Pharmacologic inhibition of cholinesterase improves survival in experimental sepsis

Hofer, Stefan; Eisenbach, Christoph; Lukić, Ivan; Schneider, Lutz; Martin, Eike; Mw, Büchler; Bierhaus, Angelika; Weigand, Markus

doi:10.1186/cc5185

Cited by 29 publications

(45 citation statements)

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“…Conversely, vagus nerve stimulation attenuated both systemic and pulmonary responses (38,41). Hofer et al (42) observed that the physostigmine, a cholinesterase inhibitor, improved survival and reduced circulating proinflammatory cytokine levels in models of sepsis induced by cecal ligation and puncture (42). Leite et al (43) have shown that VAChT-knockdown mice are more susceptible to LPS-induced systemic inflammation and sickness.…”

Section: Discussionmentioning

confidence: 99%

Acute lung injury is reduced by the α7nAChR agonist PNU‐282987 through changes in the macrophage profile

et al. 2016

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Nicotinic α-7 acetylcholine receptor (nAChRα7) is a critical regulator of cholinergic anti-inflammatory actions in several diseases, including acute respiratory distress syndrome (ARDS). Given the potential importance of α7nAChR as a therapeutic target, we evaluated whether PNU-282987, an α7nAChR agonist, is effective in protecting the lung against inflammation. We performed intratracheal instillation of LPS to generate acute lung injury (ALI) in C57BL/6 mice. PNU-282987 treatment, either before or after ALI induction, reduced neutrophil recruitment and IL-1β, TNF-α, IL-6, keratinocyte chemoattractant (KC), and IL-10 cytokine levels in the bronchoalveolar lavage fluid (P< 0.05). In addition, lung NF-κB phosphorylation decreased, along with collagen fiber deposition and the number of matrix metalloproteinase-9 and -2 cells, whereas the number of tissue inhibitor of metalloproteinase-1 cells increased (P < 0.05). PNU-282987 treatment also reduced lung mRNA levels and the frequency of M1 macrophages, whereas cells expressing the M2-related markers CD206 and IL-10 increased, suggesting changes in the macrophage profile. Finally, PNU-282987 improved lung function in LPS-treated animals. The collective results suggest that PNU-282987, an agonist of α7nAChR, reduces LPS-induced experimental ALI, thus supporting the notion that drugs that act on α7nAChRs should be explored for ARDS treatment in humans.-Pinheiro, N. M., Santana, F. P. R., Almeida, R. R., Guerreiro, M., Martins, M. A., Caperuto, L. C., Câmara, N. O. S., Wensing, L. A., Prado, V. F., Tibério, I. F. L. C., Prado, M. A. M., Prado, C. M. Acute lung injury is reduced by the α7nAChR agonist PNU-282987 through changes in the macrophage profile.

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Section: Discussionmentioning

confidence: 99%

Acute lung injury is reduced by the α7nAChR agonist PNU‐282987 through changes in the macrophage profile

et al. 2016

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“…5,39 Furthermore, stimulation of the vagus nerve protects against septic shock in experimental septicaemia. 4,13 Currently, it is thought that cholinergic stimulation of splenic macrophages via the vagus nerve results in the induction of an anti-inflammatory pathway that counteracts endotoxaemia-induced inflammation. [40][41][42] One of the main consequences of a dysregulated immune system is increased susceptibility to microbial infections, as we have previously demonstrated in animals following a chronic exposure to lead.…”

Section: Discussionmentioning

confidence: 99%

“…This conclusion is supported by a recent study, which reported that control of overwhelming inflammation and improvement in host survival were dependent on the activation of the cholinergic anti-inflammatory pathway by systemic cholinesterase inhibition. 13 It is intriguing that continuous dosing with paraoxon was apparently required to be maintained for an extended time ($ 2 weeks) before the consequences on resistance to infection were manifested. In studies in which mice were exposed to paraoxon for 1, 2 or 3 weeks, the level of AChE activity reached a nadir by 1 week of treatment and persisted at this low level for another 2 weeks.…”

Section: Discussionmentioning

confidence: 99%

“…12 In contrast, another group observed that intraperitoneal injections of either nicotine or the AChE inhibitors physostigmine or neostigmine significantly reduced lethality after sepsis induced by caecal ligation. 13 In addition, significant reductions in the concentrations of TNF-a and other circulating pro-inflammatory cytokines as well as in the binding activity of nuclear factor-jB were observed following the injection of AChE inhibitors. 13 However, in neither of the two above studies were AChE activities determined, precluding any direct correlation between the observed effects and AChE levels.…”

Section: Introductionmentioning

confidence: 99%

“…13 In addition, significant reductions in the concentrations of TNF-a and other circulating pro-inflammatory cytokines as well as in the binding activity of nuclear factor-jB were observed following the injection of AChE inhibitors. 13 However, in neither of the two above studies were AChE activities determined, precluding any direct correlation between the observed effects and AChE levels.…”

Section: Introductionmentioning

confidence: 99%

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Cholinergic stimulation of the immune system protects against lethal infection by Salmonella enterica serovar Typhimurium

et al. 2010

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SummaryThe cholinergic nervous system has been demonstrated to attenuate the inflammatory response during sepsis via the inhibitory action of acetylcholine (ACh) on macrophages. These findings were largely based on experimental sepsis models using endotoxin as the inducing agent. Herein, however, we report that the specific inhibition of acetylcholinesterase (AChE) renders animals more resistant to infection by a virulent strain of Salmonella enterica serovar Typhimurium, a Gram-negative enteric pathogen. Inhibition of AChE was induced by a subchronic exposure to paraoxon, a potent anti-cholinesterase metabolite of the organophosphorous compound parathion. Our findings indicate that inhibition of AChE enhanced survival of infected mice in a dose-dependent fashion and this correlated with efficient control of bacterial proliferation in target organs. Immunologically, inhibition of AChE enabled the animals to mount a more effective inflammatory anti-microbial response, and to secrete higher levels of interleukin-12, a key T helper type 1-promoting cytokine. The ACh-induced enhancement in resistance to infection was abrogated by co-administration of an oxime which can reactivate AChE. Hence, in a model of Gram-negative bacterial infection, cholinergic stimulation is shown to enhance the anti-microbial immune response leading to effective control of bacterial proliferation and enhanced animal survival.

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Blood pro‐inflammatory cytokines in Alzheimer's disease in relation to the use of acetylcholinesterase inhibitors

Richardson

Gard

Klugman

et al. 2013

Int J Geriat Psychiatry

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Results from animal studies suggesting a modulatory anti-inflammatory role for AChEIs was not advanced in this study. In individuals with AD, very limited evidence currently exists to support the hypothesis that AChEIs may influence inflammatory blood markers and function beyond the enhancement of neuronal transmission. However, further studies assessing a wider range of inflammatory markers and processes are still needed before this hypothesis can be ruled out.

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Pharmacologic inhibition of cholinesterase improves survival in experimental sepsis

Cited by 29 publications

References 0 publications

Acute lung injury is reduced by the α7nAChR agonist PNU‐282987 through changes in the macrophage profile

Acute lung injury is reduced by the α7nAChR agonist PNU‐282987 through changes in the macrophage profile

Cholinergic stimulation of the immune system protects against lethal infection by Salmonella enterica serovar Typhimurium

Blood pro‐inflammatory cytokines in Alzheimer's disease in relation to the use of acetylcholinesterase inhibitors

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