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Endogenous Adenosine 5′-Monophosphate, But Not Acetylcholine or Histamine, is Associated with Asthma Control, Quality of Life, and Exacerbations

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Abstract

Objective

Endogenous adenosine 5′-monophosphate (AMP), acetylcholine (ACh), and histamine (HA) are known to be important in bronchial contraction, but their clinical relevance to asthma is poorly understood. We aimed to quantify endogenous AMP, ACh, and HA in induced sputum samples and explore their relationships with asthma control and exacerbations.

Methods

20 healthy subjects and 112 asthmatics underwent clinical assessment, sputum induction, and blood sampling. The level of asthma control was determined by the asthma control test (ACT) questionnaire. Asthma exacerbation was evaluated according to the criteria of the American Thoracic Society/European Respiratory Society. Levels of AMP, ACh, and HA in sputum were measured by liquid chromatography coupled to tandem mass spectrometry. IL-β, IL-4, IL-5, IL-6, IL-8, IL-13, IL-17A, TNF-α, IFN-γ, and macrophage-derived chemokine (MDC) were also measured.

Results

Compared to healthy controls, asthmatics had higher levels of HA, lower levels of ACh, and similar levels of AMP in induced sputum samples. Compared to controlled asthma (n = 54), uncontrolled asthma (n = 58) showed higher AMP levels (P = 0.002), but similar HA and ACh levels. AMP was negatively correlated with ACT scores (r = − 0.348) and asthma quality of life questionnaire scores (r = − 0.188) and positively correlated with blood monocytes percentage (r = 0.195), sputum MDC (r = 0.214), and IL-6 levels (r = 0.196). Furthermore, AMP was associated with an increased risk of exacerbations in the preceding year.

Conclusion

Endogenous AMP, but not ACh or HA, was associated with asthma control, quality of life, and exacerbations in the previous year, which indicates that AMP could be a clinically useful biomarker of asthma.

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Abbreviations

AHR:

Airway hyper responsiveness

ACh:

Acetylcholine

AMP:

Adenosine 5′-monophosphate

AChE:

Acetylcholinesterase

ACT:

Asthma control test

AQLQ:

Asthma quality of life questionnaire

ASAN:

Australasian severe asthma network

ATS:

American thoracic society

BMI:

Body mass index

CA:

Controlled asthma

CRF:

Case report form

CI:

Confidence interval

COL4A3:

Collagen type 4 alpha 3

ERS:

European respiratory society.

EPA:

Exacerbation-prone asthma

FEV1 :

Forced expiratory volume in 1 s

FVC:

Forced vital capacity

FT-ICR-MS:

Fourier transform ion cyclotron resonance mass spectrometry

FeNO:

Fractional exhaled nitric oxide

GINA:

Global initiative for asthma

HA:

Histamine

HADS:

Hospital anxiety and depression scale

HADS-A:

Hospital anxiety and depression scale-anxiety

HADS-D:

Hospital anxiety and depression scale-depression

IL:

Interleukin

IFN:

Interferon

ICS:

Inhaled corticosteroid

LC–MS/MS:

Liquid chromatography coupled to tandem mass spectrometry

LLD:

Lower limit of detection

IRR:

Incidence rate ratio

MDC:

Macrophage-derived chemokine

N:

Number

OR:

Odds ratio

Q:

Quartile

SAWD:

Severe asthma web-based database

SPT:

Skin prick tests

SD:

Standard error

SEM:

Standard error of the mean

TNF:

Tumor necrosis factor

TGF:

Transforming growth factor

UA:

Uncontrolled asthma

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Acknowledgements

The authors are grateful to Ms. Michelle Gleeson (Hunter Medical Research Institute, the University of Newcastle, Australia), Ms. Zhi Lin (West China Hospital, Sichuan University, China) for their sputum processing. The authors also thank all the participants for participating in this study.

Funding

This study was supported by the National Natural Science Foundation of China (Grant Nos. 81920108002, 81870027, and 81900026), and 1.3.5 project for disciplines of excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University (Grant No. 2018HXFH016), and Post-Doctor Research Project, West China Hospital, Sichuan University, China (Grant No. 2021HXBH013).

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Author notes

  1. Xue Mei Fang and Ying Liu have contributed equally to this work.

Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Xue Mei Fang, Ying Liu, Ji Wang, Xin Zhang, Li Zhang, Hong Ping Zhang, Lei Liu, Dan Huang, Dan Liu, Ke Deng, Feng Ming Luo, Hua Jing Wan, Wei Min Li & Gang Wang

  2. Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, Sichuan University, Chengdu, 610041, Sichuan, China

    Xue Mei Fang, Ying Liu, Ji Wang, Xin Zhang, Lei Wang, Li Zhang, Hong Ping Zhang, Lei Liu, Dan Huang, Dan Liu, Ke Deng, Feng Ming Luo, Hua Jing Wan & Gang Wang

  3. Pneumology Group, Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Ying Liu, Xin Zhang, Lei Wang, Li Zhang, Hong Ping Zhang, Lei Liu & Dan Huang

  4. Respiratory Microbiome Laboratory, Frontiers Science Center for Disease-Related Molecular Network, Sichuan University, Chengdu, Sichuan, China

    Wei Min Li

  5. School of Life Sciences, University of Technology Sydney, Ultimo, NSW, 2007, Australia

    Brian G. Oliver

  6. Respiratory Cellular and Molecule Biology, Woolcock Institute of Medical Research, The University of Sydney, Sydney, NSW, 2017, Australia

    Brian G. Oliver

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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by all authors. The first draft of the manuscript was written by XMF, YL, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Wei Min Li or Gang Wang.

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Conflict of interest

G. Wang reports personal fees from AstraZeneca, GlaxoSmithKline, Novartis, Chiesi; and grants from AstraZeneca outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest.

Ethical Approval

This study was approved by the Institutional Review Board of West China Hospital, Sichuan University (No. 2014–30).

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Written informed consent was sought and obtained from all participants before enrollment.

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Fang, X.M., Liu, Y., Wang, J. et al. Endogenous Adenosine 5′-Monophosphate, But Not Acetylcholine or Histamine, is Associated with Asthma Control, Quality of Life, and Exacerbations. Lung 200, 579–589 (2022). https://doi.org/10.1007/s00408-022-00570-x

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