The α7 Nicotinic Acetylcholine Receptor Agonist GTS-21 Improves Bacterial Clearance in Mice by Restoring Hyperoxia-Compromised Macrophage Function

Sitapara, Ravikumar; Antoine, Daniel J.; Sharma, Lokesh; Patel, Vivek; Ashby, Charles R.; Gorasiya, Samir; Yang, Huan; Zur, Michelle; Mantell, Lin L.

doi:10.2119/molmed.2013.00086

Cited by 46 publications

(38 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…GTS-21, a selective partial α7nAchR agonist (22), has been proven to effectively reduce the inflammatory reaction and improve prognosis in animals (23)(24)(25). Similar to previous studies (22), our findings suggest that GTS-21 suppresses TNF-α and HMGB1 expression in a dose-dependent manner in experiments using mouse macrophages. The curves indicated the optimal concentration of GTS-21 as 8 µg/ml for marophages.…”

Section: Discussionsupporting

confidence: 88%

MicroRNA-205-5b inhibits HMGB1 expression in LPS-induced sepsis

Zhou

Wang

et al. 2016

International Journal of Molecular Medicine

View full text Add to dashboard Cite

Inflammatory cytokines belonging to high mobility group box (HMGB)1 play a key role in sepsis through yet unknown mechanisms. The inflammatory response is modulated by microRNAs (miRNAs or miRs) at multiple levels and is poorly understood. In this study, the regulation of HMGB1 by miRNAs was evaluated using 3-(2,4-dimethoxybenzylidene)anabaseine (GTS-21) to activate the cholinergic anti-inflammatory pathway (CAP) and decrease HMGB1 expression in RAW264.7 cells. Microarray-based miRNA expression profiling of RAW264.7 cells was used to screen target miRNAs through genetic screening, GO analysis and hierarchical clustering. The expression of miRNA targets in the serum, colon, spleen, livers and lungs of BALB/c mice was quantified by RT-qPCR. Serum protein levels were quantified by ELISA. Western blot analysis and RT-qPCR were used for verification in vitro. Using miRNA array analysis, we screened 3 miRNAs (miR‑205‑5b, miR‑196a and miR‑193b). Animal experiments with miR‑205‑5b indicated its high degree of expression in the serum, colon, spleen, liver and lungs following the downregulation of HMGB1 in the tissues. RAW264.7 cells transfected with miR‑205‑5b mimics downregulated HMGB1 protein expression, suggesting translational regulation. HMGB1 expression negatively correlated with miR‑205‑5b expression in LPS-induced sepsis. By contrast, HMGB1 expression in LPS-stimulated RAW264.7 cells was increased following transfection with miR‑205‑5b inhibitor. miR‑205‑5b is a critical mediator of cholinergic anti-inflammatory activity in late sepsis. The upregulation of miR‑205‑5b as a potential therapeutic target for the treatment of inflammatory diseases is a possible novel therapeutic strategy against late sepsis. The mechanisms involved include the by post-transcriptional suppression of HMGB1 in cells and tissues.

show abstract

Section: Discussionsupporting

confidence: 88%

MicroRNA-205-5b inhibits HMGB1 expression in LPS-induced sepsis

Zhou

Wang

et al. 2016

International Journal of Molecular Medicine

View full text Add to dashboard Cite

show abstract

“…Ravikumar and colleagues have also noted that enhanced bacteria eradication was seen in hyperoxia implicated macrophages after treated by GTS-21, which were related to improved macrophages phagocytosis 55. Hence, α7nAChR acted as an effective target for alleviating tissue damage and improving outcome partly through regulating immune function of macrophages in critical diseases.…”

Section: α7nachr and Immune Functionmentioning

confidence: 95%

“…In addition, α7nAchR levels were considered to be inversely associated with the magnitude of severity and mortality rate in severe septic patients 52, Activation of α7nAchR by GTS-21 significantly improved survival in septic models, but it failed by antagonizing α7nAchR or gene knockdown 16, 17. Further researches showed that stimulation of α7nAchR alleviated inflammatory response of macrophages 53, and attenuated sepsis-induced acute lung injury by inhibiting chemokines production and neutrophils migration 54, 55. Additionally, α7nAchR activation showed benefits for septic conditions by improving bacterial clearance of macrophages 54, 55.…”

Section: The Protective Effect Of α7 Nicotinic Acetylcholine Receptormentioning

confidence: 99%

“…Further researches showed that stimulation of α7nAchR alleviated inflammatory response of macrophages 53, and attenuated sepsis-induced acute lung injury by inhibiting chemokines production and neutrophils migration 54, 55. Additionally, α7nAchR activation showed benefits for septic conditions by improving bacterial clearance of macrophages 54, 55.…”

Section: The Protective Effect Of α7 Nicotinic Acetylcholine Receptormentioning

confidence: 99%

See 1 more Smart Citation

The Protective Effect of Alpha 7 Nicotinic Acetylcholine Receptor Activation on Critical Illness and Its Mechanism

Ren

Tong

et al. 2017

Int. J. Biol. Sci.

View full text Add to dashboard Cite

Critical illnesses and injuries are recognized as major threats to human health, and they are usually accompanied by uncontrolled inflammation and dysfunction of immune response. The alpha 7 nicotinic acetylcholine receptor (α7nAchR), which is a primary receptor of cholinergic anti-inflammatory pathway (CAP), exhibits great benefits for critical ill conditions. It is composed of 5 identical α7 subunits that form a central pore with high permeability for calcium. This putative structure is closely associated with its functional states. Activated α7nAChR exhibits extensive anti-inflammatory and immune modulatory reactions, including lowered pro-inflammatory cytokines levels, decreased expressions of chemokines as well as adhesion molecules, and altered differentiation and activation of immune cells, which are important in maintaining immune homeostasis. Well understanding of the effects and mechanisms of α7nAChR will be of great value in exploring effective targets for treating critical diseases.

show abstract

“…Hyperoxia impairs macrophage function in phagocytosis, thereby diminishing the host defense in clearing apoptotic neutrophils, resulting in pronounced accumulation of leukocytes in the airways [14,18,28,29]. To determine if SFN, which was recently shown to-attenuate HALI [22], can enhance macrophage functions, the phagocytic function of macrophages was determined using cultured macrophages.…”

Section: Sulforaphane Significantly Attenuates Hyperoxia-induced Dysfmentioning

confidence: 99%

Dietary Antioxidants Significantly Attenuate Hyperoxia-Induced Acute Inflammatory Lung Injury by Enhancing Macrophage Function via Reducing the Accumulation of Airway HMGB1

Patel

Dial

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

Mechanical ventilation with hyperoxia is the major supportive measure to treat patients with acute lung injury and acute respiratory distress syndrome (ARDS). However, prolonged exposure to hyperoxia can induce oxidative inflammatory lung injury. Previously, we have shown that high levels of airway high-mobility group box 1 protein (HMGB1) mediate hyperoxia-induced acute lung injury (HALI). Using both ascorbic acid (AA, also known as vitamin C) and sulforaphane (SFN), an inducer of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), we tested the hypothesis that dietary antioxidants can mitigate HALI by ameliorating HMGB1-compromised macrophage function in phagocytosis by attenuating hyperoxia-induced extracellular HMGB1 accumulation. Our results indicated that SFN, which has been shown to attenute HALI in mice exposed to hyperoxia, dose-dependently restored hyperoxia-compromised macrophage function in phagocytosis (75.9 ± 3.5% in 0.33 µM SFN versus 50.7 ± 1.8% in dimethyl sulfoxide (DMSO) control, p < 0.05) by reducing oxidative stress and HMGB1 release from cultured macrophages (47.7 ± 14.7% in 0.33 µM SFN versus 93.1 ± 14.6% in DMSO control, p < 0.05). Previously, we have shown that AA enhances hyperoxic macrophage functions by reducing hyperoxia-induced HMGB1 release. Using a mouse model of HALI, we determined the effects of AA on hyperoxia-induced inflammatory lung injury. The i.p. administration of 50 mg/kg of AA to mice exposed to 72 h of ≥98% O2 significantly decreased hyperoxia-induced oxidative and nitrosative stress in mouse lungs. There was a significant decrease in the levels of airway HMGB1 (43.3 ± 12.2% in 50 mg/kg AA versus 96.7 ± 9.39% in hyperoxic control, p < 0.05), leukocyte infiltration (60.39 ± 4.137% leukocytes numbers in 50 mg/kg AA versus 100 ± 5.82% in hyperoxic control, p < 0.05) and improved lung integrity in mice treated with AA. Our study is the first to report that the dietary antioxidants, ascorbic acid and sulforaphane, ameliorate HALI and attenuate hyperoxia-induced macrophage dysfunction through an HMGB1-mediated pathway. Thus, dietary antioxidants could be used as potential treatments for oxidative-stress-induced acute inflammatory lung injury in patients receiving mechanical ventilation.

show abstract

The α7 Nicotinic Acetylcholine Receptor Agonist GTS-21 Improves Bacterial Clearance in Mice by Restoring Hyperoxia-Compromised Macrophage Function

Cited by 46 publications

References 46 publications

MicroRNA-205-5b inhibits HMGB1 expression in LPS-induced sepsis

MicroRNA-205-5b inhibits HMGB1 expression in LPS-induced sepsis

The Protective Effect of Alpha 7 Nicotinic Acetylcholine Receptor Activation on Critical Illness and Its Mechanism

Dietary Antioxidants Significantly Attenuate Hyperoxia-Induced Acute Inflammatory Lung Injury by Enhancing Macrophage Function via Reducing the Accumulation of Airway HMGB1

Contact Info

Product

Resources

About