma due to major surgery or closed injury increases vulnerability to pneumonia, urinary infection, alimentary infection, sepsis and multi-organ failure, and these outcomes are exacerbated by haemorrhage, transfusion and ageing [4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Post-traumatic immunosuppression is reversed by anti-coagulated salvaged blood transfusion: deductions from studying immune status after knee arthroplasty

Islam

Whitehouse

Mehendale

et al. 2014

Clinical and Experimental Immunology

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SummaryMajor trauma increases vulnerability to systemic infections due to poorly defined immunosuppressive mechanisms. It confers no evolutionary advantage. Our objective was to develop better biomarkers of post-traumatic immunosuppression (PTI) and to extend our observation that PTI was reversed by anti-coagulated salvaged blood transfusion, in the knowledge that others have shown that non-anti-coagulated (fibrinolysed) salvaged blood was immunosuppressive. A prospective non-randomized cohort study of patients undergoing primary total knee arthroplasty included 25 who received salvaged blood transfusions collected post-operatively into acid-citrate-dextrose anti-coagulant (ASBT cohort), and 18 non-transfused patients (NSBT cohort). Biomarkers of sterile trauma included haematological values, damage-associated molecular patterns (DAMPs), cytokines and chemokines. Salvaged blood was analysed within 1 and 6 h after commencing collection. Biomarkers were expressed as fold-changes over preoperative values. Certain biomarkers of sterile trauma were common to all 43 patients, including supranormal levels of: interleukin (IL)-6, IL-1-receptor-antagonist, IL-8, heat shock protein-70 and calgranulin-S100-A8/9. Other proinflammatory biomarkers which were subnormal in NSBT became supranormal in ASBT patients, including IL-1β, IL-2, IL-17A, interferon (IFN)-γ, tumour necrosis factor (TNF)-α and annexin-A2. Furthermore, ASBT exhibited subnormal levels of anti-inflammatory biomarkers: IL-4, IL-5, IL-10 and IL-13. Salvaged blood analyses revealed sustained high levels of IL-9, IL-10 and certain DAMPs, including calgranulin-S100-A8/9, alpha-defensin and heat shock proteins 27, 60 and 70. Active synthesis during salvaged blood collection yielded increasingly elevated levels of annexin-A2, IL-1β, Il-1-receptor-antagonist, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IFN-γ, TNF-α, transforming growth factor (TGF)-β1, monocyte chemotactic protein-1 and macrophage inflammatory protein-1α. Elevated levels of high-mobility group-box protein-1 decreased. In conclusion, we demonstrated that anti-coagulated salvaged blood reversed PTI, and was attributed to immune stimulants generated during salvaged blood collection.

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Section: Introductionmentioning

confidence: 99%

Post-traumatic immunosuppression is reversed by anti-coagulated salvaged blood transfusion: deductions from studying immune status after knee arthroplasty

Islam

Whitehouse

Mehendale

et al. 2014

Clinical and Experimental Immunology

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“…In patients with sepsis, reduced oxygen consumption and lower mitochondrial membrane potential in PBMCs have been associated with disease severity, immune dysregulation, and decreased survival (11,12). In a recent study, we have also observed that mitochondrial function is altered in PBMCs following hemorrhagic shock and resuscitation in a rodent model (13). Similar to a report by Belikova et al (12), we found that PBMCs recovered mitochondrial function when incubated in serum from control animals with control PBMCs developed depressed function when incubated with serum collected following severe shock; suggesting a systemic factor may be responsible for mitochondrial dysfunction in PBMCs.…”

Section: Introductionmentioning

confidence: 82%

“…In particular, PBMC respiratory function may reflect disease severity in sepsis (12) and we have noted that PBMC mitochondrial function is dramatically altered during hemorrhagic shock and resuscitation (13). As such, monitoring PBMC respiratory capacity may provide a minimally invasive surrogate for end-organ mitochondrial function.…”

Section: Discussionmentioning

confidence: 99%

Can Peripheral Blood Mononuclear Cells Be Used as a Proxy for Mitochondrial Dysfunction in Vital Organs During Hemorrhagic Shock and Resuscitation?

Karamercan¹,

Weiss²,

Villarroel

et al. 2013

Shock

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INTRODUCTION Although mitochondrial dysfunction is thought to contribute to the development of post-traumatic organ failure, current techniques to assess mitochondrial function in tissues are invasive and clinically impractical. We hypothesized that mitochondrial function in peripheral blood mononuclear cells (PBMCs) would reflect cellular respiration in other organs during hemorrhagic shock and resuscitation (HS&R). METHODS Using a fixed pressure HS model, Long Evan’s rats were bled to a mean arterial pressure (MAP) of 40 mmHg. When blood pressure could no longer be sustained without intermittent fluid infusion (Decompensated HS), Lactated Ringer’s (LR) was incrementally infused to maintain the MAP at 40 mmHg until 40% of the shed blood volume was returned (Severe HS). Animals were then resuscitated with 4X total shed volume in LR over 60 minutes (Resuscitation). Control animals underwent the same surgical procedures, but were not hemorrhaged. Animals were randomized to Control (n=6), Decompensated HS (n=6), Severe HS (n=6) or Resuscitation (n=6) groups. Kidney, liver, and heart tissues as well as PBMC’s were harvested from animals in each group to measure mitochondrial oxygen consumption using high resolution respirometry. Flow cytometry was used to assess mitochondrial membrane potential (Ψm) in PBMCs. One-way ANOVA and Pearson correlations were performed. RESULTS Mitochondrial oxygen consumption decreased in all tissues, including PBMC’s, following Decompensated HS, Severe HS, and Resuscitation. However, the degree of impairment varied significantly across tissues during HS&R. Of the tissues investigated, PBMC mitochondrial oxygen consumption and Ψm provided the closest correlation to kidney mitochondrial function during HS (complex I: r =0.65; complex II: r=0.65; complex IV: r=0.52; p<0.05). This association, however, disappeared with resuscitation. A weaker association between PBMC and heart mitochondrial function was observed but no association was noted between PBMC and liver mitochondrial function. CONCLUSION All tissues including PBMC’s demonstrated significant mitochondrial dysfunction following HS&R. Although PBMC and kidney mitochondrial function correlated well during hemorrhagic shock, the variability in mitochondrial response across tissues over the spectrum of hemorrhagic shock and resuscitation limits the usefulness of using PBMC’s as a proxy for tissue-specific cellular respiration.

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“…The rat model of hemorrhagic shock was constructed based on Chaudry's method (Villarroel et al, 2013) with some modifications. The rats were anesthetized by intraperitoneal injection of pentobarbital sodium (40 mg/kg) and immobilized on a 25°C heating plate using 500 U/kg heparin anticoagulation.…”

Section: Construction Of Rat Model Of Hemorrhagic Shockmentioning

confidence: 99%

“…Although the short-term survival of patients after resuscitation increases, the long-term mortality is still high, which may be attributed to the resulting immunological stress and inflammatory response. Different fluid resuscitation techniques may have different effects on the immune response after hemorrhagic shock (Gao et al, 2009;Gao et al, 2013;Villarroel et al, 2013;Cheng et al, 2014). Myeloid cells, first discovered in tumor patients, play a negative regulatory role in the immune system and have recently acquired the collective term myeloid-derived suppressor cells (MDSCs) (Krystal et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Influence of different fluid resuscitation techniques on the number of myeloid-derived suppressor cells in rats

Wang

et al. 2016

Genet. Mol. Res.

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ABSTRACT. We investigated the influence of different fluid resuscitation techniques on the number of myeloid-derived suppressor cells (MDSCs) in rats. Seventy-two healthy Sprague-Dawley rats were randomly divided into groups that received sham operation (Sham group), hypertonic saline (HRS group), lactated ringer's solution (LRS group), or crystalloid solution (LCRS group). Six rats from each group were sacrificed by cervical dislocation at 12, 24, and 48 h after resuscitation. The spleens were harvested under sterile conditions and spleen cell suspension was prepared. The number of MDSCs was detected using flow cytometry. The number of MDSCs in the Sham group did not differ significantly among the different time points. Compared with the Sham group, the number of MDSCs after the use of the different fluid resuscitation techniques increased to varying extents and the differences among the groups were significant. The number of MDSCs in the HRS group was much lower than that of the LRS and LCRS groups at both 24 and 48 h (P < 0.05). At 12 h, the number of MDSCs in the HRS group was significantly lower than that of the LRS group (P < 0.05). The differences between the HRS and LCRS groups were not statistically significant. Shortly after hemorrhagic shock resuscitation, the immune function of rats was suppressed to a varying extent and was gradually restored over time. Resuscitation with HRS alleviated the immunosuppression at the early stage after shock.

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Hemorrhagic shock and resuscitation are associated with peripheral blood mononuclear cell mitochondrial dysfunction and immunosuppression

Cited by 39 publications

References 38 publications

Post-traumatic immunosuppression is reversed by anti-coagulated salvaged blood transfusion: deductions from studying immune status after knee arthroplasty

Post-traumatic immunosuppression is reversed by anti-coagulated salvaged blood transfusion: deductions from studying immune status after knee arthroplasty

Can Peripheral Blood Mononuclear Cells Be Used as a Proxy for Mitochondrial Dysfunction in Vital Organs During Hemorrhagic Shock and Resuscitation?

Influence of different fluid resuscitation techniques on the number of myeloid-derived suppressor cells in rats

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