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Browse ATS 2021 Abstracts

HomeProgram ▶ Browse ATS 2021 Abstracts
 

ATS 2021 will feature presentations of original research from accepted abstracts. Mini Symposia and Thematic Poster Sessions are abstract based sessions.

Please use the form below to browse scientific abstracts and case reports accepted for ATS 2021. Abstracts presented at the ATS 2021 will be published in the Online Abstract Issue of the American Journal of Respiratory and Critical Care Medicine, Volume 203, May 3, 2021.

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Preclinical In Vitro Differentiation of FLAP Inhibitors vs Montelukast and ICS

Session Title
TP118 - TP118 AIRWAY HYPERRESPONSIVENESS AND INFLAMMATION IN ASTHMA
Abstract
A4497 - Preclinical In Vitro Differentiation of FLAP Inhibitors vs Montelukast and ICS
Author Block: H. Olsson1, S. Vollmer1, E. Israelsson1, J. Lindgren2, M. Glover3, L. Cazares3, E. Franssen4, S. Burns5, Z. Jevnikar Rojnik1; 1Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immun, AstraZeneca Gothenburg, Gothenburg, Sweden, 2Translational Genomics, Discovery Sciences, AstraZeneca Gothenburg, Gothenburg, Sweden, 3Dynamic Omics, ADPE, AstraZeneca Gaithersburg, Gaithersburg, MD, United States, 4Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immun, AstraZeneca Cambridge, Cambridge, United Kingdom, 5Projects, Research and Early Development, Respiratory & Immunology, AstraZeneca Cambridge, Cambridge, United Kingdom.
RATIONALE
Leukotrienes are potent mediators in asthma and pathway modulators are clinically validated, but how leukotriene synthesis inhibitors, receptor antagonists and glucocorticoids differentiate with respect to biological effects and scope for clinical efficacy remains unclear.
METHODS
Here we describe a human ex vivo lung tissue explant model allowing interactions between cells that produce and respond to leukotrienes. In this system baseline leukotriene production was low, whereas stimulation with fMLP or calcium ionophore induced robust production of LTB4 and LTE4.
RESULTS
Leukotriene pathway activation was effectively blocked by inhibitors of 5-lipoxygenase-activating protein (FLAP), whereas the CysLTR1 antagonist montelukast had no effect on leukotriene production. The glucocorticoid receptor agonist budesonide also had no effect, indicating the leukotriene pathway is largely insensitive to treatment by steroids. A novel FLAP inhibitor-induced gene signature identified by RNA sequencing was not affected by montelukast, suggesting differential effects of FLAPi and montelukast in asthma. Pathway analysis of FLAP-regulated genes and FLAP-dependent metabolite profiling are ongoing.
CONCLUSIONS
FLAP inhibition has potential as add-on therapy to steroids in the treatment of asthma and may drive more profound anti-inflammatory effects than montelukast due to pan leukotriene inhibition.