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  • Huber-Lang, Markus  (11)
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  • 1
    Language: English
    In: PLoS ONE, July 30, 2015, Vol.10(7)
    Description: Cigarette smoking (CS) aggravates post-traumatic acute lung injury and increases ventilator-induced lung injury due to more severe tissue inflammation and apoptosis. Hyper-inflammation after chest trauma is due to the physical damage, the drop in alveolar PO.sub.2, and the consecutive hypoxemia and tissue hypoxia. Therefore, we tested the hypotheses that 1) CS exposure prior to blunt chest trauma causes more severe post-traumatic inflammation and thereby aggravates lung injury, and that 2) hyperoxia may attenuate this effect. Immediately after blast wave-induced blunt chest trauma, mice (n=32) with or without 3-4 weeks of CS exposure underwent 4 hours of pressure-controlled, thoraco-pulmonary compliance-titrated, lung-protective mechanical ventilation with air or 100 % O.sub.2 . Hemodynamics, lung mechanics, gas exchange, and acid-base status were measured together with blood and tissue cytokine and chemokine concentrations, heme oxygenase-1 (HO-1), activated caspase-3, and hypoxia-inducible factor 1-[alpha] (HIF-1[alpha]) expression, nuclear factor-[kappa]B (NF-[kappa]B) activation, nitrotyrosine formation, purinergic receptor 2X.sub.4 (P2XR.sub.4) and 2X.sub.7 (P2XR.sub.7) expression, and histological scoring. CS exposure prior to chest trauma lead to higher pulmonary compliance and lower PaO.sub.2 and Horovitz-index, associated with increased tissue IL-18 and blood MCP-1 concentrations, a 2-4-fold higher inflammatory cell infiltration, and more pronounced alveolar membrane thickening. This effect coincided with increased activated caspase-3, nitrotyrosine, P2XR.sub.4, and P2XR.sub.7 expression, NF-[kappa]B activation, and reduced HIF-1[alpha] expression. Hyperoxia did not further affect lung mechanics, gas exchange, pulmonary and systemic cytokine and chemokine concentrations, or histological scoring, except for some patchy alveolar edema in CS exposed mice. However, hyperoxia attenuated tissue HIF-1[alpha], nitrotyrosine, P2XR.sub.7, and P2XR.sub.4 expression, while it increased HO-1 formation in CS exposed mice. Overall, CS exposure aggravated post-traumatic inflammation, nitrosative stress and thereby organ dysfunction and injury; short-term, lung-protective, hyperoxic mechanical ventilation have no major beneficial effect despite attenuation of nitrosative stress, possibly due to compensation of by regional alveolar hypoxia and/or consecutive hypoxemia, resulting in down-regulation of HIF-1[alpha] expression.
    Keywords: Smoking – Analysis ; Inflammation – Analysis ; Apoptosis – Analysis
    ISSN: 1932-6203
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  • 2
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(7), p.e0132810
    Description: Cigarette smoking (CS) aggravates post-traumatic acute lung injury and increases ventilator-induced lung injury due to more severe tissue inflammation and apoptosis. Hyper-inflammation after chest trauma is due to the physical damage, the drop in alveolar PO2, and the consecutive hypoxemia...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: BMC Anesthesiology, 01 December 2010, Vol.10(1), p.22
    Description: Abstract Background It has never been specified how many of the extended general and inflammatory variables of the 2003 SCCM/ESICM/ACCP/ATS/SIS consensus sepsis definitions are mandatory to define sepsis. Objectives To find out how many of these variables are needed to identify almost all patients...
    Keywords: Research Article;
    ISSN: 1471-2253
    E-ISSN: 1471-2253
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  • 4
    Language: English
    In: International Immunopharmacology, October 2017, Vol.51, pp.66-75
    Description: Ethanol intoxication is a common comorbidity in traumatic brain injury. To date, the effect of ethanol on TBI pathogenic cascades and resulting outcomes remains debated. A closed blunt weight-drop murine TBI model has been implemented to investigate behavioral (by sensorimotor and neurological tests), and neuro-immunological (by tissue cytokine arrays and immuno-histology) effects of ethanol intoxication on TBI. The effect of the occurrence of traumatic intracerebral hemorrhage was also studied. The results indicate that ethanol pretreatment results in a faster and better recovery after TBI with reduced infiltration of leukocytes and reduced microglia activation. These outcomes correspond to reduced parenchymal levels of GM-CSF, IL-6 and IL-3 and to the transient upregulation of IL-13 and VEGF, indicating an early shift in the cytokine profile towards reduced inflammation. A significant difference in the cytokine profile was still observed 24 h post injury in the ethanol pretreated mice, as shown by the delayed peak in IL-6 and by the suppression of GM-CSF, IFN-γ, and IL-3. Seven days post-injury, ethanol-pretreated mice displayed a significant decrease both in CD45 + cells infiltration and in microglial activation. On the other hand, in the case of traumatic intracerebral hemorrhage, the cytokine profile was dominated by KC, CCL5, M-CSF and several interleukins and ethanol pretreatment did not produce any modification. We can thus conclude that ethanol intoxication suppresses the acute neuro-inflammatory response to TBI, an effect which is correlated with a faster and complete neurological recovery, whereas, the presence of traumatic intracerebral hemorrhage overrides the effects of ethanol.
    Keywords: Traumatic Brain Injury ; Ethanol ; Cytokines ; Microglia ; Biology ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 1567-5769
    E-ISSN: 1878-1705
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  • 5
    Language: English
    In: Journal of neurotrauma, 15 November 2018, Vol.35(22), pp.2718-2735
    Description: Ethanol intoxication (EI) is a frequent comorbidity of traumatic brain injury (TBI), but the impact of EI on TBI pathogenic cascades and prognosis is unclear. Although clinical evidence suggests that EI may have neuroprotective effects, experimental support is, to date, inconclusive. We aimed at elucidating the impact of EI on TBI-associated neurological deficits, signaling pathways, and pathogenic cascades in order to identify new modifiers of TBI pathophysiology. We have shown that ethanol administration (5 g/kg) before trauma enhances behavioral recovery in a weight-drop TBI model. Neuronal survival in the injured somatosensory cortex was also enhanced by EI. We have used phospho-receptor tyrosine kinase (RTK) arrays to screen the impact of ethanol on TBI-induced activation of RTK in somatosensory cortex, identifying ErbB2/ErbB3 among the RTKs activated by TBI and suppressed by ethanol. Phosphorylation of ErbB2/3/4 RTKs were upregulated in vGlut2 excitatory synapses in the injured cortex, including excitatory synapses located on parvalbumin (PV)-positive interneurons. Administration of selective ErbB inhibitors was able to recapitulate, to a significant extent, the neuroprotective effects of ethanol both in sensorimotor performance and structural integrity. Further, suppression of PV interneurons in somatosensory cortex before TBI, by engineered receptors with orthogonal pharmacology, could mimic the beneficial effects of ErbB inhibitors. Thus, we have shown that EI interferes with TBI-induced pathogenic cascades at multiple levels, with one prominent pathway, involving ErbB-dependent modulation of PV interneurons.
    Keywords: Chemogenetics ; Ethanol Intoxication ; Inhibitory Interneurons ; Traumatic Brain Injury ; Tyrosine Kinase Receptors
    ISSN: 08977151
    E-ISSN: 1557-9042
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  • 6
    In: SHOCK, 2017, Vol.47(2), pp.193-199
    Description: ABSTRACT: Both acute and chronic lung injury are associated with up-regulation of the pulmonary expression of the purinergic receptors P2XR4 and P2XR7. Genetic deletion or blockade of P2XR7 attenuated pulmonary hyperinflammation, but simultaneous P2XR4 up-regulation compensated for P2XR7 deletion. Therefore, we tested the hypothesis whether genetic P2XR4 deletion would attenuate the pulmonary inflammatory response and thereby improve organ function after blunt chest trauma in mice with and without pretraumatic cigarette smoke (CS) exposure.After 3 weeks to 4 weeks of exposure to CS, anesthetized wildtype or P2XR4 mice (n = 32) underwent a blast wave-induced blunt chest trauma followed by 4 h of lung-protective mechanical ventilation, fluid resuscitation, and noradrenaline support to maintain mean arterial pressure 〉55 mm Hg. Hemodynamics, lung mechanics, gas exchange, and acid-base status were measured together with blood and tissue cytokine and chemokine concentrations, heme oxygenase-1, B-cell lymphoma-extra large (Bcl-xL), endogenous nuclear factor-κB inhibitor (IκBα) expression, nitrotyrosine formation, purinergic receptor expression, and histological scoring.Despite a significant increase in the histopathology score in both CS-exposed groups, neither CS exposure nor P2XR4 deletion had any significant effect on post-traumatic pulmonary function and inflammatory response. However, P2XR4 deletion was associated with attenuated impairment of glucose homeostasis and acid-base-status after CS exposure and chest trauma.In conclusion, genetic P2XR4 deletion failed to attenuate the acute post-traumatic pulmonary inflammatory response. The improved glucose homeostasis and acid-base-status after CS exposure in the P2XR4 group was possibly due to less alveolar hypoxia-induced right ventricular remodeling resulting in preserved liver metabolic capacity.
    Keywords: Receptors, Purinergic -- Metabolism ; Receptors, Purinergic P2y2 -- Metabolism ; Smoking -- Adverse Effects ; Thoracic Injuries -- Metabolism ; Wounds, Nonpenetrating -- Metabolism;
    ISSN: 1073-2322
    E-ISSN: 15400514
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  • 7
    In: SHOCK, 2019, Vol.51(1), pp.68-77
    Description: INTRODUCTION:: Hemorrhagic shock accounts for a large amount of trauma-related mortality. The severity of trauma can be further aggravated by an additional blunt chest trauma (TxT), which independently contributes to mortality upon the development of an acute lung injury (ALI). Besides, cigarette smoke (CS) exposure before TxT enhanced posttraumatic inflammation, thereby aggravating ALI. We therefore aimed to characterize the impact of an acute and/or chronic lung injury on organ dysfunction in a murine model of traumatic hemorrhagic shock (HS). METHODS:: After 3 weeks of CS exposure, anesthetized mice underwent HS with/without TxT. Hemorrhagic shock was implemented for 1 h followed by retransfusion of shed blood and intensive care therapy for 4 h including lung-protective mechanical ventilation, fluid resuscitation, and noradrenaline titrated to maintain mean arterial pressure ≥50 mmHg. Lung mechanics and gas exchange were assessed together with systemic hemodynamics, metabolism, and acid-base status. Postmortem blood and tissue samples were analyzed for cytokine and chemokine levels, protein expression, mitochondrial respiration, and histological changes. RESULTS:: CS exposure and HS alone coincided with increased inflammation, decreased whole blood sulfide concentrations, and decreased diaphragmatic mitochondrial respiration. CS-exposed mice, which were subjected to TxT and subsequent HS, showed hemodynamic instability, acute kidney injury, and high mortality. CONCLUSIONS:: Chronic CS exposure per se had the strongest impact on inflammatory responses. The degree of inflammation was similar upon an additional TxT, however, mice presented with organ dysfunction and increased mortality rates. Hence, in mice the degree of inflammation may be dissociated from the severity of organ dysfunction or injury.
    ISSN: 1073-2322
    E-ISSN: 15400514
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  • 8
    In: SHOCK, 2017, Vol.47(4), pp.491-499
    Description: ABSTRACT: Pretraumatic cigarette smoke (CS) exposure aggravates posttraumatic acute lung injury (ALI). Cystathionine-γ-lyase (CSE) protects against ALI and CS exposure-induced chronic obstructive lung disease (COPD). Therefore, we tested the hypothesis whether genetic CSE knockout (CSE) would aggravate posttraumatic ALI after CS exposure. After 3 to 4 weeks of CS exposure, anesthetized wild-type (WT) and CSE mice underwent blunt chest trauma, surgical instrumentation and 4 h of lung-protective mechanical ventilation. We measured hemodynamics, lung mechanics, gas exchange, metabolism, and acid–base status together with blood and tissue cytokine and chemokine levels, tissue expression of mediator proteins, parameters of oxidative and nitrosative stress, and histology. CSE mice without CS exposure showed higher cytokine and chemokine levels, and this was further enhanced by CS exposure, particularly in males. CS exposure in WT mice aggravated posttraumatic alveolar membrane thickening, dystelectasis, and inflammatory cell accumulation, which was associated with higher thoracopulmonary compliance. Pretraumatic CS exposure in CSE mice produced a similar response, except for less alveolar membrane thickening, most likely due to lung hyperinflation. CS-exposed WT mice showed the most pronounced metabolic acidosis, while CS exposure in CSE mice resulted in the lowest blood glucose levels. Urinary output and anesthesia rate were highest in male CS-exposed CSE animals. In conclusion, in murine acute-on-chronic pulmonary disease, CSE knockout aggravated posttraumatic inflammation, which was further worsened upon pretraumatic CS exposure, and this effect was particularly pronounced in males. Hence, maintaining CSE expression is critically important for stress adaptation during ALI and CS-induced COPD, most likely in a gender-dependent manner.
    Keywords: Cigarette Smoking -- Adverse Effects ; Cystathionine Gamma-Lyase -- Metabolism ; Thoracic Injuries -- Enzymology ; Wounds, Nonpenetrating -- Enzymology;
    ISSN: 1073-2322
    E-ISSN: 15400514
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  • 9
    In: Shock, 2015, Vol.43(2), pp.140-147
    Description: ABSTRACT: Blunt chest trauma causes pulmonary and systemic inflammation. It is still a matter of debate whether the long-term course of this inflammatory response is associated with persistent impairment of lung function. We hypothesized that an increase of inflammatory biomarkers may still be present at later time points after blunt chest trauma, eventually, despite normalized lung mechanics and gas exchange. Anesthetized spontaneously breathing male C57BL/6J mice underwent a blast wave–induced blunt chest trauma or sham procedure. Twelve and 24 h later, blood gases and lung mechanics were measured, together with blood, bronchoalveolar lavage (BAL), and tissue cytokine concentrations (multiplex cytokine kit); heme oxygenase 1 (HO-1), activated caspase-3, Bcl-xL, and Bax expression (Western blotting); nuclear factor-κB activation (electrophoretic mobility shift assay); nitrotyrosine formation; and purinergic (P2XR4 and P2XR7) receptor expression (immunohistochemistry). Histological damage was assessed by hematoxylin and eosin and periodic acid-Schiff staining. High-resolution respirometry allowed assessing mitochondrial respiration in diaphragm biopsies. Chest trauma significantly increased tissue and BAL cytokine levels, associated with a significant increase in HO-1, purinergic receptor expression, and tissue nitrotyrosine formation. In contrast, lung mechanics, gas exchange, and histological damage did not show any significant difference between sham and trauma groups. Activation of the immune response remains present at later time points after murine blunt chest trauma. Discordance of the increased local inflammatory response and preserved pulmonary function may be explained by a dissociation of the immune response and lung function, such as previously suggested after experimental sepsis.
    Keywords: Thoracic Injuries -- Physiopathology ; Wounds, Nonpenetrating -- Physiopathology;
    ISSN: 1073-2322
    ISSN: 1466609X
    E-ISSN: 15400514
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  • 10
    Language: English
    In: BMC Medical Informatics and Decision Making, 01 May 2009, Vol.9(1), p.25
    Description: Abstract Background Revised consensus sepsis definitions have been published in 2003. The present study was performed to compare the prevalence of different stages of sepsis and ICU mortality rates and find out the case mix within the same collective of postoperative/posttraumatic patients...
    Keywords: Medicine
    ISSN: 1472-6947
    E-ISSN: 1472-6947
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