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Allergen inhalation generates pro-inflammatory oxidised phosphatidylcholine associated with airway dysfunction

Christopher D. Pascoe, Aruni Jha, Min Hyung Ryu, Mirna Ragheb, Jignesh Vaghasiya, Sujata Basu, Gerald L. Stelmack, Sadeesh Srinathan, Biniam Kidane, Jason Kindrachuk, Paul M. O'Byrne, Gail M. Gauvreau, Amir Ravandi, Christopher Carlsten, Andrew J. Halayko on behalf of the Canadian Respiratory Research Network
European Respiratory Journal 2021 57: 2000839; DOI: 10.1183/13993003.00839-2020
Christopher D. Pascoe
1Dept of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
2Biology of Breathing Group, Children's Research Hospital of Manitoba, Winnipeg, MB, Canada
8Co-first authors
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  • ORCID record for Christopher D. Pascoe
Aruni Jha
1Dept of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
2Biology of Breathing Group, Children's Research Hospital of Manitoba, Winnipeg, MB, Canada
8Co-first authors
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Min Hyung Ryu
3Dept of Medicine, University of British Columbia, Vancouver, BC, Canada
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Mirna Ragheb
1Dept of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
2Biology of Breathing Group, Children's Research Hospital of Manitoba, Winnipeg, MB, Canada
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Jignesh Vaghasiya
1Dept of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
2Biology of Breathing Group, Children's Research Hospital of Manitoba, Winnipeg, MB, Canada
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Sujata Basu
2Biology of Breathing Group, Children's Research Hospital of Manitoba, Winnipeg, MB, Canada
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Gerald L. Stelmack
2Biology of Breathing Group, Children's Research Hospital of Manitoba, Winnipeg, MB, Canada
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Sadeesh Srinathan
4Dept of Surgery, University of Manitoba, Winnipeg, MB, Canada
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Biniam Kidane
4Dept of Surgery, University of Manitoba, Winnipeg, MB, Canada
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Jason Kindrachuk
5Dept of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada
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Paul M. O'Byrne
6Dept of Medicine, Firestone Institute of Respiratory Health, McMaster University, Hamilton, ON, Canada
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Gail M. Gauvreau
6Dept of Medicine, Firestone Institute of Respiratory Health, McMaster University, Hamilton, ON, Canada
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Amir Ravandi
7Dept of Medicine, University of Manitoba, Winnipeg, MB, Canada
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Christopher Carlsten
3Dept of Medicine, University of British Columbia, Vancouver, BC, Canada
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Andrew J. Halayko
1Dept of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
2Biology of Breathing Group, Children's Research Hospital of Manitoba, Winnipeg, MB, Canada
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Abstract

Oxidised phosphatidylcholines (OxPCs) are produced under conditions of elevated oxidative stress and can contribute to human disease pathobiology. However, their role in allergic asthma is unexplored. The aim of this study was to characterise the OxPC profile in the airways after allergen challenge of people with airway hyperresponsiveness (AHR) or mild asthma. The capacity of OxPCs to contribute to pathobiology associated with asthma was also to be determined.

Using bronchoalveolar lavage fluid from two human cohorts, OxPC species were quantified using ultra-high performance liquid chromatography-tandem mass spectrometry. Murine thin-cut lung slices were used to measure airway narrowing caused by OxPCs. Human airway smooth muscle (HASM) cells were exposed to OxPCs to assess concentration-associated changes in inflammatory phenotype and activation of signalling networks.

OxPC profiles in the airways were different between people with and without AHR and correlated with methacholine responsiveness. Exposing patients with mild asthma to allergens produced unique OxPC signatures that associated with the severity of the late asthma response. OxPCs dose-dependently induced 15% airway narrowing in murine thin-cut lung slices. In HASM cells, OxPCs dose-dependently increased the biosynthesis of cyclooxygenase-2, interleukin (IL)-6, IL-8, granulocyte−macrophage colony-stimulating factor and the production of oxylipins via protein kinase C-dependent pathways.

Data from human cohorts and primary HASM cell culture show that OxPCs are present in the airways, increase after allergen challenge and correlate with metrics of airway dysfunction. Furthermore, OxPCs may contribute to asthma pathobiology by promoting airway narrowing and inducing a pro-inflammatory phenotype and contraction of airway smooth muscle. OxPCs represent a potential novel target for treating oxidative stress-associated pathobiology in asthma.

Abstract

Unique profiles of oxidised phospholipids in the human lung correlate with airway pathophysiology. They are novel pro-inflammatory mediators with direct effects in structural cells via complex pathways, and are not targeted by standard asthma therapies. https://bit.ly/34UO2AL

Footnotes

  • This article has an editorial commentary: https://doi.org/10.1183/13993003.03736-2020

  • This article has supplementary material available from erj.ersjournals.com

  • Author contributions: C.D. Pascoe performed cell culture experiments, data analysis and preparation of manuscript draft. A. Jha performed isolation of OxPC from human samples, data analysis and preparation of manuscript draft. M.H. Ryu performed isolation of OxPC for DE3 BAL sample and assisted in collecting samples for DE3 study. J. Vaghasiya performed and analysed studies using thin-cut lung slices and preparation of the manuscript. S. Basu assisted with animal experiments and editing of the manuscript. M. Ragheb and G.L. Stelmack contributed to collection of data from cell culture experiments and data analysis. S. Srinathan and B. Kidane recruited thoracic surgery subjects and collected human lung specimens that were used to generate primary HASM cell cultures, and they edited the manuscript. J. Kindrachuk performed the kinomics array on cell culture lysates. A. Ravandi contributed to experimental design and performed OxPC analyses in human samples. C. Carlsten, G.M. Gauvreau and P.M. O'Byrne performed human exposures and collected human samples. A.J. Halayko conceived the project, its design and data plan, and contributed to drafting the manuscript.

  • Conflict of interest: C.D. Pascoe has nothing to disclose.

  • Conflict of interest: A. Jha has nothing to disclose.

  • Conflict of interest: M.H. Ryu has nothing to disclose.

  • Conflict of interest: M. Ragheb has nothing to disclose.

  • Conflict of interest: J. Vaghasiya has nothing to disclose.

  • Conflict of interest: S. Basu has nothing to disclose.

  • Conflict of interest: G.L. Stelmack has nothing to disclose.

  • Conflict of interest: S. Srinathan has nothing to disclose.

  • Conflict of interest: B. Kidane has nothing to disclose.

  • Conflict of interest: J. Kindrachuk has nothing to disclose.

  • Conflict of interest: P.M. O'Byrne has received consulting and/or speakers fees from AstraZeneca, GSK, Chiesi and Meranari, and grants in aid from AstraZeneca, Medimmune, GSK, Novartis and Merck, outside the submitted work.

  • Conflict of interest: G.M. Gauvreau has nothing to disclose.

  • Conflict of interest: A. Ravandi has nothing to disclose.

  • Conflict of interest: C. Carlsten has nothing to disclose.

  • Conflict of interest: A.J. Halayko has nothing to disclose.

  • Support statement: Funding was received from CIHR-ICRH Emerging Network Grant for the Canadian Respiratory Research Network (CIHR (MOP 123319)), WorkSafe BC (RG2011-OG07) and AllerGen National Centre for Excellence (GxE4). Funding information for this article has been deposited with the Crossref Funder Registry. J. Kindrachuk is funded by a Tier 2 Canada Research Chair in the Molecular Pathogenesis of Emerging and Re-Emerging Viruses provided by the CIHR (Grant no. 950-231498). A.J. Halayko is funded by a Tier 1 Canada Research Chair in Lung Pathobiology and Treatment. C. Carlsten is funded by both Tier 2 Canada Research Chair and an AstraZeneca Chair in Occupational and Environmental Lung Disease. A. Ravandi is supported by the FW Du Val Clinical Research Professorship from the Manitoba Medical Services Foundation. C.D. Pascoe is supported by a CIHR Banting Fellowship. J. Vaghasiya is supported by a PhD Studentship from Research Manitoba and the Children's Hospital Research Institute of Manitoba.

  • Received March 24, 2020.
  • Accepted August 26, 2020.
  • Copyright ©ERS 2021
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Allergen inhalation generates pro-inflammatory oxidised phosphatidylcholine associated with airway dysfunction
Christopher D. Pascoe, Aruni Jha, Min Hyung Ryu, Mirna Ragheb, Jignesh Vaghasiya, Sujata Basu, Gerald L. Stelmack, Sadeesh Srinathan, Biniam Kidane, Jason Kindrachuk, Paul M. O'Byrne, Gail M. Gauvreau, Amir Ravandi, Christopher Carlsten, Andrew J. Halayko
European Respiratory Journal Feb 2021, 57 (2) 2000839; DOI: 10.1183/13993003.00839-2020

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Allergen inhalation generates pro-inflammatory oxidised phosphatidylcholine associated with airway dysfunction
Christopher D. Pascoe, Aruni Jha, Min Hyung Ryu, Mirna Ragheb, Jignesh Vaghasiya, Sujata Basu, Gerald L. Stelmack, Sadeesh Srinathan, Biniam Kidane, Jason Kindrachuk, Paul M. O'Byrne, Gail M. Gauvreau, Amir Ravandi, Christopher Carlsten, Andrew J. Halayko
European Respiratory Journal Feb 2021, 57 (2) 2000839; DOI: 10.1183/13993003.00839-2020
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