Simulated Aeromedical Evacuation Does Not Affect Systemic Inflammation or Organ Injury in a Murine Model of Hemorrhagic Shock

Makley, Amy T.; Belizaire, Ritha M.; Campion, Eric M.; Goodman, Michael D.; Sonnier, Dennis I.; Friend, Lou Ann; Schuster, Rebecca; Bailey, Stephanie R.; Johannigman, Jay A.; Dorlac, Warren C.; Lentsch, Alex B.; Pritts, Timothy A.

doi:10.7205/milmed-d-11-00385

Cited by 10 publications

(4 citation statements)

References 21 publications

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“…In severe trauma situations, hemorrhagic shock can accompany muscle injury or other types of tissue damage. Since hemorrhagic shock and/or tissue damage induce an inflammatory response 6,27,28 and hemorrhagic shock causes systemic hypoxia, 6 polytrauma likely drives splenic erythropoiesis. However, our understanding of the effect of polytrauma on splenic erythropoiesis is limited.…”

Section: Introductionmentioning

confidence: 99%

Mild hypobaric hypoxia influences splenic proliferation during the later phase of stress erythropoiesis

Zhang

Patel

Soulakova

et al. 2021

Exp Biol Med (Maywood)

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Tissue trauma and hemorrhagic shock are common battlefield injuries that can induce hypoxia, inflammation, and/or anemia. Inflammation and hypoxia can initiate adaptive mechanisms, such as stress erythropoiesis in the spleen, to produce red blood cells and restore the oxygen supply. In a military context, mild hypobaric hypoxia—part of the environmental milieu during aeromedical evacuation or en route care—may influence adaptive mechanisms, such as stress erythropoiesis, and host defense. In the present study, healthy (control), muscle trauma, and polytrauma (muscle trauma and hemorrhagic shock) mice were exposed to normobaric normoxia or hypobaric hypoxia for ∼17.5 h to test the hypothesis that hypobaric hypoxia exposure influences splenic erythropoiesis and splenic inflammation after polytrauma. This hypothesis was partially supported. The polytrauma + hypobaric hypoxia group exhibited more splenic neutrophils, fewer total spleen cells, and fewer splenic proliferating cells than the polytrauma+normobaric normoxia group; however, no splenic erythroid cell differences were detected between the two polytrauma groups. We also compared splenic erythropoiesis and myeloid cell numbers among control, muscle trauma, and polytrauma groups. More reticulocytes at 1.7 days (40 h) post-trauma (dpt) and neutrophils at 4 dpt were produced in the muscle trauma mice than corresponding control mice. In contrast to muscle trauma, polytrauma led to a reduced red blood cell count and elevated serum erythropoietin levels at 1.7 dpt. There were more erythroid subsets and apoptotic reticulocytes in the polytrauma mice than muscle trauma mice at 4 and 8 dpt. At 14 dpt, the red blood cell count of the polytrauma + normobaric normoxia mice was 12% lower than that of the control + normobaric normoxia mice; however, no difference was observed between polytrauma + hypobaric hypoxia and control + hypobaric hypoxia mice. Our findings suggest muscle trauma alone induces stress erythropoiesis; in a polytrauma model, hypobaric hypoxia exposure may result in the dysregulation of splenic cells, requiring a treatment plan to ensure adequate immune functioning.

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Section: Introductionmentioning

confidence: 99%

Mild hypobaric hypoxia influences splenic proliferation during the later phase of stress erythropoiesis

Zhang

Patel

Soulakova

et al. 2021

Exp Biol Med (Maywood)

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“…Fluid resuscitation after HS can lead to ischemia/ reperfusion injury, which can trigger an excessive inflammatory response. [28] Macrophages play a crucial role in sensing and initiating the inflammatory response during H/R. [6,15,29] Our study demonstrated that the upregulation of HDAC6, Hsp90, and iNOS led to an increase in ROS levels in macrophages under H/R.…”

Section: Discussionmentioning

confidence: 66%

Effect of tubastatin A on NLRP3 inflammasome activation in macrophages under hypoxia/reoxygenation conditions

Li,

Liu,

Cui

et al. 2024

World Journal of Emergency Medicine

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BACKGROUND: There are currently no effective drugs to mitigate the ischemia/reperfusion injury caused by fluid resuscitation after hemorrhagic shock (HS). The aim of this study was to explore the potential of the histone deacetylase 6 (HDAC6)-specific inhibitor tubastatin A (TubA) to suppress nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation in macrophages under hypoxia/reoxygenation (H/R) conditions. METHODS:The viability of RAW264.7 cells subjected to H/R after treatment with different concentrations of TubA was assessed using a cell-counting kit-8 (CCK8) assay. Briefly, 2.5 µmol/L TubA was used with RAW264.7 cells under H/R condition. RAW264.7 cells were divided into three groups, namely the control, H/R, and TubA groups. The levels of reactive oxygen species (ROS) in the cells were detected using fluorescence microscopy. The protein expression of HDAC6, heat shock protein 90 (Hsp90), inducible nitric oxide synthase (iNOS), NLRP3, gasdermin-D (GSDMD), Caspase-1, GSDMD-N, and Caspase-1 p20 was detected by western blotting. The levels of interleukin-1β (IL-1β) and IL-18 in the supernatants were detected using enzyme-linked immunosorbent assay (ELISA).RESULTS: HDAC6, Hsp90, and iNOS expression levels were significantly higher (P<0.01) in the H/R group than in the control group, but lower (P<0.05) in the TubA group than in the H/R group. When comparing the H/R group to the control group, ROS levels were significantly higher (P<0.01), but significantly reduced (P<0.05) in the TubA group. The H/R group had higher NLRP3, GSDMD, Caspase-1, GSDMD-N, and Caspase-1 p20 expression levels than the control group (P<0.05), however the TubA group had significantly lower expression levels than the H/R group (P<0.05). L-1β and IL-18 levels in the supernatants were significantly higher in the H/R group compared to the control group (P<0.01), but significantly lower in the TubA group compared to the H/R group (P<0.01).CONCLUSION: TubA inhibited the expression of HDAC6, Hsp90, and iNOS in macrophages subjected to H/R. This inhibition led to a decrease in the content of ROS in cells, which subsequently inhibited the activation of the NLRP3 inflammasome and the secretion of IL-1β and IL-18.

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“…Using a rat model of polymicrobial sepsis, there were no significant changes in serum cytokine levels or mortality when rats were exposed to 8,000 ft hypobaria for 6 h, starting at 24 h postinjury (6). A similar exposure to hypobaria also had no significant effect in a mouse model of hemorrhagic shock (7). Nevertheless, exposure of lung-injured pigs to 8,000 ft hypobaria for 4 h resulted in greater pulmonary neutrophilic inflammation and micro-atelectasis compared with pigs maintained under anesthesia without exposure to hypobaria (8).…”

Section: Introductionmentioning

confidence: 91%

Air-Evacuation-Relevant Hypobaria Following Traumatic Brain Injury Plus Hemorrhagic Shock in Rats Increases Mortality and Injury to the Gut, Lungs, and Kidneys

Proctor

Medina

Rangghran

et al. 2021

Shock

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Rats exposed to hypobaria equivalent to what occurs during aeromedical evacuation within a few days after isolated traumatic brain injury exhibit greater neurologic injury than those remaining at sea level. Moreover, administration of excessive supplemental O 2 during hypobaria further exacerbates brain injury. This study tested the hypothesis that exposure of rats to hypobaria following controlled cortical impact (CCI)-induced brain injury plus mild hemorrhagic shock worsens multiple organ inflammation and associated mortality. In this study, at 24 h after CCI plus hemorrhagic shock, rats were exposed to either normobaria (sea level) or hypobaria (¼8,000 ft altitude) for 6 h under normoxic or hyperoxic conditions. Injured rats exhibited mortality ranging from 30% for those maintained under normobaria and normoxia to 60% for those exposed to 6 h under hypobaric and hyperoxia. Lung histopathology and neutrophil infiltration at 2 days postinjury were exacerbated by hypobaria and hyperoxia. Gut and kidney inflammation at 30 days postinjury were also worsened by hypobaric hyperoxia. In conclusion, exposure of rats after brain injury and hemorrhagic shock to hypobaria or hyperoxia results in increased mortality. Based on gut, lung, and kidney histopathology at 2 to 30 days postinjury, increased mortality is consistent with multi-organ inflammation. These findings support epidemiological studies indicating that increasing aircraft cabin pressures to 4,000 ft altitude (compared with standard 8,000 ft) and limiting excessive oxygen administration will decrease critical complications during and following aeromedical transport.

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Simulated Aeromedical Evacuation Does Not Affect Systemic Inflammation or Organ Injury in a Murine Model of Hemorrhagic Shock

Cited by 10 publications

References 21 publications

Mild hypobaric hypoxia influences splenic proliferation during the later phase of stress erythropoiesis

Mild hypobaric hypoxia influences splenic proliferation during the later phase of stress erythropoiesis

Effect of tubastatin A on NLRP3 inflammasome activation in macrophages under hypoxia/reoxygenation conditions

Air-Evacuation-Relevant Hypobaria Following Traumatic Brain Injury Plus Hemorrhagic Shock in Rats Increases Mortality and Injury to the Gut, Lungs, and Kidneys

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