Facts and Fiction: The Impact of Hypothermia on Molecular Mechanisms following Major Challenge

Frink, Michael; Flohé, Sascha; Griensven, Martijn van; Mommsen, Philipp; Hildebrand, Frank

doi:10.1155/2012/762840

Cited by 28 publications

(21 citation statements)

References 140 publications

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“…These pro-inflammatory cytokines are produced by activated microglia/macrophages and many other cell types, mediating various cell signaling such as apoptosis and oxidative stress (Doyle et al, 2008; Morganti-Kossmann et al, 2001). The expression of TNF-α and IL-1β was reduced by TH therapy, which is consistent with previous reports using physical cooling (Frink et al, 2012). The expression of IL-10 has been shown to be cellular protective after brain injurious insults such as stroke and TBI but is controversial during or after hypothermia (Kline et al, 2002; Stewart et al, 2010).…”

Section: Discussionsupporting

confidence: 92%

Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice

Lee

Wei

Cao

et al. 2016

Neurobiology of Disease

111

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Stroke is a leading threat to human life and health in the US and around the globe, while very few effective treatments are available for stroke patients. Preclinical and clinical studies have shown that therapeutic hypothermia (TH) is a potential treatment for stroke. Using novel neurotensin receptor 1 (NTR1) agonists, we have demonstrated pharmacologically induced hypothermia and protective effects against brain damages after ischemic stroke, hemorrhage stroke, and traumatic brain injury (TBI) in rodent models. To further characterize the mechanism of TH-induced brain protection, we examined the effect of TH (at ±33°C for 6 hrs) induced by the NTR1 agonist HPI-201 or physical (ice/cold air) cooling on inflammatory responses after ischemic stroke in mice and oxygen glucose deprivation (OGD) in cortical neuronal cultures. Seven days after focal cortical ischemia, microglia activation in the penumbra reached a peak level, which was significantly attenuated by TH treatments commenced 30 min after stroke. The TH treatment decreased the expression of M1 type reactive factors including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-12, IL-23, and inducible nitric oxide synthase (iNOS) measured by RT-PCR and Western blot analyses. Meanwhile, TH treatments increased the expression of M2 type reactive factors including IL-10, Fizz1, Ym1, and arginase-1. In the ischemic brain and in cortical neuronal/BV2 microglia cultures subjected to OGD, TH attenuated the expression of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α), two key chemokines in the regulation of microglia activation and infiltration. Consistently, physical cooling during OGD significantly decreased microglia migration 16 hrs after OGD. Finally, TH improved functional recovery at 1, 3, and 7 days after stroke. This study reveals the first evidence for hypothermia mediated regulation on inflammatory factor expression, microglia polarization, migration and indicates that the anti-inflammatory effect is an important mechanism underlying the brain protective effects of a TH therapy.

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Section: Discussionsupporting

confidence: 92%

Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice

Lee

Wei

Cao

et al. 2016

Neurobiology of Disease

111

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“…Various other studies agree and state thatVdue to the limited experimental and observation timeVno valid and reliable assessments on kinetics of functional recovery or deterioration of endothelial or organ function, kinetics of the immune response, long-term treatment effects, or compensation mechanisms are possible (54,76,100). Hypothermia seems to affect this apoptotic process including the inhibition of activation of caspase enzymes and the preservation of mitochondrial function (101). Hypothermia seems to affect this apoptotic process including the inhibition of activation of caspase enzymes and the preservation of mitochondrial function (101).…”

Section: Studies With Long-term Observationmentioning

confidence: 87%

Combined Hemorrhage/Trauma Models in Pigs—Current State and Future Perspectives

Hildebrand¹,

Andruszkow

Huber‐Lang

et al. 2013

Shock

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The majority of injury combinations in multiply injured patients entail the chest, abdomen, and extremities. Numerous pig models focus on the investigation of posttraumatic pathophysiology, organ performance monitoring and on potential treatment options. Depending on the experimental question, previous authors have included isolated insults (controlled or uncontrolled hemorrhage, chest trauma) or a combination of these injuries (hemorrhage with abdominal trauma, chest trauma, traumatic brain injury, and/or long-bone fractures). Combined trauma models in pigs can provide a high level of clinical relevance, when they are properly designed and mimicking the clinical situation. Most of these models focus on the first hours after trauma, to assess the acute sequel of traumatic hemorrhage. However, hemorrhagic shock and the associated mass transfusion are also major causes for organ failure and mortality in the later clinical course. Thus, most models lack information on the pathomechanisms during the late posttraumatic phase. Studying new therapies only during the early phase is also not reflective of the clinical situation. Therefore, a longer observation period is required to study the effects of therapeutic approaches during intensive care treatment when using animal models. These long-term studies of combined trauma models will allow the development of valuable therapeutic approaches relevant for the later posttraumatic course. This review summarizes the existing porcine models and outlines the need for long-term models to provide real effective novel therapeutics for multiply injured patients to improve organ function and clinical outcome.

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“…This is believed to be associated with myocardial intracellular Ca 2+ overload, which promotes backward failure and subsequently leads to increased microvascular pressure and emergence of lung edema (12). Moreover, activation of leukocytes and various inflammatory mediators may damage endothelial integrity and indirectly increase pulmonary microvascular permeability, thus, causing fluid accumulation and derangement of gas exchange (13, 14). Besides these direct effects of hypothermia, CPB per se has been shown to increase the extravascular lung water content by as much as 35–40%, in comparison with the preoperative values.…”

Section: Introductionmentioning

confidence: 99%

Effects of Constant Flow vs. Constant Pressure Perfusion on Fluid Filtration in Severe Hypothermic Isolated Blood-Perfused Rat Lungs

et al. 2016

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BackgroundVictims of severe accidental hypothermia are prone to fluid extravasation but rarely develop lung edema. We hypothesize that combined hypothermia-induced increase in pulmonary vascular resistance (PVR) and a concomitant fall in cardiac output protect the lungs against edema development. Our aim was to explore in hypothermic-isolated blood-perfused rat lungs whether perfusion at constant pressure influences fluid filtration differently from perfusion at constant flow.MethodsIsolated blood-perfused rat lungs were hanging freely in a weight transducer for measuring weight changes (ΔW). Fluid filtration coefficient (Kfc), was determined by transiently elevating left atrial pressure (Pla) by 5.8 mmHg two times each during normothermia (37°C) and during hypothermia (15°C). The lung preparations were randomized to two groups. One group was perfused with constant flow (Constant flow group) and the other group with constant pulmonary artery pressure (Constant PPA group). Microvascular pressure (Pmv) was determined before and during elevation of Pla (ΔPmv) by means of the double occlusion technique. Kfc was calculated with the formula Kfc = ΔW/ΔPmv/min. All Kfc values were normalized to predicted lung weight (PLW), which was based on body weight (BW) according to the formula: PLW = 0.0053 BW − 0.48 and presented as KfcPLW in mg/min/mmHg/g. At cessation, bronchoalveolar lavage (BAL) fluid/perfusate protein concentration (B/P) ratio was determined photometrically. Data were analyzed with parametric or non-parametric tests as appropriate. p < 0.05 considered as significant.ResultsPerfusate flow remained constant in the Constant flow group, but was more than halved during hypothermia in the Constant PPA group concomitant with a more fold increase in PVR. In the Constant flow group, KfcPLW and B/P ratio increased significantly by more than 10-fold during hypothermia concerted by visible signs of edema in the trachea. Hemoglobin and hematocrit increased within the Constant flow group and between the groups at cessation of the experiments.ConclusionIn hypothermic rat lungs perfused at constant flow, fluid filtration coefficient per gram PLW and B/P ratio increased more than 10-fold concerted by increased hemoconcentration, but the changes were less in hypothermic lungs perfused at constant PPA.

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Facts and Fiction: The Impact of Hypothermia on Molecular Mechanisms following Major Challenge

Cited by 28 publications

References 140 publications

Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice

Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice

Combined Hemorrhage/Trauma Models in Pigs—Current State and Future Perspectives

Effects of Constant Flow vs. Constant Pressure Perfusion on Fluid Filtration in Severe Hypothermic Isolated Blood-Perfused Rat Lungs

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