Correction: Role of heme in lung bacterial infection after trauma hemorrhage and stored red blood cell transfusion: A preclinical experimental study.
Ontology highlight
ABSTRACT:
SUBMITTER: Wagener BM
PROVIDER: S-EPMC6853293 | biostudies-literature | 2019 Nov
REPOSITORIES: biostudies-literature
Publications
Correction: Role of heme in lung bacterial infection after trauma hemorrhage and stored red blood cell transfusion: A preclinical experimental study.
Wagener Brant M BM Hu Parker J PJ Oh Joo-Yeun JY Evans Cilina A CA Richter Jillian R JR Honavar Jaideep J Brandon Angela P AP Creighton Judy J Stephens Shannon W SW Morgan Charity C Dull Randal O RO Marques Marisa B MB Kerby Jeffrey D JD Pittet Jean-Francois JF Patel Rakesh P RP
PLoS medicine 20191113 11
[This corrects the article DOI: 10.1371/journal.pmed.1002522.]. ...[more]
Similar Datasets
Project description:BACKGROUND:Trauma is the leading cause of death and disability in patients aged 1-46 y. Severely injured patients experience considerable blood loss and hemorrhagic shock requiring treatment with massive transfusion of red blood cells (RBCs). Preclinical and retrospective human studies in trauma patients have suggested that poorer therapeutic efficacy, increased severity of organ injury, and increased bacterial infection are associated with transfusion of large volumes of stored RBCs, although the mechanisms are not fully understood. METHODS AND FINDINGS:We developed a murine model of trauma hemorrhage (TH) followed by resuscitation with plasma and leukoreduced RBCs (in a 1:1 ratio) that were banked for 0 (fresh) or 14 (stored) days. Two days later, lungs were infected with Pseudomonas aeruginosa K-strain (PAK). Resuscitation with stored RBCs significantly increased the severity of lung injury caused by P. aeruginosa, as demonstrated by higher mortality (median survival 35 h for fresh RBC group and 8 h for stored RBC group; p < 0.001), increased pulmonary edema (mean [95% CI] 106.4 μl [88.5-124.3] for fresh RBCs and 192.5 μl [140.9-244.0] for stored RBCs; p = 0.003), and higher bacterial numbers in the lung (mean [95% CI] 1.2 × 10(7) [-1.0 × 10(7) to 2.5 × 10(7)] for fresh RBCs and 3.6 × 10(7) [2.5 × 10(7) to 4.7 × 10(7)] for stored RBCs; p = 0.014). The mechanism underlying this increased infection susceptibility and severity was free-heme-dependent, as recombinant hemopexin or pharmacological inhibition or genetic deletion of toll-like receptor 4 (TLR4) during TH and resuscitation completely prevented P. aeruginosa-induced mortality after stored RBC transfusion (p < 0.001 for all groups relative to stored RBC group). Evidence from studies transfusing fresh and stored RBCs mixed with stored and fresh RBC supernatants, respectively, indicated that heme arising both during storage and from RBC hemolysis post-resuscitation plays a role in increased mortality after PAK (p < 0.001). Heme also increased endothelial permeability and inhibited macrophage-dependent phagocytosis in cultured cells. Stored RBCs also increased circulating high mobility group box 1 (HMGB1; mean [95% CI] 15.4 ng/ml [6.7-24.0] for fresh RBCs and 50.3 ng/ml [12.3-88.2] for stored RBCs), and anti-HMGB1 blocking antibody protected against PAK-induced mortality in vivo (p = 0.001) and restored macrophage-dependent phagocytosis of P. aeruginosa in vitro. Finally, we showed that TH patients, admitted to the University of Alabama at Birmingham ER between 1 January 2015 and 30 April 2016 (n = 50), received high micromolar-millimolar levels of heme proportional to the number of units transfused, sufficient to overwhelm endogenous hemopexin levels early after TH and resuscitation. Limitations of the study include lack of assessment of temporal changes in different products of hemolysis after resuscitation and the small sample size precluding testing of associations between heme levels and adverse outcomes in resuscitated TH patients. CONCLUSIONS:We provide evidence that large volume resuscitation with stored blood, compared to fresh blood, in mice increases mortality from subsequent pneumonia, which occurs via mechanisms sensitive to hemopexin and TLR4 and HMGB1 inhibition.
| S-EPMC5844517 | biostudies-literature
Project description:Transfusion of stored red blood cells (RBCs) is associated with increased morbidity and mortality in trauma patients. Pro-oxidant, pro-inflammatory, and nitric oxide (NO) scavenging properties of stored RBCs are thought to underlie this association. In this study we determined the effects of RBC washing and nitrite and antiheme therapy on stored RBC-dependent toxicity in the setting of trauma-induced hemorrhage. A murine (C57BL/6) model of trauma-hemorrhage and resuscitation with 1 or 3 units of RBCs stored for 0-10 days was used. Tested variables included washing RBCs to remove lower MW components that scavenge NO, NO-repletion therapy using nitrite, or mitigation of free heme toxicity by heme scavenging or preventing TLR4 activation. Stored RBC toxicity was determined by assessment of acute lung injury indices (airway edema and inflammation) and survival. Transfusion with 5 day RBCs increased acute lung injury indexed by BAL protein and neutrophil accumulation. Washing 5 day RBCs prior to transfusion did not decrease this injury, whereas nitrite therapy did. Transfusion with 10 day RBCs elicited a more severe injury resulting in ~90% lethality, compared to <15% with 5 day RBCs. Both washing and nitrite therapy significantly protected against 10 day RBC-induced lethality, suggesting that washing may be protective when the injury stimulus is more severe. Finally, a spectral deconvolution assay was developed to simultaneously measure free heme and hemoglobin in stored RBC supernatants, which demonstrated significant increases of both in stored human and mouse RBCs. Transfusion with free heme partially recapitulated the toxicity mediated by stored RBCs. Furthermore, inhibition of TLR4 signaling, which is stimulated by heme, using TAK-242, or hemopexin-dependent sequestration of free heme significantly protected against both 5 day and 10 day mouse RBC-dependent toxicity. These data suggest that RBC washing, nitrite therapy, and/or antiheme and TLR4 strategies may prevent stored RBC toxicities.
| S-EPMC4508223 | biostudies-literature
Project description:Our aim was to study the impact of bleeding and red blood cell (RBC) resuscitation on liver regeneration. We assessed the impact of RBC storage time on liver regeneration following 50% partial hepatectomy (PHx) in rats, and explored possible contributing molecular mechanisms using immunohistochemistry, RNA-Seq, and macrophage depletion.
2022-11-14 | GSE216924 | GEO
Project description:Although a subset of recent studies have suggested that red blood cell (RBC) storage length is associated with adverse patient outcomes, others have shown no such relationship. Adults may be transfused with RBC units of different storage lengths, and existing studies do not take into consideration that fresh RBCs may alter responses to concurrently transfused stored RBCs. To test this possibility, we utilized a murine model and investigated transfusion outcomes of fresh, stored, or fresh-plus-stored RBCs.Fresh, 14-day-stored or fresh plus 14-day-stored leukoreduced RBCs from HOD-transgenic donors (with RBC-specific expression of hen egg lysozyme, ovalbumin, and human Duffy(b)) were transfused into naïve C57BL/6 recipients. Serum cytokines and anti-HOD alloimmunization were evaluated after transfusion.In six of six experiments (n = 90 mice total), a proinflammatory serum cytokine storm of interleukin-6, keratinocyte-derived chemokine/CXCL1, and monocyte chemoattractant protein-1 was observed in transfusion recipients of stored but not fresh RBCs, along with high degrees of anti-HOD alloimmunization. However, concurrent transfusion of fresh HOD RBCs along with stored HOD RBCs significantly decreased these adverse outcomes (p < 0.05).These results are consistent with fresh murine HOD RBCs losing protective properties during storage, and introduce a previously unrecognized variable in RBC storage studies. If translatable to humans, uniform "old blood" groups may be needed in future clinical studies to more accurately investigate the biologic effects of older RBC units.
| S-EPMC3175330 | biostudies-other
Project description: Not available
| S-EPMC6516801 | biostudies-literature
Project description:Infection is a common complication of major trauma that causes significantly increased morbidity and mortality. The mechanisms, however, linking tissue injury to increased susceptibility to infection remain poorly understood. To study this relationship, we present a potentially novel murine model in which a major liver crush injury is followed by bacterial inoculation into the lung. We find that such tissue trauma both impaired bacterial clearance and was associated with significant elevations in plasma heme levels. While neutrophil (PMN) recruitment to the lung in response to Staphylococcus aureus was unchanged after trauma, PMN cleared bacteria poorly. Moreover, PMN show > 50% less expression of TLR2, which is responsible, in part, for bacterial recognition. Administration of heme effectively substituted for trauma. Finally, day 1 trauma patients (n = 9) showed similar elevations in free heme compared with that seen after murine liver injury, and circulating PMN showed similar TLR2 reduction compared with volunteers (n = 6). These findings correlate to high infection rates.
| S-EPMC8564912 | biostudies-literature
Project description:Two-year-old purpose-bred beagles (n = 24) infected with Staphylococcus aureus pneumonia were randomized in a blinded fashion for exchange transfusion with either 7- or 42-day-old canine universal donor blood (80 mL/kg in 4 divided doses). Older blood increased mortality (P = .0005), the arterial alveolar oxygen gradient (24-48 hours after infection; P ? .01), systemic and pulmonary pressures during transfusion (4-16 hours) and pulmonary pressures for ~ 10 hours afterward (all P ? .02). Further, older blood caused more severe lung damage, evidenced by increased necrosis, hemorrhage, and thrombosis (P = .03) noted at the infection site postmortem. Plasma cell–free hemoglobin and nitric oxide (NO) consumption capability were elevated and haptoglobin levels were decreased with older blood during and for 32 hours after transfusion (all P ? .03). The low haptoglobin (r = 0.61; P = .003) and high NO consumption levels at 24 hours (r = ?0.76; P < .0001) were associated with poor survival. Plasma nontransferrin-bound and labile iron were significantly elevated only during transfusion (both P = .03) and not associated with survival (P = NS). These data from canines indicate that older blood after transfusion has a propensity to hemolyze in vivo, releases vasoconstrictive cell-free hemoglobin over days, worsens pulmonary hypertension, gas exchange, and ischemic vascular damage in the infected lung, and thereby increases the risk of death from transfusion.
| S-EPMC3587329 | biostudies-literature
Project description:RBCs undergo numerous changes during storage and stored RBCs may induce adverse effects, ultimately resulting in organ injury in transfusion recipients. We tested the hypothesis that the addition of SP to stored RBCs would improve the quality of the stored RBCs and mitigate liver injury after transfusion in a murine model. RBCs were harvested from C57BL/6J mice and stored for 14 days in CPDA-1 containing either a solution of SP in saline or saline alone. Haemolysis, the 24-hour posttransfusion recovery, the oxygen-carrying capacity, and the SOD activity of stored RBCs were evaluated. The plasma biochemistry, hepatic MDA level, MPO activity, IL-6, TNF-? concentrations, and histopathology were measured two hours after the transfusion of stored RBCs. Compared with RBCs stored in CPDA-1 and saline, the addition of SP to stored RBCs restored their oxygen-carrying capacity and SOD activity, reduced the AST activity, BUN concentrations, and LDH activity in the plasma, and decreased the MDA level, MPO activity, and concentrations of IL-6 and TNF-? in the liver. These data indicate that the addition of SP to RBCs during storage has a beneficial effect on storage lesions in vitro and subsequently alleviates liver injury after the transfusion of stored RBCs in vivo.
| S-EPMC5056311 | biostudies-literature
Project description:IntroductionAnemia is associated with poor outcomes in patients with aneurysmal subarachnoid hemorrhage (SAH). It remains unclear whether this association can be modified with more aggressive use of red blood cell (RBC) transfusions. The degree to which restrictive thresholds have been adopted in neurocritical care patients remains unknown.MethodsWe performed a survey of North American academic neurointensivists, vascular neurosurgeons and multidisciplinary intensivists who regularly care for patients with SAH to determine hemoglobin (Hb) concentrations which commonly trigger a decision to initiate transfusion. We also assessed minimum and maximum acceptable Hb goals in the context of a clinical trial and how decision-making is influenced by advanced neurological monitoring, clinician characteristics and patient-specific factors.ResultsThe survey was sent to 531 clinicians, of whom 282 (53%) responded. In a hypothetical patient with high-grade SAH (WFNS 4), the mean Hb concentration at which clinicians administered RBCs was 8.19 g/dL (95% CI, 8.07 to 8.30 g/dL). Transfusion practices were comparatively more restrictive in patients with low-grade SAH (mean Hb 7.85 g/dL (95% CI, 7.73 to 7.97 g/dL)) (P < 0.0001) and more liberal in patients with delayed cerebral ischemia (DCI) (mean Hb 8.58 g/dL (95% CI, 8.45 to 8.72 g/dL)) (P < 0.0001). In each setting, there was a broad range of opinions. The majority of respondents expressed a willingness to study a restrictive threshold of ?8 g/dL (92%) and a liberal goal of ?10 g/dl (75%); in both cases, the preferred transfusion thresholds were significantly higher for patients with DCI (P < 0.0001). Neurosurgeons expressed higher minimum Hb goals than intensivists, especially for patients with high-grade SAH (? = 0.46, P = 0.003), and were more likely to administer two rather than one unit of RBCs (56% vs. 19%; P < 0.0001). Institutional use of transfusion protocols was associated with more restrictive practices. More senior clinicians preferred higher Hb goals in the context of a clinical trial. Respondents were more likely to transfuse patients with brain tissue oxygen tension values <15 mmHg and lactate-to-pyruvate ratios >40.ConclusionsThere is widespread variation in the use of RBC transfusions in SAH patients. Practices are heavily influenced by the specific dynamic clinical characteristics of patients and may be further modified by clinician specialty and seniority, the use of protocols and advanced neurological monitoring.
| S-EPMC3222066 | biostudies-literature
Project description:Hemorrhage is the leading cause of survivable death in trauma and resuscitation strategies including early RBC transfusion have reduced this. Pre-trauma center (PTC) RBC transfusion is growing and preliminary evidence suggests improved outcomes. The study objective was to evaluate the association of PTC RBC transfusion with outcomes in air medical trauma patients.We conducted a retrospective cohort study of trauma patients transported by helicopter to a Level I trauma center from 2007 to 2012. Patients receiving PTC RBC transfusion were matched to control patients (receiving no PTC RBC transfusion during transport) in a 1:2 ratio using a propensity score based on prehospital variables. Conditional logistic regression and mixed-effects linear regression were used to determine the association of PTC RBC transfusion with outcomes. Subgroup analysis was performed for scene transport patients.Two-hundred and forty treatment patients were matched to 480 control patients receiving no PTC RBC transfusion. Pre-trauma center RBC transfusion was associated with increased odds of 24-hour survival (adjusted odds ratio [AOR] = 4.92; 95% CI, 1.51-16.04; p = 0.01), lower odds of shock (AOR = 0.28; 95% CI, 0.09-0.85; p = 0.03), and lower 24-hour RBC requirement (Coefficient -3.6 RBC units; 95% CI, -7.0 to -0.2; p = 0.04). Among matched scene patients, PTC RBC was also associated with increased odds of 24-hour survival (AOR = 6.31; 95% CI, 1.88-21.14; p < 0.01), lower odds of shock (AOR = 0.24; 95% CI, 0.07-0.80; p = 0.02), and lower 24-hour RBC requirement (Coefficient -4.5 RBC units; 95% CI, -8.3 to -0.7; p = 0.02).Pre-trauma center RBC was associated with an increased probability of 24-hour survival, decreased risk of shock, and lower 24-hour RBC requirement. Pre-trauma center RBC appears beneficial in severely injured air medical trauma patients and prospective study is warranted as PTC RBC transfusion becomes more readily available.
| S-EPMC4409495 | biostudies-other