High-dose antithrombin III prevents heat stroke by attenuating systemic inflammation in rats

Hagiwara, Satoshi; Iwasaka, Hideo; Shingu, Chihiro; Matsumoto, Shigekiyo; Uchida, Tomohisa; Noguchi, Takayuki

doi:10.1007/s00011-009-0155-y

Cited by 28 publications

(18 citation statements)

References 28 publications

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“…The evaluation of temperature distribution and identification of hot spots are important as the order and severity of organ dysfunction in MODS is dependent on the inflammatory response, which in turn depends, at least partially, on the thermal injury (6,24,80). Because differences in anatomy and heat transfer properties can lead to distinct thermal injury in different organs, invoking differential tissue damage and organ dysfunction (42,53,80), it is critical to spatially monitor the temperature in various organs to obtain greater insights on disease progression. In the absence of experimental methods, a computational model based on a realistic description of an animal's anatomy and capable of emulating the underlying thermoregulatory mechanisms would be useful for quantifying the spatial distribution and temporal dynamics of temperatures in the entire body.…”

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confidence: 99%

A 3-D mathematical model to identify organ-specific risks in rats during thermal stress

Rakesh

Stallings

Helwig

et al. 2013

Journal of Applied Physiology

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Early prediction of the adverse outcomes associated with heat stress is critical for effective management and mitigation of injury, which may sometimes lead to extreme undesirable clinical conditions, such as multiorgan dysfunction syndrome and death. Here, we developed a computational model to predict the spatiotemporal temperature distribution in a rat exposed to heat stress in an attempt to understand the correlation between heat load and differential organ dysfunction. The model includes a three-dimensional representation of the rat anatomy obtained from medical imaging and incorporates the key mechanisms of heat transfer during thermoregulation. We formulated a novel approach to estimate blood temperature by accounting for blood mixing from the different organs and to estimate the effects of the circadian rhythm in body temperature by considering day-night variations in metabolic heat generation and blood perfusion. We validated the model using in vivo core temperature measurements in control and heat-stressed rats and other published experimental data. The model predictions were within 1 SD of the measured data. The liver demonstrated the greatest susceptibility to heat stress, with the maximum temperature reaching 2°C higher than the measured core temperature and 95% of its volume exceeding the targeted experimental core temperature. Other organs also attained temperatures greater than the core temperature, illustrating the need to monitor multiple organs during heat stress. The model facilitates the identification of organ-specific risks during heat stress and has the potential to aid in the development of improved clinical strategies for thermal-injury prevention and management.

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confidence: 99%

A 3-D mathematical model to identify organ-specific risks in rats during thermal stress

Rakesh

Stallings

Helwig

et al. 2013

Journal of Applied Physiology

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“…Additionally, brain hyperthermia causes CNS abnormalities, increasing metabolic rate with a reduction in blood flow in the cerebrum [21]. Although some anticoagulant agents such as recombinant activated protein C [22], [23], recombinant thrombomodulin [18], and antithrombin [19] attenuate inflammation and multi-organ system dysfunction in animal experiments, the clinical syndrome of heatstroke is still a challenging problem, and there remains an urgent unmet need for development of new therapeutics. We demonstrated for the first time, to our knowledge, that cholinergic activation by electrical VNS attenuated heat stress-related systemic inflammation, resulting in an increased survival rate in a rat model of heatstroke.…”

Section: Discussionmentioning

confidence: 99%

Electrical Vagus Nerve Stimulation Attenuates Systemic Inflammation and Improves Survival in a Rat Heatstroke Model

et al. 2013

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This study was performed to gain insights into novel therapeutic approaches for the treatment of heatstroke. The central nervous system regulates peripheral immune responses via the vagus nerve, the primary neural component of the cholinergic anti-inflammatory pathway. Electrical vagus nerve stimulation (VNS) reportedly suppresses pro-inflammatory cytokine release in several models of inflammatory disease. Here, we evaluated whether electrical VNS attenuates severe heatstroke, which induces a systemic inflammatory response. Anesthetized rats were subjected to heat stress (41.5°C for 30 minutes) with/without electrical VNS. In the VNS-treated group, the cervical vagus nerve was stimulated with constant voltage (10 V, 2 ms, 5 Hz) for 20 minutes immediately after completion of heat stress. Sham-operated animals underwent the same procedure without stimulation under a normothermic condition. Seven-day mortality improved significantly in the VNS-treated group versus control group. Electrical VNS significantly suppressed induction of pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-6 in the serum 6 hours after heat stress. Simultaneously, the increase of soluble thrombomodulin and E-selectin following heat stress was also suppressed by VNS treatment, suggesting its protective effect on endothelium. Immunohistochemical analysis using tissue preparations obtained 6 hours after heat stress revealed that VNS treatment attenuated infiltration of inflammatory (CD11b-positive) cells in lung and spleen. Interestingly, most cells with increased CD11b positivity in response to heat stress did not express α7 nicotinic acetylcholine receptor in the spleen. These data indicate that electrical VNS modulated cholinergic anti-inflammatory pathway abnormalities induced by heat stress, and this protective effect was associated with improved mortality. These findings may provide a novel therapeutic strategy to combat severe heatstroke in the critical care setting.

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“…Anti-factor Xa (anti-FXa) assay was performed with pentasaccharide, bovine FXa, and S-2765 chromogenic substrate (Chromogenix, IZASA, Spain). Antithrombin levels were determined by enzyme-linked immunosorbent assay and electro-immunodiffusion (Laurell), as previously reported [15]. Values were expressed as a percentage relative to a pool of citrated plasma from 10 adult control mice (100%).…”

Section: Methodsmentioning

confidence: 99%

Control of post-translational modifications in antithrombin during murine post-natal development by miR-200a

et al. 2013

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BackgroundDevelopmental haemostatic studies may help identifying new elements involved in the control of key haemostatic proteins like antithrombin, the most relevant endogenous anticoagulant.ResultsIn this study, we showed a significant reduction of sialic acid content in neonatal antithrombin compared with adult antithrombin in mice. mRNA levels of St3gal3 and St3gal4, two sialyltransferases potentially involved in antithrombin sialylation, were 85% lower in neonates in comparison with adults. In silico analysis of miRNAs overexpressed in neonates revealed that mir-200a might target these sialyltransferases. Moreover, in vitro studies in murine primary hepatocytes sustain this potential control.ConclusionsThese data suggest that in addition to the direct protein regulation, microRNAs may also modulate qualitative traits of selected proteins by an indirect control of post-translational processes.

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High-dose antithrombin III prevents heat stroke by attenuating systemic inflammation in rats

Abstract: Our data suggest that AT III pretreatment inhibited the secretion of cytokines, NOx, and HMGB1, and prevented heat stress-induced acute inflammation.

Cited by 28 publications

References 28 publications

A 3-D mathematical model to identify organ-specific risks in rats during thermal stress

A 3-D mathematical model to identify organ-specific risks in rats during thermal stress

Electrical Vagus Nerve Stimulation Attenuates Systemic Inflammation and Improves Survival in a Rat Heatstroke Model

Control of post-translational modifications in antithrombin during murine post-natal development by miR-200a

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