Asthmatic Airway Vagal Hypertonia Involves Chloride Dyshomeostasis of Preganglionic Neurons in Rats

He, Ding Sheng; Chen, Hong; Zeng, Ming; Xia, Chunmei; Wang, Jin; Shen, Lin‐Lin; Zhu, Dawei; Chen, Yonghua

doi:10.3389/fnins.2020.00031

Cited by 7 publications

(7 citation statements)

References 37 publications

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“…Meanwhile, Western-blot essay showed increased expression of ECP1 in the lungs, indicating infiltration of eosinophils and pulmonary inflammation. These functional and inflammatory changes suggest a successful model of allergic asthma, as we have previously reported (22).…”

Section: Discussionsupporting

confidence: 75%

Rosuvastatin blocks allergic airway vagal hypertonia via reversed central CD73 downregulation in rats

Chen

Zeng

Lin

et al. 2020

Preprint

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Background In asthma, the decrease of pulmonary function and occurrence of pulmonary inflammation are largely attributed to the increase of airway vagal activity, of which the genesis involves disrupted degradation of central extracellular ATP to adenosine due to decreased expression and activity of ecto-5'-nucleotidase (CD73). Meanwhile, the therapeutic use of statins reportedly is able to alleviate asthma; however, the mechanisms remain unclear. This study test whether rosuvastatin is able to attenuate the downregulation of central CD73 and, subsequently, attenuate the increase of airway vagal activity in the rat model of allergic asthma. Methods An experimental rat model of allergic asthma was prepared using ovalbumin. During the sensitization period, ovalbumin was inhaled alone or in combination with rosuvastatin. Plethysmographic measurement of pulmonary function was used to evaluate airway vagal activity; molecular biological assay was used to examine the expression and activity of medullary CD73 and the expression of eosinophil cationic protein 1 (ECP1) in the lungs. Results In ovalbuminsensitized rats, the decreases in the expression and activity of medullary CD73 and the increases in the expression of ECP1 in the lungs and ATP concentration in cerebral spinal fluid were completely reversed by inhaled rosuvastatin, so was the increase of airway vagal activity manifested by the atropine-sensitive increase of airway resistance and decrease of airway compliance. Conclusions In the rat model of allergic asthma, inhaled rosuvastatin reverses the decreases in the expression and activity of brainstem CD73, which prevents pulmonary function decrease via an abolished increase of airway vagal activity.

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Section: Discussionsupporting

confidence: 75%

Rosuvastatin blocks allergic airway vagal hypertonia via reversed central CD73 downregulation in rats

Chen

Zeng

Lin

et al. 2020

Preprint

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“…He and colleagues examined the role of neuronal Cl − homeostasis in asthma [ 163 ]. It is known that vagal hypertonia is closely related to the severity of asthma as it controls airway smooth muscle.…”

Section: Other Disease Statesmentioning

confidence: 99%

“…The mechanism behind this hypertonia, however, was unclear. They found increased microglial activation in the brainstem, particularly in the nucleus accumbens [ 163 ]. He et al then identified an upregulation of NKCC1 and downregulation of KCC2 in the nucleus accumbens, which would augment the excitatory vagal response.…”

Section: Other Disease Statesmentioning

confidence: 99%

“…He et al then identified an upregulation of NKCC1 and downregulation of KCC2 in the nucleus accumbens, which would augment the excitatory vagal response. Injected GABA caused an excitatory response leading to airway hyperresponsiveness that was attenuated by injection of bumetanide, the NKCC1 inhibitor [ 163 ]. Wang and colleagues assessed the efficacy of furosemide treatment in allergic asthma and in the process identified increased NKCC1 immunoreactivity in the lungs of an asthmatic mice model [ 164 ].…”

Section: Other Disease Statesmentioning

confidence: 99%

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Ionic Plasticity: Common Mechanistic Underpinnings of Pathology in Spinal Cord Injury and the Brain

Hudson

Grau

2022

Cells

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The neurotransmitter GABA is normally characterized as having an inhibitory effect on neural activity in the adult central nervous system (CNS), which quells over-excitation and limits neural plasticity. Spinal cord injury (SCI) can bring about a modification that weakens the inhibitory effect of GABA in the central gray caudal to injury. This change is linked to the downregulation of the potassium/chloride cotransporter (KCC2) and the consequent rise in intracellular Cl− in the postsynaptic neuron. As the intracellular concentration increases, the inward flow of Cl− through an ionotropic GABA-A receptor is reduced, which decreases its hyperpolarizing (inhibitory) effect, a modulatory effect known as ionic plasticity. The loss of GABA-dependent inhibition enables a state of over-excitation within the spinal cord that fosters aberrant motor activity (spasticity) and chronic pain. A downregulation of KCC2 also contributes to the development of a number of brain-dependent pathologies linked to states of neural over-excitation, including epilepsy, addiction, and developmental disorders, along with other diseases such as hypertension, asthma, and irritable bowel syndrome. Pharmacological treatments that target ionic plasticity have been shown to bring therapeutic benefits.

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“…It was found that minocycline can inhibit the proliferation of T lymphocytes stimulated by GITRL and regulate the expression of IL-17 and RORγt in T lymphocytes [ 44 ]. Moreover, other studies have found that minocycline can reduce the symptoms of asthma [ 45 , 46 ]. As blocking GITRL showed a protective effect for asthma in our research and other research on GITRL-associated clinical trials and blocking or agonist drugs of GITR are relatively mature, GITRL may be a therapeutic target for asthma in the future, which has important clinical significance.…”

Section: Discussionmentioning

confidence: 99%

GITRL on dendritic cells aggravates house dust mite-induced airway inflammation and airway hyperresponsiveness by modulating CD4+ T cell differentiation

et al. 2021

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Background Glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL) plays an important role in tumors, autoimmunity and inflammation. However, GITRL is not known to modulate the pathogenesis of allergic asthma. In this study, we investigated whether regulating GITRL expressed on dendritic cells (DCs) can prevent asthma and to elucidate its mechanism of action. Methods In vivo, the role of GITRL in modulating house dust mite (HDM)-induced asthma was assessed in adeno-associated virus (AAV)-shGITRL mice. In vitro, the role of GITRL expression by DCs was evaluated in LV-shGITRL bone marrow dendritic cells (BMDCs) under HDM stimulation. And the direct effect of GITRL was observed by stimulating splenocytes with GITRL protein. The effect of regulating GITRL on CD4+ T cell differentiation was detected. Further, GITRL mRNA in the peripheral blood of asthmatic children was tested. Results GITRL was significantly increased in HDM-challenged mice. In GITRL knockdown mice, allergen-induced airway inflammation, serum total IgE levels and airway hyperresponsiveness (AHR) were reduced. In vitro, GITRL expression on BMDCs was increased after HDM stimulation. Further, knocking down GITRL on DCs partially restored the balance of Th1/Th2 and Th17/Treg cells. Moreover, GITRL stimulation in vitro inhibited Treg cell differentiation and promoted Th2 and Th17 cell differentiation. Similarly, GITRL mRNA expression was increased in the peripheral blood from asthmatic children. Conclusions This study identified a novel role for GITRL expressed by DCs as a positive regulator of CD4+ T cells responses in asthma, which implicates that GITRL inhibitors may be a potential immunotherapy for asthma.

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Asthmatic Airway Vagal Hypertonia Involves Chloride Dyshomeostasis of Preganglionic Neurons in Rats

Cited by 7 publications

References 37 publications

Rosuvastatin blocks allergic airway vagal hypertonia via reversed central CD73 downregulation in rats

Rosuvastatin blocks allergic airway vagal hypertonia via reversed central CD73 downregulation in rats

Ionic Plasticity: Common Mechanistic Underpinnings of Pathology in Spinal Cord Injury and the Brain

GITRL on dendritic cells aggravates house dust mite-induced airway inflammation and airway hyperresponsiveness by modulating CD4+ T cell differentiation

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