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Endothelin-1-mediated Brainstem Glial Activation Produces Asthmatic Airway Vagal Hypertonia Via Enhanced ATP-P2X4 Receptor Signaling in Sprague–Dawley Rats

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Abstract

The occurrence of major asthma symptoms is largely attributed to airway vagal hypertonia, of which the central mechanisms remain unclear. This study tests the hypotheses that endothelin-1-mediated brainstem glial activation produces asthmatic airway vagal hypertonia via enhanced action of adenosine 5’-triphosphate on neuronal purinergic P2X4 receptors. A rat model of asthma was prepared using ovalbumin. Airway vagal tone was evaluated by the recurrent laryngeal discharge and plethysmographic measurement of pulmonary function. The changes in the brainstem were examined using ELISA, Western blot, luciferin-luciferase, quantitative reverse transcription-polymerase chain reaction, enzyme activity assay and immunofluorescent staining, respectively. The results showed that in the medulla of rats, endothelin receptor type B and P2X4 receptors were primarily expressed in astrocytes and neurons, respectively, and both of which, along with endothelin-1 content, were significantly increased after ovalbumin sensitization. Ovalbumin sensitization significantly increased recurrent laryngeal discharge, which was blocked by acute intracisternal injection of P2X4 receptor antagonist 5-BDBD, knockdown of brainstem P2X4 receptors, and chronic intraperitoneal injection of endothelin receptor type B antagonist BQ788, respectively. Ovalbumin sensitization activated microglia and astrocytes and significantly decreased ecto-5’-nucleotidase activity in the medulla, and all of which, together with the increase of medullary P2X4 receptor expression and decrease of pulmonary function, were reversed by chronic BQ788 treatment. These results demonstrated that in rats, allergic airway challenge activates both microglia and astrocytes in the medulla via enhanced endothelin-1/endothelin receptor type B signaling, which subsequently causes airway vagal hypertonia via augmented adenosine 5’-triphosphate/P2X4 receptor signaling in central neurons of airway vagal reflex.

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All data generated or analyzed during this study are included in this article.

Abbreviations

ATP:

Adenosine 5’-triphosphate

CD73:

Ecto-5’-nucleotidase

Cdyn :

Dynamic compliance of the lungs

CSF:

Cerebral spinal fluid

DMV:

Dorsal motor nucleus of the vagus

EDNRA:

Endothelin receptor type A

EDNRB:

Endothelin receptor type B

ET-1:

Endothelin-1

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GFAP:

Glial fibrillary acidic protein

Iba1:

Ionized calcium binding adapter molecule 1

NA:

Nucleus ambiguus

NTS:

Nucleus tractus solitarius

P2X4R:

Purinergic P2X4 receptors

OVA:

Ovalbumin

Ri :

Inspiratory resistance of the airway

Re :

Expiratory resistance of the airway

RLD:

Recurrent laryngeal discharge

RLN:

Recurrent laryngeal nerve

RT-qPCR:

Quantitative reverse transcription-polymerase chain reaction

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Acknowledgements

This study was sponsored by the NSFC (National Natural Science Foundation of China) grants 81770003 and 81970002 to Jijiang Wang.

Funding

This study was sponsored by the NSFC (National Natural Science Foundation of China) grants 81770003 and 81970002 to Jijiang Wang.

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Author notes

  1. Yun Lin, Tian Liu and Hong Chen contribute equally to this study.

Authors and Affiliations

  1. Department of Physiology and Pathophysiology, Fudan University School of Basic Medical Sciences, 130 Dong’an Rd., 207 Seventh Building, West Campus, Shanghai, 200032, China

    Yun Lin, Tian Liu, Hong Chen, Ming Zeng, Shunwei Hu, Xiaoning Yu, Yonghua Chen, Chunmei Xia, Jin Wang & Jijiang Wang

Authors
  1. Yun Lin
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  2. Tian Liu
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  3. Hong Chen
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  6. Xiaoning Yu
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  8. Chunmei Xia
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  9. Jin Wang
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Contributions

Jijiang Wang designed the study and revised the manuscript; Yun Lin wrote the main manuscript text and prepared Figs. 1–6; Tian Liu prepared Fig. 7; Hong Chen prepared Fig. 8; Ming Zeng, Shunwei Hu and Xiaoning Yu performed statistical analysis of all of the experimental data; Yonghua Chen, Chunmei Xia and Jin Wang reviewed and improved the manuscript.

Corresponding author

Correspondence to Jijiang Wang.

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Ethical Approval

This study were performed in Sprague–Dawley rats. All of the animal procedures are in accordance with the recommendations of the ARRIVE guidelines, and were consented by the Ethical Committee of the Fudan University School of Basic Medical Sciences (No. 20170223–073 and No. 20190221–027).

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The authors declare no competing financial interests.

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Lin, Y., Liu, T., Chen, H. et al. Endothelin-1-mediated Brainstem Glial Activation Produces Asthmatic Airway Vagal Hypertonia Via Enhanced ATP-P2X4 Receptor Signaling in Sprague–Dawley Rats. J Neuroimmune Pharmacol 19, 13 (2024). https://doi.org/10.1007/s11481-024-10116-y

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