Latrophilin receptors

Novel bronchodilator targets in asthma

Mohammed Abul Faiz, C Donovan, M. A E Nieuwenhuis, M. Van Den Berge, D. S. Postma, S Yao, C. Y. Park, Raphael Hirsch, Jeffrey J Fredberg, G. Tjin, Andrew J Halayko, K. L. Rempel, J. P T Ward, T. Lee, Y. Bossé, D. C. Nickle, M. Obeidat, Judith M. Vonk, J. L. Black, B. G. Oliver & 4 others R Krishnan, B. McParland, J E Bourke, J. K. Burgess

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)74-82
Number of pages9
JournalThorax
Volume72
Issue number1
DOIs
Publication statusPublished - 1 Jan 2017

Keywords

  • Asthma
  • Asthma Genetics

Cite this

Faiz, M. A., Donovan, C., Nieuwenhuis, M. A. E., Van Den Berge, M., Postma, D. S., Yao, S., ... Burgess, J. K. (2017). Latrophilin receptors: Novel bronchodilator targets in asthma. Thorax, 72(1), 74-82. https://doi.org/10.1136/thoraxjnl-2015-207236
Faiz, Mohammed Abul ; Donovan, C ; Nieuwenhuis, M. A E ; Van Den Berge, M. ; Postma, D. S. ; Yao, S ; Park, C. Y. ; Hirsch, Raphael ; Fredberg, Jeffrey J ; Tjin, G. ; Halayko, Andrew J ; Rempel, K. L. ; Ward, J. P T ; Lee, T. ; Bossé, Y. ; Nickle, D. C. ; Obeidat, M. ; Vonk, Judith M. ; Black, J. L. ; Oliver, B. G. ; Krishnan, R ; McParland, B. ; Bourke, J E ; Burgess, J. K. / Latrophilin receptors : Novel bronchodilator targets in asthma. In: Thorax. 2017 ; Vol. 72, No. 1. pp. 74-82.
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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.",
keywords = "Asthma, Asthma Genetics",
author = "Faiz, {Mohammed Abul} and C Donovan and Nieuwenhuis, {M. A E} and {Van Den Berge}, M. and Postma, {D. S.} and S Yao and Park, {C. Y.} and Raphael Hirsch and Fredberg, {Jeffrey J} and G. Tjin and Halayko, {Andrew J} and Rempel, {K. L.} and Ward, {J. P T} and T. Lee and Y. Boss{\'e} and Nickle, {D. C.} and M. Obeidat and Vonk, {Judith M.} and Black, {J. L.} and Oliver, {B. G.} and R Krishnan and B. McParland and Bourke, {J E} and Burgess, {J. K.}",
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Faiz, MA, Donovan, C, Nieuwenhuis, MAE, Van Den Berge, M, Postma, DS, Yao, S, Park, CY, Hirsch, R, Fredberg, JJ, Tjin, G, Halayko, AJ, Rempel, KL, Ward, JPT, Lee, T, Bossé, Y, Nickle, DC, Obeidat, M, Vonk, JM, Black, JL, Oliver, BG, Krishnan, R, McParland, B, Bourke, JE & Burgess, JK 2017, 'Latrophilin receptors: Novel bronchodilator targets in asthma', Thorax, vol. 72, no. 1, pp. 74-82. https://doi.org/10.1136/thoraxjnl-2015-207236

Latrophilin receptors : Novel bronchodilator targets in asthma. / Faiz, Mohammed Abul; Donovan, C; Nieuwenhuis, M. A E; Van Den Berge, M.; Postma, D. S.; Yao, S; Park, C. Y.; Hirsch, Raphael; Fredberg, Jeffrey J; Tjin, G.; Halayko, Andrew J; Rempel, K. L.; Ward, J. P T; Lee, T.; Bossé, Y.; Nickle, D. C.; Obeidat, M.; Vonk, Judith M.; Black, J. L.; Oliver, B. G.; Krishnan, R; McParland, B.; Bourke, J E; Burgess, J. K.

In: Thorax, Vol. 72, No. 1, 01.01.2017, p. 74-82.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Latrophilin receptors

T2 - Novel bronchodilator targets in asthma

AU - Faiz, Mohammed Abul

AU - Donovan, C

AU - Nieuwenhuis, M. A E

AU - Van Den Berge, M.

AU - Postma, D. S.

AU - Yao, S

AU - Park, C. Y.

AU - Hirsch, Raphael

AU - Fredberg, Jeffrey J

AU - Tjin, G.

AU - Halayko, Andrew J

AU - Rempel, K. L.

AU - Ward, J. P T

AU - Lee, T.

AU - Bossé, Y.

AU - Nickle, D. C.

AU - Obeidat, M.

AU - Vonk, Judith M.

AU - Black, J. L.

AU - Oliver, B. G.

AU - Krishnan, R

AU - McParland, B.

AU - Bourke, J E

AU - Burgess, J. K.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

KW - Asthma

KW - Asthma Genetics

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U2 - 10.1136/thoraxjnl-2015-207236

DO - 10.1136/thoraxjnl-2015-207236

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SN - 0040-6376

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Faiz MA, Donovan C, Nieuwenhuis MAE, Van Den Berge M, Postma DS, Yao S et al. Latrophilin receptors: Novel bronchodilator targets in asthma. Thorax. 2017 Jan 1;72(1):74-82. https://doi.org/10.1136/thoraxjnl-2015-207236