Lipopolysaccharides induce a RAGE-mediated  sensitization of sensory neurons and fluid hypersecretion in the upper airways

AbstractThoracic dorsal root ganglia (tDRG) contribute to fluid secretion in the upper airways. Inflammation potentiates DRG responses, but the mechanisms remain under investigation. The receptor for advanced glycation end-products (RAGE) underlies potentiation of DRG responses in pain pathologies; however, its role in other sensory modalities is less understood. We hypothesize that RAGE contributes to electrophysiological and biochemical changes in tDRGs during inflammation. We used tDRGs and tracheas from wild types (WT), RAGE knock-out (RAGE-KO), and with the RAGE antagonist FPS-ZM1, and exposed them to lipopolysaccharides (LPS). We studied: capsaicin (CAP)-evoked currents and action potentials (AP), tracheal submucosal gland secretion, RAGE expression and downstream pathways. In WT neurons, LPS increased CAP-evoked currents and AP generation, and it caused submucosal gland hypersecretion in tracheas from WT mice exposed to LPS. In contrast, LPS had no effect on tDRG excitability or gland secretion in RAGE-KO mice or mice treated with FPS-ZM1. LPS upregulated full-length RAGE (encoded by Tv1-RAGE) and downregulated a soluble (sRAGE) splice variant (encoded by MmusRAGEv4) in tDRG neurons. These data suggest that sensitization of tDRG neurons contributes to hypersecretion in the upper airways during inflammation. And at least two RAGE variants may be involved in these effects of LPS.

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Muscarinic receptor subtypes in feline tracheal submucosal gland secretion

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1992.262.2.l223 ◽

1992 ◽

Vol 262 (2) ◽

pp. L223-L228 ◽

Cited By ~ 7

Author(s):

H. Ishihara ◽

S. Shimura ◽

M. Satoh ◽

T. Masuda ◽

H. Nonaka ◽

...

Keyword(s):

Muscarinic Receptor ◽

Gland Secretion ◽

Receptor Subtype ◽

Receptor Subtypes ◽

Submucosal Gland ◽

Muscarinic Receptor Subtypes ◽

Binding Assays ◽

Submucosal Glands ◽

Electrolyte Secretion ◽

Quinuclidinyl Benzilate

To determine what muscarinic receptor subtype regulates [Ca2+]i mediating airway submucosal gland secretion, we examined the effects of atropine (Atr), pirenzepine (PZ), 11([2-(diethylamino)methyl-1-piperidinyl] acetyl)-5,11-dihydro-6H-pyrido (2,3-b)(1,4)-benzo-diazepin-6-one (AF-DX116) and 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP) on methacholine (MCh)-evoked [Ca2+]i rise in acinar cells, and compared this with mucus glycoprotein (MGP) and electrolyte secretion evoked by MCh from submucosal glands isolated from feline trachea. [Ca2+]i was measured with the Ca(2+)-sensitive fluorescent dye, fura 2. We determined MGP secretion by measuring TCA-precipitable 3H-labeled glycoconjugates and electrolyte secretion by the change in the rate constant of 22Na-efflux from isolated glands. Half-maximal inhibitory concentrations (IC50) of PZ, AF-DX116, 4-DAMP, and Atr against MCh-evoked [Ca2+]i rise were 10(-7) M, 6 x 10(-6) M, 8 x 10(-9) M, and 6 x 10(-9) M, respectively. IC50 of PZ, AF-DX116, 4-DAMP, and Atr against MCh-evoked MGP secretion were 10(-6) M, 2 x 10(-5) M, 8 x 10(-9) M, and 6 x 10(-9) M, respectively. MCh (10(-5) M)-evoked 22Na efflux was significantly inhibited by 10(-7) M 4-DAMP and 10(-7) M Atr (P less than 0.01, each) but not by 10(-7) M PZ. Receptor binding assays with [3H]quinuclidinyl benzilate showed that the Ki values for PZ, AF-D x 116, 4-DAMP and Atr were 2.2 x 10(-8) M, 6.6 x 10(-7) M, 6.2 x 10(-10) M, and 2.9 x 10(-10) M, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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ONO-2506 alleviates lipopolysaccharide-induced hippocampal neuroinflammation and apoptosis

10.21203/rs.2.17161/v1 ◽

2019 ◽

Author(s):

Jian-yu Liu ◽

Wei Fang ◽

Shi-xia Cai ◽

Ming-ying Dai ◽

Bo Yao

Keyword(s):

S100 Protein ◽

Brain Cell ◽

Potential Treatment ◽

Advanced Glycation ◽

High Concentration ◽

Tnf Α ◽

Glycation End Products ◽

End Products ◽

Neurotoxic Effects ◽

Rage Expression

Abstract Background Sepsis associated encephalopathy has high mortality rate, but there is no targeted therapy to reduce brain damage in septic patients. In our previous study, we found that S100β concentration was higher in patients with SAE. At high concentration, S100β exerts neurotoxic effects through receptor for advanced glycation end products (RAGE). RAGE-activated signalling could induce the inflammatory response. And neuroinflammation is an important mechanism of SAE. So inhibiting S100β expression may be a potential treatment of SAE. ONO-2506 can inhibit the production and release of S100 protein from astrocytes. In this study, we administered ONO-2506 to mice in order to evaluate its effectiveness on neuroinflammation and apoptosis in hippocampus induced by lipopolysaccharides. Results We found administration with lipopolysaccharides increased the levels of S100β, RAGE, IL-β, TNF-α and the TUNEL positive brain cells in hippocampus tissue. The ONO-2506 30mg/kg and 90mg/kg could reduce the levels of neuroinflammation (IL-β and TNF-α), and alleviate the apoptosis in hippocampus. Conclusions ONO-2506 could reduce the neuroinflammation and alleviate brain cell apoptosis in hippocampus of LPS mice models. Moreover, the RAGE expression was inhibited after ONO-2506 treatment.

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TLRs and RAGE are elevated in carotid plaques from patients with moderate-to-severe obstructive sleep apnea syndrome

Sleep And Breathing ◽

10.1007/s11325-020-02029-w ◽

2020 ◽

Vol 24 (4) ◽

pp. 1573-1580 ◽

Cited By ~ 2

Author(s):

Wioletta Olejarz ◽

Alicja Głuszko ◽

Agata Cyran ◽

Katarzyna Bednarek-Rajewska ◽

Robert Proczka ◽

...

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Significant Role ◽

Sleep Apnea Syndrome ◽

Vascular Endothelial ◽

Sleep Study ◽

Carotid Plaques ◽

Obstructive Sleep ◽

Glycation End Products ◽

Rage Expression

Abstract Background There is growing evidence that obstructive sleep apnea (OSA) promotes vascular endothelial dysfunction and atherogenesis. Pathways that mediate this pathology may include Toll-like receptors (TLRs) and receptor for advanced glycation end products (RAGE) which play a significant role in proinflammatory processes. The aim of this study was to measure the expression of the above-mentioned receptors in relation to OSA severity in carotid plaques obtained during open endarterectomy. Methods This prospective study included patients with a sleep study prior to surgery and a plaque specimen obtained during standard open endarterectomy. Immunohistochemistry of TLR2, TLR4, TLR7, TLR9, RAGE, HMGB1, and NF-κB was performed on atherosclerotic plaques from carotid arteries of patients with and without OSA. Results There were 46 patients (22 women, mean age 73.2 ± 1.3 years): 14 control patients, 13 with mild, 11 with moderate, and 8 with severe OSA. The expression of all TLRs and RAGE increased proportionately with increasing OSA severity. The largest differences between patients with severe OSA and no OSA were found for TLR2 (2.88 ± 0.35 vs. 1.27 ± 0.47, p < 0.001), TLR4 (2.88 ± 0.35 vs. 1.64 ± 0.5, p < 0.001), TLR9 (2.38 ± 0.52 vs. 1.45 ± 0.52, p < 0.01), and RAGE (2.5 ± 0.53 vs. 1.82 ± 0.6, p < 0.05). Conclusion TLR2, TLR4, TLR9, and RAGE expression was significantly increased in carotid plaques of patients with moderate-to-severe OSA when compared with control patients with no OSA and those with mild OSA. TLR and RAGE-mediated pathways may play a significant role in OSA-dependent atherogenesis.

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Ambient Ozone Causes Upper Airways Inflammation in Children

American Review of Respiratory Disease ◽

10.1164/ajrccm/148.4_pt_1.961 ◽

1993 ◽

Vol 148 (4_pt_1) ◽

pp. 961-964 ◽

Cited By ~ 60

Author(s):

Thomas M. Frischer ◽

Joachim Kuehr ◽

Andrea Pullwitt ◽

Rolf Meinert ◽

Johannes Forster ◽

...

Keyword(s):

Upper Airways ◽

Ambient Ozone ◽

Airways Inflammation

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Sitagliptin attenuates arterial calcification by downregulating oxidative stress-induced receptor for advanced glycation end products in LDLR knockout mice

Scientific Reports ◽

10.1038/s41598-021-97361-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Chih-Pei Lin ◽

Po-Hsun Huang ◽

Chi-Yu Chen ◽

Meng-Yu Wu ◽

Jia-Shiong Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Nadph Oxidase ◽

Advanced Glycation End Products ◽

Calcium Deposition ◽

Arterial Calcification ◽

Advanced Glycation ◽

Tnf Α ◽

Glycation End Products ◽

End Products ◽

Rage Expression

AbstractDiabetes is a complex disease characterized by hyperglycemia, dyslipidemia, and insulin resistance. Plasma advanced glycation end products (AGEs) activated the receptor for advanced glycation end products (RAGE) and the activation of RAGE is implicated to be the pathogenesis of type 2 diabetic mellitus (T2DM) patient vascular complications. Sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, is a new oral hypoglycemic agent for the treatment of T2DM. However, the beneficial effects on vascular calcification remain unclear. In this study, we used a high-fat diet (HFD)-fed low-density lipoprotein receptor deficiency (LDLR−/−) mice model to investigate the potential effects of sitagliptin on HFD-induced arterial calcification. Mice were randomly divided into 3 groups: (1) normal diet group, (2) HFD group and (3) HFD + sitagliptin group. After 24 weeks treatment, we collected the blood for chemistry parameters and DPP4 activity measurement, and harvested the aorta to evaluate calcification using immunohistochemistry and calcium content. To determine the effects of sitagliptin, tumor necrosis factor (TNF)-α combined with S100A12 was used to induce oxidative stress, activation of nicotinamide adenine dinucleotide phosphate (NADPH), up-regulation of bone markers and RAGE expression, and cell calcium deposition on human aortic smooth muscle cells (HASMCs). We found that sitagliptin effectively blunted the HFD-induced artery calcification and significantly lowered the levels of fasting serum glucose, triglyceride (TG), nitrotyrosine and TNF-α, decreased the calcium deposits, and reduced arterial calcification. In an in-vitro study, both S100A12 and TNF-α stimulated RAGE expression and cellular calcium deposits in HASMCs. The potency of S100A12 on HASMCs was amplified by the presence of TNF-α. Sitagliptin and Apocynin (APO), an NADPH oxidase inhibitor, inhibited the TNF-α + S100A12-induced NADPH oxidase and nuclear factor (NF)-κB activation, cellular oxidative stress, RAGE expression, osteo transcription factors expression and calcium deposition. In addition, treatment with sitagliptin, knockdown of RAGE or TNF-α receptor blunted the TNF-α + S100A12-induced RAGE expression. Our findings suggest that sitagliptin may suppress the initiation and progression of arterial calcification by inhibiting the activation of NADPH oxidase and NF-κB, followed by decreasing the expression of RAGE.

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Hypoxemia reflexly increases secretion from tracheal submucosal glands in dogs

Journal of Applied Physiology ◽

10.1152/jappl.1982.52.6.1416 ◽

1982 ◽

Vol 52 (6) ◽

pp. 1416-1419 ◽

Cited By ~ 26

Author(s):

B. Davis ◽

R. Chinn ◽

J. Gold ◽

D. Popovac ◽

J. G. Widdicombe ◽

...

Keyword(s):

Carotid Body ◽

Carotid Sinus ◽

Gland Secretion ◽

Submucosal Gland ◽

Vagus Nerves ◽

Epithelial Surface ◽

O2 Concentration ◽

Submucosal Glands ◽

Lower Trachea ◽

Anesthetized Dogs

We anesthetized dogs, ventilated their lungs via the lower trachea, and exposed the epithelial surface of the upper trachea and coated it with powdered tantalum. Secretions from submucosal gland ducts formed elevations (hillocks) in the tantalum layer; we counted the number of hillocks that appeared in a 1.2-cm2 field. In 12 dogs, during normoxemia, 12 +/- 2 hillocks/cm2 formed in 90 s; during severe hypoxemia [fractional inspired O2 concentration (FIO2) = 0.05], 40 +/- 4 hillocks/cm2 formed in 90 s. Injections of sodium cyanide (25–75 micrograms) into the arterial supply to the carotid body also stimulated tracheal submucosal gland secretion. Secretory response to hypoxemia was suppressed by 1) section of both carotid sinus body nerves in six dogs and 2) section of both superior laryngeal nerves and vagus nerves in six other dogs. During mild hypoxemia (FIO2 = 0.10 or 0.15) tracheal submucosal gland secretion still increased. We conclude that hypoxemia increases secretion from submucosal glands in canine trachea by a carotid body chemoreflex.

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AGE–RAGE Stress in the Pathophysiology of Pulmonary Hypertension and its Treatment

International Journal of Angiology ◽

10.1055/s-0039-1687818 ◽

2019 ◽

Vol 28 (02) ◽

pp. 071-079 ◽

Cited By ~ 4

Author(s):

Kailash Prasad

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Artery ◽

Heart Diseases ◽

Therapeutic Targets ◽

Vascular Hypertrophy ◽

Soluble Rage ◽

Glycation End Products ◽

Rage Expression ◽

Pathophysiologic Mechanisms ◽

Group 1

AbstractPulmonary hypertension (PH) is a rare and fatal disease characterized by elevation of pulmonary artery pressure ≥ 25 mm Hg. There are five groups of PH: (1) pulmonary artery (PA) hypertension (PAH), (2) PH due to heart diseases, (3) PH associated with lung diseases/hypoxia, (4) PH associated with chronic obstruction of PA, and (5) PH due to unclear and/or multifactorial mechanisms. The pathophysiologic mechanisms of group 1 have been studied in detail; however, those for groups 2 to 5 are not that well known. PH pathology is characterized by smooth muscle cells (SMC) proliferation, muscularization of peripheral PA, accumulation of extracellular matrix (ECM), plexiform lesions, thromboembolism, and recanalization of thrombi. Advanced glycation end products (AGE) and its receptor (RAGE) and soluble RAGE (sRAGE) appear to be involved in the pathogenesis of PH. AGE and its interaction with RAGE induce vascular hypertrophy through proliferation of vascular SMC, accumulation of ECM, and suppression of apoptosis. Reactive oxygen species (ROS) generated by interaction of AGE and RAGE modulates SMC proliferation, attenuate apoptosis, and constricts PA. Increased stiffness in the artery due to vascular hypertrophy, and vasoconstriction due to ROS resulted in PH. The data also suggest that reduction in consumption and formation of AGE, suppression of RAGE expression, blockage of RAGE ligand binding, elevation of sRAGE levels, and antioxidants may be novel therapeutic targets for prevention, regression, and slowing of progression of PH. In conclusion, AGE–RAGE stress may be involved in the pathogenesis of PH and the therapeutic targets should be the AGE–RAGE axis.

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Neutrophil elastase stimulates tracheal submucosal gland secretion that is inhibited by ICI 200,355

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1992.262.1.l86 ◽

1992 ◽

Vol 262 (1) ◽

pp. L86-L91 ◽

Cited By ~ 6

Author(s):

A. Schuster ◽

I. Ueki ◽

J. A. Nadel

Keyword(s):

Morphometric Analysis ◽

Therapeutic Intervention ◽

Neutrophil Elastase ◽

Human Neutrophil ◽

Specific Inhibitor ◽

Gland Secretion ◽

Maximal Response ◽

Human Neutrophil Elastase ◽

Human Tissues ◽

Submucosal Gland

To investigate whether human neutrophil elastase (HNE) stimulates airway submucosal gland secretion, we studied the effect of purified HNE on secretion of 35S-labeled macromolecules from isolated tracheal tissues from ferrets, dogs, and humans. HNE stimulated secretion in a concentration-dependent fashion, the secretory response being most pronounced in ferret tissues with a maximal response of 1,498 +/- 384% above baseline at 10(-5) M. In dog tissues, maximal secretory responses (509 +/- 169%) to HNE were much greater than to bethanechol (80 +/- 26%). Human tissues obtained several hours postmortem still responded to HNE (179 +/- 48% at 10(-5) M) significantly more than to the combination of isoproterenol, phenylephrine, and bethanechol (23 +/- 10%). Morphometric analysis of canine tracheal tissues showed degranulation of submucosal gland cells after HNE. A specific inhibitor of HNE (ICI 200,355) potently inhibited secretory responses in a concentration-dependent fashion. We suggest that HNE in airways of patients may cause hypersecretion and that treatment with ICI 200,355 may provide a strategy for therapeutic intervention.

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