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Original article
Latrophilin receptors: novel bronchodilator targets in asthma
  1. A Faiz1,2,
  2. C Donovan3,4,
  3. M AE Nieuwenhuis2,
  4. M van den Berge2,
  5. D S Postma2,
  6. S Yao5,
  7. C Y Park6,
  8. R Hirsch6,
  9. J J Fredberg6,
  10. G Tjin1,
  11. A J Halayko7,
  12. K L Rempel7,
  13. J P T Ward8,
  14. T Lee8,
  15. Y Bossé9,
  16. D C Nickle10,
  17. M Obeidat11,
  18. Judith M Vonk12,
  19. J L Black1,13,
  20. B G Oliver1,14,
  21. R Krishnan5,
  22. B McParland13,
  23. J E Bourke3,4,
  24. J K Burgess1,13,15
  1. 1Woolcock Institute of Medical Research, The University of Sydney, Glebe, New South Wales, Australia
  2. 2University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, Groningen, The Netherlands
  3. 3Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  4. 4Department of Pharmacology and Therapeutics, Lung Health Research Centre, University of Melbourne, Melbourne, Victoria, Australia
  5. 5Center for Vascular Biology Research, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
  6. 6Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
  7. 7Manitoba Institute of Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
  8. 8Kings College London, London, UK
  9. 9Department of Molecular Medicine, Institut universitaire de cardiologie et de pneumologie de Québec, Laval University, Québec, Quebec, Canada
  10. 10Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, Massachusetts, USA
  11. 11Centre for Heart Lung Innovation, University of British Columbia, St. Paul's Hospital, Vancouver, British Columbia, Canada
  12. 12University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands
  13. 13Discipline of Pharmacology, Faculty of Medicine, The University of Sydney, Sydney, New South Wales, Australia
  14. 14School of Medical and Molecular Biosciences, University of Technology, Sydney, New South Wales, Australia
  15. 15University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands
  1. Correspondence to Dr Alen Faiz, Department of Pathology and Medical Biology, University Medical Center Groningen, Hanzeplein 1, Groningen 9700 RB, The Netherlands; a.faiz{at}umcg.nl

Abstract

Background Asthma affects 300 million people worldwide. In asthma, the major cause of morbidity and mortality is acute airway narrowing, due to airway smooth muscle (ASM) hypercontraction, associated with airway remodelling. However, little is known about the transcriptional differences between healthy and asthmatic ASM cells.

Objectives To investigate the transcriptional differences between asthmatic and healthy airway smooth muscle cells (ASMC) in culture and investigate the identified targets using in vitro and ex vivo techniques.

Methods Human asthmatic and healthy ASMC grown in culture were run on Affymetrix_Hugene_1.0_ST microarrays. Identified candidates were confirmed by PCR, and immunohistochemistry. Functional analysis was conducted using in vitro ASMC proliferation, attachment and contraction assays and ex vivo contraction of mouse airways.

Results We suggest a novel role for latrophilin (LPHN) receptors, finding increased expression on ASMC from asthmatics, compared with non-asthmatics in vivo and in vitro, suggesting a role in mediating airway function. A single nucleotide polymorphism in LPHN1 was associated with asthma and with increased LPHN1 expression in lung tissue. When activated, LPHNs regulated ASMC adhesion and proliferation in vitro, and promoted contraction of mouse airways and ASMC.

Conclusions Given the need for novel inhibitors of airway remodelling and bronchodilators in asthma, the LPHN family may represent promising novel targets for future dual therapeutic intervention.

  • Asthma
  • Asthma Genetics

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

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Footnotes

  • Contributors AF participated in project design, microarray analysis, in vitro cellular work, writing and proofreading of the manuscript. CD participated in animal ex vivo work and analysis, and participated in the writing and proofreading of the manuscript. MAEN participated in the GWAS and eQTL analysis, and participated in the writing and proofreading of the manuscript. MvdB participated in the writing and proofreading of the manuscript. DSP participated in the GWAS and eQTL analysis, and participated in the writing and proofreading of the manuscript. AJH, KD, JPTW and TL, provided IASMC samples, and participated in the proofreading of the manuscript. YB, DCN, and MO provided access to the Lung tissue database for eQTL analysis, and participated in the proofreading of the manuscript. JKB, JLB and BGO participated in project design, provided funding for project, writing and proofreading of the manuscript. BM and JEB participated in project design of contraction related work, writing and proofreading of the manuscript.

  • Funding This work was supported by the National Health and Medical Research Council (NHMRC), Australia (Grant # 570867). AF and CD were supported by Australian Postgraduate Awards (APA). AF was supported by RESIPRE2 fellowship. JKB was supported by a NHMRC Career Development Fellowship #APP1032695. JLB was supported by a NHMRC Senior Principal Research Fellowship #APP571098. BGO was supported by an NHMRC Career Development Fellowship #APP1026880. YB was the recipient of a Junior 2 Research Scholar award from the Fonds de recherche Québec—Santé (FRQS). MO is the recipient of postdoctoral fellowship awards from the Michael Smith Foundation for Health Research (MSFHR) and the Canadian Institute for Health Research (CIHR) Integrated and Mentored Pulmonary and Cardiovascular Training programme (IMPACT). AJH is supported by the Canada Research Chairs Program.

  • Competing interests None declared.

  • Ethics approval Ethics Review Committee of the South West Sydney Area Health Service, the Human Research Ethics Committee of The University of Sydney.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Gene expression data are available through the Gene Expression Omnibus repository with the accession number GSE63383 (asthmatic and healthy ASMC profiling) and GSE23546 (eQTL analysis).

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