Nicotine Protects Kidney from Renal Ischemia/Reperfusion Injury through the Cholinergic Anti-Inflammatory Pathway

Kidney ischemia/reperfusion injury (I/R) is characterized by renal dysfunction and tubular damages resulting from an early activation of innate immunity. Recently, nicotine administration has been shown to be a powerful inhibitor of a variety of innate immune responses, including LPS-induced toxaemia. This cholinergic anti-inflammatory pathway acts via the α7 nicotinic acetylcholine receptor (α7nAChR). Herein, we tested the potential protective effect of nicotine administration in a mouse model of renal I/R injury induced by bilateral clamping of kidney arteries. Renal function, tubular damages and inflammatory response were compared between control animals and mice receiving nicotine at the time of ischemia. Nicotine pretreatment protected mice from renal dysfunction in a dose-dependent manner and through the α7nAChR, as attested by the absence of protection in α7nAChR-deficient mice. Additionally, nicotine significantly reduced tubular damages, prevented neutrophil infiltration and decreased productions of the CXC-chemokine KC, TNF-α and the proinflammatory high-mobility group box 1 protein. Reduced tubular damage in nicotine pre-treated mice was associated with a decrease in tubular cell apoptosis and proliferative response as attested by the reduction of caspase-3 and Ki67 positive cells, respectively. All together, these data highlight that nicotine exerts a protective anti-inflammatory effect during kidney I/R through the cholinergic α7nAChR pathway. In addition, this could provide an opportunity to overcome the effect of surgical cholinergic denervation during kidney transplantation

Immunomodulation through the anti-inflammatory cholinergic pathway: impact on innate and acquired immunity in transplantation

Up to now, solid organ transplantation remains the ultimate life-saving treatment for end-stage organ failure. However, transplantation could be complicated by allograft rejection wherein inflammation plays a pivotal role. In this process, inflammation secondary to ischemia/reperfusion and cell necrosis plays the role of adjuvant and enhances the antigen-specific adaptive response ultimately leading to allograft rejection. Therefore, anti-inflammatory strategies have to be developed to dampen inflammation and secondary alloreactivity. Recently, neuroimmune pathways and particularly the cholinergic anti-inflammatory pathway have been described to modulate inflammation in several experimental models as sepsis. The Vagus Nerve, the α7 nicotinic receptor (α7nAChR) and its agonists are specific targets to regulate the inflammatory response in several pathologies.The aim of this work is to investigate the potential protective effect of the cholinergic pathway in solid organ transplantation. In a model of renal ischemia/reperfusion injury induced by bilateral clamping of renal arteries, nicotine protects from renal dysfunction and tubular damages. This protection is associated to a reduction of inflammatory cytokines and neutrophils and is α7nAChR dependent. In a second part, we test the effect of the α7nACh receptor in a model of minor antigen mismatched skin allograft. Mice deficient for the α7nAChR reject earlier the skin allograft compared to α7nAChR +/+ mice and this is associated to higher Th1 and Th17 T cell responses. α7nAChR expressed on T cells is involved in skin allograft rejection as attested by adoptive transfer experiments in Rag H/H mice with either α7nAChR +/+ or α7nAChR H/H alloreactive T cells. The cholinergic pathway by itself or boosted by nicotinic agonists is able to modulate innate as well as acquired immune components involved in allograft rejection. Other agonists or devices used to stimulate the cholinergic pathway are actually developed in order to be more specific and to reduce toxicity. Our results are particularly relevant in human medicine as grafted organs lose their Vagus Nerve endings and their cholinergic regulatory innervation.Doctorat en Sciences médicales (Médecine)info:eu-repo/semantics/nonPublishe

Cholinergic anti-inflammatory pathway protects kidney from ischemia-reperfusion injury

info:eu-repo/semantics/nonPublishe

Ultrasonic stimulation of the cholinergic anti-inflammatory pathway for renal protection.

CommentEditorialSCOPUS: re.jinfo:eu-repo/semantics/publishe

Reversible hypoglycemic coma despite bilateral absence of the median nerve N20 evoked potential

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Are multiple blood transfusions really a cause of acute respiratory distress syndrome?

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Deficiency of alpha7 cholinergic receptors facilitates bacterial clearance in Escherichia coli peritonitis.

BACKGROUND: The efferent vagus nerve can inhibit inflammation via interaction between acetylcholine and alpha7 cholinergic receptors. METHODS: To determine the role played by alpha7 receptors in antibacterial defense, peritonitis was induced in alpha7 receptor-deficient (alpha7(-/-)) and wild-type (WT) mice by intraperitoneal injection with Escherichia coli. RESULTS: At 20 h after infection, virtually all alpha7(-/-) mice had cleared the infection from their peritoneal cavities and had sterile blood cultures, whereas WT mice had high bacterial loads at the primary site of infection and were bacteremic. In addition, bacterial burdens in liver, spleen, kidneys, and lungs were much lower in alpha7(-/-) mice, and these animals displayed a diminished inflammatory response, as reflected by a reduced number of infiltrating neutrophils in peritoneal lavage fluid and lower circulating cytokine levels. At 2 h after infection, however, when bacterial loads were still similar in alpha7(-/-) and WT mice, the former mouse strain showed a more robust influx of neutrophils into the peritoneal cavity. CONCLUSIONS: Deficiency of the alpha7 receptor is associated with an accelerated clearance of E. coli after intraperitoneal infection, preceded by a faster recruitment of neutrophils. These data provide the first evidence for a detrimental role of alpha7 receptors in the host defense against bacteria.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Ticlopidine and clopidogrel, sometimes combined with aspirin, only minimally increase the surgical risk in renal transplantation: a case-control study.

Patients undergoing kidney transplantation are sometimes being treated with antiplatelet agents such as ticlopidine or clopidogrel. Some teams refuse to wait-list these patients for fear of bleeding during transplant surgery.Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Nicotine pretreatment prevents neutrophil infiltration.

<p>LY-6G immunostaining was performed to assess neutrophil infiltration in the corticomedullary junction 24 hours after I/R (panel A, magnification ×40). Sham operated animals displayed no neutrophil (data not shown). Nicotine administration completely prevented neutrophil infiltration (panel B, magnification ×40). Quantification is represented in panel C. Black bars represent saline-treated animals and white bars nicotine-treated groups after either sham operation (n = 6 in each group) or I/R (n = 8 in each group). Data are expressed as mean ± SEM, (*) p≤0.05.</p