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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Novel Pharmacodynamic Model to Profile Inhibitors of NLRP3 in the Mouse Lung
Session Title
TP40 - TP040 COPD CLINICAL TRIALS AND THERAPIES
Abstract
A2270 - Novel Pharmacodynamic Model to Profile Inhibitors of NLRP3 in the Mouse Lung
Author Block: G. Kasetty1, M. Rhedin2, S. Arlbrandt1, J. Marie1, J. Johan2, B. Annika1, M. Birrell1; 1Bioscience In Vivo, Research and Early Development, Respiratory and Immunology (R&I), AstraZeneca, Gothenburg, Sweden, 2Bioscience and COPD-IPF, Research and Early Development, Respiratory and Immunology (R&I), AstraZeneca, Gothenburg, Sweden.
Rationale: NLRP3 inflammasome activation and release of bioactive cytokines such as IL-1β and IL-18 are thoughts to play a pivotal role in the amplification of inflammatory processes and in the development of chronic airway diseases. Thus inhibition of the NLRP3 Inflammasome assembly/function represents an attractive target for the treatment for respiratory diseases. The aim of this study was to develop an acute murine model to profile NLRP3 inhibitors. This would allow us to understand PD/PK profile of inhibitors (helping with dose-to-man predictions) and create a step between cell based assays and complex disease-replicating in vivo systems. Methods: To line up with the protocols used in the cell based assays, female C57/Bl6 N mice were challenged with inhaled aerosolised LPS followed by an intranasal ATP challenge. Activation of the inflammasome was assess by measuring cytokine levels in the BAL fluid (BALF). The role of NLRP3 was confirmed using genetically modified (GM) mice (NLRP3 KOs) and a selective NLRP3 inhibitor molecule MCC950. Results: BALF cytokine data from challenge response studies allowed us to select appropriate levels of LPS and ATP to use. The combination of LPS and ATP significantly increased the levels of both IL-1β and IL-18, whilst not effecting control cytokines such as TNFα. This increase was not seen in mice missing functional NLRP3. Based on cell based EC50 values and pharmacokinetic profiles, we selected a dose range of the NRLP3 inhibitor MCC950 to test in the model system. The resulting data showed that increasing doses of the compound was able to inhibit the release of the NRLP3 linked cytokines but not impacting on control cytokines. Together with the GM mouse data, it would suggest that NRLP3 plays a key role in this acute PD model system. Conclusions: We have developed an acute in vivo model to help study the effect of NLRP3 inhibitors in the airways. This short mechanistic model will serve as an invaluable tool in the development of modulators of the NLRP3 inflammasome and will help with the drive to finding novel therapies for chronic lung diseases.
Author Block: G. Kasetty1, M. Rhedin2, S. Arlbrandt1, J. Marie1, J. Johan2, B. Annika1, M. Birrell1; 1Bioscience In Vivo, Research and Early Development, Respiratory and Immunology (R&I), AstraZeneca, Gothenburg, Sweden, 2Bioscience and COPD-IPF, Research and Early Development, Respiratory and Immunology (R&I), AstraZeneca, Gothenburg, Sweden.
Rationale: NLRP3 inflammasome activation and release of bioactive cytokines such as IL-1β and IL-18 are thoughts to play a pivotal role in the amplification of inflammatory processes and in the development of chronic airway diseases. Thus inhibition of the NLRP3 Inflammasome assembly/function represents an attractive target for the treatment for respiratory diseases. The aim of this study was to develop an acute murine model to profile NLRP3 inhibitors. This would allow us to understand PD/PK profile of inhibitors (helping with dose-to-man predictions) and create a step between cell based assays and complex disease-replicating in vivo systems. Methods: To line up with the protocols used in the cell based assays, female C57/Bl6 N mice were challenged with inhaled aerosolised LPS followed by an intranasal ATP challenge. Activation of the inflammasome was assess by measuring cytokine levels in the BAL fluid (BALF). The role of NLRP3 was confirmed using genetically modified (GM) mice (NLRP3 KOs) and a selective NLRP3 inhibitor molecule MCC950. Results: BALF cytokine data from challenge response studies allowed us to select appropriate levels of LPS and ATP to use. The combination of LPS and ATP significantly increased the levels of both IL-1β and IL-18, whilst not effecting control cytokines such as TNFα. This increase was not seen in mice missing functional NLRP3. Based on cell based EC50 values and pharmacokinetic profiles, we selected a dose range of the NRLP3 inhibitor MCC950 to test in the model system. The resulting data showed that increasing doses of the compound was able to inhibit the release of the NRLP3 linked cytokines but not impacting on control cytokines. Together with the GM mouse data, it would suggest that NRLP3 plays a key role in this acute PD model system. Conclusions: We have developed an acute in vivo model to help study the effect of NLRP3 inhibitors in the airways. This short mechanistic model will serve as an invaluable tool in the development of modulators of the NLRP3 inflammasome and will help with the drive to finding novel therapies for chronic lung diseases.
