Neuroprotective effects of intravenous immunoglobulin are mediated through inhibition of complement activation and apoptosis in a rat model of sepsis

Esen, Figen; Orhun, Günseli; Ozcan, Perihan Ergin; Şentürk, Evren; Küçükerden, Melike; Giriş, Murat; Akcan, Uğur; Yılmaz, Canan Uğur; Orhan, Nurcan; Arıcan, Nadir; Kaya, Mehmet; Gazioglu, Sema Bilgic; Tüzün, Erdem

doi:10.1186/s40635-016-0114-1

Cited by 24 publications

(23 citation statements)

References 39 publications

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“…Cytokine levels also did not correlate with neuronal loss and Alzheimer-type neurodegeneration markers amyloid β and tau. Thus, our results suggest that cytokines are not directly involved in cognitive dysfunction observed in SIBD patients and cognition is presumably afflicted by altered activation of intracellular pathways that regulate neuronal functions and cell survival by other inflammatory mediators, as demonstrated in animal models of sepsis (17,18). By contrast, IFN-γ levels correlated with S100b, a marker of blood-brain barrier damage suggesting that this cytokine induces leakage of S100b to the peripheral blood, as previously implied (19).…”

Section: Discussionsupporting

confidence: 66%

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Association between inflammatory markers and cognitive outcome in patients with acute brain dysfunction due to sepsis

Orhun

Tüzün

Özcan

et al. 2018

Archives of Neuropsychiatry

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Introduction: Sepsis-induced brain dysfunction (SIBD) has been neglected until recently due to the absence of specific clinical or biological markers. There is increasing evidence that sepsis may pose substantial risks for long term cognitive impairment. Methods: To find out clinical and inflammatory factors associated with acute SIBD serum levels of cytokines, complement breakdown products and neurodegeneration markers were measured by ELISA in sera of 86 SIBD patients and 33 healthy controls. Association between these biological markers and cognitive test results was investigated. Results: SIBD patients showed significantly increased IL-6, IL-8, IL-10 and C4 d levels and decreased TNF-α, IL-12, C5a and iC3b levels than healthy controls. No significant alteration was observed in neuronal loss and neurodegeneration marker [neuron specific enolase (NSE), amyloid β, tau] levels. Increased IL-1β, IL-6, IL-8, IL-10, TNF-α and decreased C4 d, C5a and iC3b levels were associated with septic shock, coma and mortality. Transient mild cognitive impairment was observed in 7 of 21 patients who underwent neuropsychological assessment. Cognitive dysfunction and neuronal loss were associated with increased duration of septic shock and delirium but not baseline serum levels of inflammation and neurodegeneration markers. Conclusion: Increased cytokine levels, decreased complement activity and increased neuronal loss are indicators of poor prognosis and adverse events in SIBD. Cognitive dysfunction and neuronal destruction in SIBD do not seem to be associated with systemic inflammation factors and Alzheimer disease-type neurodegeneration but rather with increased duration of neuronal dysfunction and enhanced exposure of the brain to sepsis-inducing pathogens.

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Section: Discussionsupporting

confidence: 66%

“…Geriatric depression scale (GDS) was employed to measure self-rated depressive symptoms in patients. Based on MMSE scores, patients were grouped as those with no cognitive impairment [24][25][26][27][28][29][30], mild cognitive impairment [18][19][20][21][22][23]…”

Section: Assessment Of Neuropsychological Functionsmentioning

confidence: 99%

Association between inflammatory markers and cognitive outcome in patients with acute brain dysfunction due to sepsis

Orhun

Tüzün

Özcan

et al. 2018

Archives of Neuropsychiatry

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“…As part of the innate immune response, during a normal infection, MPO is secreted by activated neutrophils, which help in bacterial killing. However, in sepsis, there is an LPS-mediated abnormal hyperproduction of MPO, a potent oxidative enzyme which causes the peroxidation of cell membrane lipids and a decrease in the levels of the antioxidant GSH, leading to tissue dysfunction (24)(25)(26)(27). The present study demonstrated that azithromycin could reverse this imbalance in the oxidant and antioxidant response and potentially minimize tissue injury in sepsis.…”

Section: Fig 10mentioning

confidence: 55%

Azithromycin in Combination with Ceftriaxone Reduces Systemic Inflammation and Provides Survival Benefit in a Murine Model of Polymicrobial Sepsis

Patel

Joseph

Periasamy

et al. 2018

Antimicrob Agents Chemother

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Sepsis is a life-threatening systemic inflammatory condition triggered as a result of an excessive host immune response to infection. In the past, immunomodulators have demonstrated a protective effect in sepsis. Azithromycin (a macrolide antibiotic) has immunomodulatory activity and was therefore evaluated in combination with ceftriaxone in a clinically relevant murine model of sepsis induced by cecal ligation and puncture (CLP). First, mice underwent CLP and 3 h later were administered the vehicle or a subprotective dose of ceftriaxone (100 mg/kg of body weight subcutaneously) alone or in combination with an immunomodulatory dose of azithromycin (100 mg/kg intraperitoneally). Survival was monitored for 5 days. In order to assess the immunomodulatory activity, parameters such as plasma and lung cytokine (interleukin-6 [IL-6], IL-1β, tumor necrosis factor alpha) concentrations, the plasma glutathione (GSH) concentration, plasma and lung myeloperoxidase (MPO) concentrations, body temperature, blood glucose concentration, and total white blood cell count, along with the bacterial load in blood, peritoneal lavage fluid, and lung homogenate, were measured 18 h after CLP challenge. Azithromycin in the presence of ceftriaxone significantly improved the survival of CLP-challenged mice. Further, the combination attenuated the elevated levels of inflammatory cytokines and MPO in plasma and lung tissue and increased the body temperature and blood glucose and GSH concentrations, which were otherwise markedly decreased in CLP-challenged mice. Ceftriaxone produced a significant reduction in the bacterial load, while coadministration of azithromycin did not produce a further reduction. Therefore, the survival benefit offered by azithromycin was due to immunomodulation and not its antibacterial action. The findings of this study indicate that azithromycin, in conjunction with appropriate antibacterial agents, could provide clinical benefits in sepsis.

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“…In the present study, we applied both PEEP and RM as OLA. There are several methods to determine optimal PEEP during mechanical ventilation [ 34 , 35 ]. We determined the PEEP level in the OLA group based on the lung mechanics required to maximize lung dynamic compliance [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Driving-pressure-independent protective effects of open lung approach against experimental acute respiratory distress syndrome

et al. 2018

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BackgroundThe open lung approach (OLA) reportedly has lung-protective effects against acute respiratory distress syndrome (ARDS). Recently, lowering of the driving pressure (ΔP), rather than improvement in lung aeration per se, has come to be considered as the primary lung-protective mechanism of OLA. However, the driving pressure-independent protective effects of OLA have never been evaluated in experimental studies. We here evaluated whether OLA shows protective effects against experimental ARDS even when the ΔP is not lowered.MethodsLipopolysaccharide was intratracheally administered to rats to establish experimental ARDS. After 24 h, rats were mechanically ventilated and randomly allocated to the OLA or control group. In the OLA group, 5 cmH2O positive end-expiratory pressure (PEEP) and recruitment maneuver (RM) were applied. Neither PEEP nor RM was applied to the rats in the control group. Dynamic ΔP was kept at 15 cmH2O in both groups. After 6 h of mechanical ventilation, rats in both groups received RM to inflate reversible atelectasis of the lungs. Arterial blood gas analysis, lung computed tomography, histological evaluation, and comprehensive biochemical analysis were performed.ResultsOLA significantly improved lung aeration, arterial oxygenation, and gas exchange. Even after RM in both groups, the differences in these parameters between the two groups persisted, indicating that the atelectasis-induced respiratory dysfunction observed in the control group is not an easily reversible functional problem. Lung histological damage was severe in the dorsal dependent area in both groups, but was attenuated by OLA. White blood cell counts, protein concentrations, and tissue injury markers in the broncho-alveolar lavage fluid (BALF) were higher in the control than in the OLA group. Furthermore, levels of CXCL-7, a platelet-derived chemokine, were higher in the BALF from the control group, indicating that OLA protects the lungs by suppressing platelet activation.ConclusionsOLA shows protective effects against experimental ARDS, even when the ΔP is not decreased. In addition to reducing ΔP, maintaining lung aeration seems to be important for lung protection in ARDS.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2154-2) contains supplementary material, which is available to authorized users.

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Neuroprotective effects of intravenous immunoglobulin are mediated through inhibition of complement activation and apoptosis in a rat model of sepsis

Cited by 24 publications

References 39 publications

Association between inflammatory markers and cognitive outcome in patients with acute brain dysfunction due to sepsis

Association between inflammatory markers and cognitive outcome in patients with acute brain dysfunction due to sepsis

Azithromycin in Combination with Ceftriaxone Reduces Systemic Inflammation and Provides Survival Benefit in a Murine Model of Polymicrobial Sepsis

Driving-pressure-independent protective effects of open lung approach against experimental acute respiratory distress syndrome

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