Search

The cholinergic anti-inflammatory pathway (CAP) is vital for the orchestration of the immune and inflammatory responses under normal and challenged conditions. Over the past two decades, peripheral and central circuits of CAP have been shown to be critically involved in dampening the inflammatory reaction in a wide array of inflammatory disorders. Additionally, emerging evidence supports a key role for CAP in the regulation of the female reproductive system during gestation as well as in the advent of serious pregnancy-related inflammatory insults such as preeclampsia (PE). Within this framework, the modulatory action of CAP encompasses the perinatal maternal and fetal adverse consequences that surface due to antenatal PE programming. Albeit, a considerable gap still exists in our knowledge of the precise cellular and molecular underpinnings of PE/CAP interaction, which hampered global efforts in safeguarding effective preventive or therapeutic measures against PE complications. Here, we summarize reports in the literature regarding the roles of peripheral and reflex cholinergic neuroinflammatory pathways of nicotinic acetylcholine receptors (nAChRs) in reprogramming PE complications in mothers and their progenies. The possible contributions of α7-nAChRs, cholinesterases, immune cells, adhesion molecules, angiogenesis, and endothelial dysfunction to the interaction have also been reviewed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The objective of the study was to test the hypothesis that nicotine guards against endotoxemia-associated renal inflammation and vasoconstrictor dysfunction via the activation of α7-nicotinic acetylcholine receptors (α7-nAChRs)/heme oxygenase-1 (HO-1) cascade., Materials: 91 male and female rats were included in the study., Treatments: Lipopolysaccharide (LPS, 5 mg kg -1 ), nicotine (0.5-2 mg kg -1 ), pentoxifylline (PTX, TNFα inhibitor, 3 mg kg -1 ), methyllycaconitine (MLA, α7-nAChR blocker), zinc protoporphyrin (ZnPP, HO-1 inhibitor), hemin (HO-1 inducer), tricarbonyldichlororuthenium (carbon monoxide-releasing molecule, CORM-2) or bilirubin was administered before LPS., Methods: Isolated perfused kidney was used to evaluate renal vasoconstriction and immunohistochemistry to assess inflammatory cytokines., Results: LPS reduced renal vasoconstrictions induced by phenylephrine or vasopressin in perfused kidneys of male, but not female, rats. Higher elevations in serum interleukin-1β and renal expressions of inducible nitric oxide synthase (iNOS) and nuclear factor-κB (NF-κB) were observed in LPS-treated male rats, whereas greater HO-1 expression was evident in endotoxic female rats. LPS effects were reversed by nicotine or PTX. Further, the favorable nicotine actions were (i) diminished by MLA or ZnPP and (ii) replicated by hemin or CORM-2, but not bilirubin, and (iii) associated with exaggerated and MLA-sensitive increases in HO-1 expression., Conclusions: α7-nAChR/HO-1/CO signaling mediates nicotine protection against renal inflammation and vasoconstrictor hyporeactivity in endotoxic male rats.

Background: Nicotine alleviates renal inflammation and injury induced by endotoxemia. This study investigated (i) the nicotine modulation of hemodynamic and renal vasodilatory responses to endotoxemia in rats, and (ii) roles of α7 or α4β2-nAChRs and related HSP70/TNFα/iNOS signaling in the interaction., Methods: Endotoxemia was induced by ip lipopolysaccharide (5 mg/kg/day, for 2 days) and changes in systolic blood pressure and vasodilator responsiveness of isolated perfused kidney to acetylcholine or 5'-N-ethylcarboxamidoadenosine (NECA, adenosine receptor agonist) were evaluated., Results: Lipopolysaccharide had no effect on serum creatinine, reduced blood pressure, and increased renal vasodilations induced by acetylcholine or NECA in male and female preparations. Immunohistochemical analyses showed that lipopolysaccharide reduced renal HSP70 expression, but increased α7-nAChRs, α4β2-nAChRs and iNOS expressions. The co-administration of aminoguanidine (iNOS inhibitor), pentoxifylline (TNFα inhibitor), or nicotine attenuated lipopolysaccharide mediation of renal vasodilations and elevations in α7/α4β2-nAChR and iNOS expressions. Nicotine also reversed the downregulating effect of lipopolysaccharide on HSP70 expression. α7-nAChRs (methyllycaconitine citrate, MLA) or α4β2-nAChRs (dihydro-β-erythroidine, DHβE) blockade potentiated the lipopolysaccharide enhancement of renal vasodilations, and abolished the depressant effect of nicotine on lipopolysaccharide responses. A similar abolition of nicotine effects was seen after HSP70 inhibition by quercetin. Alternatively, lipopolysaccharide hypotension was eliminated in rats treated with DHβE/nicotine or quercetin/nicotine regimen in contrast to no effect for nicotine alone or combined with MLA., Conclusions: These findings establish that nicotine offsets lipopolysaccharide facilitation of renal vasodilations possibly through a crosstalk between HSP70 and nAChRs of the α7 and α4β2 types., (Copyright © 2019 Maj Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)