Abstract
Chronic inflammatory diseases of the respiratory tract, such as chronic obstructive pulmonary disease (COPD) and asthma, are severe lung diseases that require effective treatments. In search for new medicines for these diseases, there is an unmet need for predictive and translatable disease-relevant in vitro/ex vivo models to determine the safety and efficacy of novel drug candidates. Here, we report the use of precision cut lung slices (PCLS) as a potential ex vivo platform to study compound effects in a physiologically relevant environment. PCLS derived from an elastase-challenged mouse model display key characteristics of increased inflammation ex vivo, which is exacerbated further upon challenge with LPS, mimicking the immune insult of a pathogen triggering disease exacerbation. Such LPS-induced inflammatory conditions are significantly abrogated by immunomodulatory agents targeting specific inflammatory signaling pathways in the absence of cytotoxic effects in lung slices. Thus, an ex vivo model of PCLS with a simulated pathogenic insult can replicate proposed in vivo pharmacological effects and thus could potentially act as a valuable tool to investigate the underlying mechanisms associated with lung safety, therapeutic efficacy and exacerbations with infection.
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References
Alflen A, Stadler N, Aranda Lopez P, Teschner D, Theobald M, Hess G, Radsak MP (2018) Idelalisib impairs TREM-1 mediated neutrophil inflammatory responses. Sci Rep 8:5558. https://doi.org/10.1038/s41598-018-23808-2
Antunes MA, Rocco PR (2011) Elastase-induced pulmonary emphysema: insights from experimental models. An Acad Bras Cienc 83:1385–1396. https://doi.org/10.1590/s0001-37652011005000039
Baines KJ, Fu JJ, McDonald VM, Gibson PG (2017) Airway gene expression of IL-1 pathway mediators predicts exacerbation risk in obstructive airway disease. Int J Chron Obstruct Pulmon Dis 12:541–550. https://doi.org/10.2147/COPD.S119443
Balogh Sivars K et al (2018) A 3D human airway model enables prediction of respiratory toxicity of inhaled drugs. Vitro Toxicol Sci 162:301–308. https://doi.org/10.1093/toxsci/kfx255
Bauer CM et al (2010) Treating viral exacerbations of chronic obstructive pulmonary disease: insights from a mouse model of cigarette smoke and H1N1 influenza infection. PLoS ONE 5:e13251. https://doi.org/10.1371/journal.pone.0013251
Calama E, Domenech A, Carreño C, De Alba J, Prats N, Miralpeix M, Ramis I (2013) Involvement of the JAK-STAT3 pathway in a lipopolysaccharide-induced rat model of airway inflammation. Eur Respir J 42(Suppl. 57):733
Camargo CA Jr, Rachelefsky G, Schatz M (2009) Managing asthma exacerbations in the emergency department: summary of the national asthma education and prevention program expert panel report 3 guidelines for the management of asthma exacerbations. J Allergy Clin Immunol 124:S5–S14. https://doi.org/10.1016/j.jaci.2009.05.010
Collaborators GBDCRD (2017) Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med 5:691–706. https://doi.org/10.1016/S2213-2600(17)30293-X
Dinarello CA, Simon A, van der Meer JW (2012) Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 11:633–652. https://doi.org/10.1038/nrd3800
Donovan C, Seow HJ, Bourke JE, Vlahos R (2016) Influenza A virus infection and cigarette smoke impair bronchodilator responsiveness to beta-adrenoceptor agonists in mouse lung. Clin Sci (lond) 130:829–837. https://doi.org/10.1042/CS20160093
Evans MD, Esnault S, Denlinger LC, Jarjour NN (2018) Sputum cell IL-1 receptor expression level is a marker of airway neutrophilia and airflow obstruction in asthmatic patients. J Allergy Clin Immunol 142:415–423. https://doi.org/10.1016/j.jaci.2017.09.035
Fernandez-Blanco JA et al (2018) Attached stratified mucus separates bacteria from the epithelial cells in COPD lungs. JCI Insight. https://doi.org/10.1172/jci.insight.120994
Fleischmann RM et al (2006) Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis 65:1006–1012. https://doi.org/10.1136/ard.2005.048371
Gao W, McGarry T, Orr C, McCormick J, Veale DJ, Fearon U (2016) Tofacitinib regulates synovial inflammation in psoriatic arthritis, inhibiting STAT activation and induction of negative feedback inhibitors. Ann Rheum Dis 75:311–315. https://doi.org/10.1136/annrheumdis-2014-207201
Guha M, Mackman N (2002) The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J Biol Chem 277:32124–32132
Hawkins PT, Stephens LR (2015) PI3K signalling in inflammation. Biochim Biophys Acta 1851:882–897. https://doi.org/10.1016/j.bbalip.2014.12.006
Horak F et al (2016) Randomized phase 1 study of the phosphatidylinositol 3-kinase delta inhibitor idelalisib in patients with allergic rhinitis. J Allergy Clin Immunol 137:1733–1741. https://doi.org/10.1016/j.jaci.2015.12.1313
Kallapur SG, Nitsos I, Moss TJ et al (2009) IL-1 mediates pulmonary and systemic inflammatory responses to chorioamnionitis induced by lipopolysaccharide. Am J Respir Crit Care Med 179:955–961
Mantovani A, Dinarello CA, Molgora M, Garlanda C (2019) Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity 50:778–795. https://doi.org/10.1016/j.immuni.2019.03.012
Marwick JA et al (2010) A role for phosphoinositol 3-kinase delta in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 125:1146–1153. https://doi.org/10.1016/j.jaci.2010.02.003
Park SJ et al (2010) Phosphoinositide 3-kinase delta inhibitor suppresses interleukin-17 expression in a murine asthma model. Eur Respir J 36:1448–1459. https://doi.org/10.1183/09031936.00106609
Percie du Sert N et al (2020) The ARRIVE guidelines 2.0 Updated guidelines for reporting animal research. PLoS Biol 18:3000410. https://doi.org/10.1371/journal.pbio.3000410
Sears MR (2008) Epidemiology of asthma exacerbations. J Allergy Clin Immunol 122:662–668. https://doi.org/10.1016/j.jaci.2008.08.003
Singh D et al (2019) Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: the GOLD science committee report 2019. Eur Respir J. https://doi.org/10.1183/13993003.00164-2019
Southworth T et al (2016) Anti-inflammatory potential of PI3Kdelta and JAK inhibitors in asthma patients. Respir Res 17:124. https://doi.org/10.1186/s12931-016-0436-2
Southworth T et al (2018) PI3K, p38 and JAK/STAT signalling in bronchial tissue from patients with asthma following allergen challenge. Biomark Res 6:14. https://doi.org/10.1186/s40364-018-0128-9
Temann A, Golovina T, Neuhaus V, Thompson C, Chichester JA, Braun A, Yusibov V (2017) Evaluation of inflammatory and immune responses in long-term cultured human precision-cut lung slices. Hum Vaccin Immunother 13:351–358. https://doi.org/10.1080/21645515.2017.1264794
To Y et al (2010) Targeting phosphoinositide-3-kinase-delta with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 182:897–904. https://doi.org/10.1164/rccm.200906-0937OC
Villarino AV, Kanno Y, Ferdinand JR, O’Shea JJ (2015) Mechanisms of Jak/STAT signaling in immunity and disease. J Immunol 194:21–27. https://doi.org/10.4049/jimmunol.1401867
Viniol C, Vogelmeier CF (2018) Exacerbations of COPD. Eur Respir Rev. https://doi.org/10.1183/16000617.0103-2017
Yew-Booth L, Birrell MA, Lau MS, Baker K, Jones V, Kilty I, Belvisi MG (2015) JAK-STAT pathway activation in COPD. Eur Respir J 46:843–845. https://doi.org/10.1183/09031936.00228414
Acknowledgements
The authors wish to acknowledge Drs. Annika Borde, James Cartwright and Marie Larsson (R&D, AstraZeneca) and Michael Aleborg (Operations, AstraZeneca) for their support on this work.
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This work was funded by BioPharmaceuticals R&D at AstraZeneca.
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Guanghui Liu, Linnea Särén, Helena Douglasson, Xiao-Hong Zhou, Per M Åberg, Anna Ollerstam, Catherine J Betts and Kinga Balogh Sivars are employees of AztraZeneca.
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Liu, G., Särén, L., Douglasson, H. et al. Precision cut lung slices: an ex vivo model for assessing the impact of immunomodulatory therapeutics on lung immune responses. Arch Toxicol 95, 2871–2877 (2021). https://doi.org/10.1007/s00204-021-03096-y
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DOI: https://doi.org/10.1007/s00204-021-03096-y