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 Genetics
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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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