{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:02:05Z","timestamp":1787022125205,"version":"build-2736575974"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T00:00:00Z","timestamp":1685664000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Elastrin Therapeutics Inc","award":["Elastrin-002"],"award-info":[{"award-number":["Elastrin-002"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background and purpose<\/jats:title>\n                    <jats:p>Cytokine storm invoked during acute and chronic lung injury promotes alveolar damage and remodeling. The current study shows that degraded elastin-targeted nanoparticles releasing doxycycline (Doxy NPs) are potent in mitigating cytokines storm, migration of immune cells in the lungs, and inhibiting inflammasome pathways in the LPS mouse model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Experimental approach<\/jats:title>\n                    <jats:p>Cytokine storm and lung injury were induced using LPS and elastase in C57BL\/6 mice (rodent model for emphysema). The mice were then treated with I.V. Doxy NPs, blank NPs, or Doxy a day before LPS administration. Cytokine levels, immune cell population, and MMP activity were analyzed in broncheo-alveolar lavage fluid (BALF) 4 hours after LPS administration. Additionally, gene expression of IL-6, IL-1beta, MCP-1, NLRP3, Caspase 1 and MMPs were investigated in alveolar cells on day 3 after LPS administration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Key results<\/jats:title>\n                    <jats:p>Doxycycline NPs but not Doxycycline significantly decreased IL-6, TNF-\u03b1, IL-23 and were significantly more effective in decreasing the percentage of immune cells in the BALF. This is the first in-vivo study to demonstrate that Doxycycline can effectively inhibit inflammasome pathways in the lungs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion and implications<\/jats:title>\n                    <jats:p>IV administration of elastin antibody conjugated Doxycycline-loaded albumin NPs can effectively modulate the local immune environment in the lungs, which is not achieved by IV Doxycycline even at 100-fold higher dose. This novel method of drug delivery can effectively lead to the repurposing of traditional Doxycycline as a potential adjunct treatment for managing the cytokine storm in the lungs in COPD and viral infections.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0286211","type":"journal-article","created":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T13:39:24Z","timestamp":1685713164000},"page":"e0286211","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Elastin-targeted nanoparticles delivering doxycycline mitigate cytokine storm and reduce immune cell infiltration in LPS-mediated lung inflammation"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7332-9953","authenticated-orcid":true,"given":"Shivani","family":"Arora","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4889-6542","authenticated-orcid":true,"given":"Narendra","family":"Vyavahare","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,6,2]]},"reference":[{"issue":"2","key":"pone.0286211.ref001","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1513\/pats.200502-015AW","article-title":"Acute and chronic airway responses to viral infection: implications for asthma and chronic obstructive pulmonary disease","volume":"2","author":"MJ Holtzman","year":"2005","journal-title":"Proc Am Thorac Soc"},{"key":"pone.0286211.ref002","first-page":"191","article-title":"Airway Remodeling in Asthma. Front","volume":"7","author":"KP Hough","year":"2020","journal-title":"Med"},{"issue":"1","key":"pone.0286211.ref003","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1165\/rcmb.2014-0290OC","article-title":"Role of Matrix Metalloproteinases-1 and -2 in Interleukin-13-Suppressed Elastin in Airway Fibroblasts in Asthma","volume":"54","author":"J. L. Ingram","year":"2016","journal-title":"American journal of respiratory cell and molecular biology"},{"key":"pone.0286211.ref004","unstructured":"COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https:\/\/www.covid19treatmentguidelines.nih.gov\/. Accessed [Feb 7, 2023]."},{"issue":"9","key":"pone.0286211.ref005","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1080\/14740338.2021.1946513","article-title":"Tocilizumab in COVID-19: a study of adverse drug events reported in the WHO database","volume":"20","author":"J Charan","year":"2021","journal-title":"Expert Opin Drug Saf"},{"issue":"21","key":"pone.0286211.ref006","doi-asserted-by":"crossref","first-page":"5064","DOI":"10.3390\/molecules25215064","article-title":"In Vitro Antiviral Activity of Doxycycline against SARS-CoV-2","volume":"25","author":"M Gendrot","year":"2020","journal-title":"Molecules"},{"key":"pone.0286211.ref007","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.ejphar.2017.05.041","article-title":"Inhibitory effects of Doxycycline on the onset and progression of abdominal aortic aneurysm and its related mechanisms","volume":"811","author":"M. 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Marjani","year":"2021","journal-title":"Journal of neuroimmunology"},{"key":"pone.0286211.ref010","doi-asserted-by":"crossref","first-page":"4733","DOI":"10.2147\/DDDT.S341242","article-title":"Clinical Effect of Doxycycline Combined with Compound Sulfamethoxazole and Rifampicin in the Treatment of Brucellosis Spondylitis","volume":"15","author":"X. M. Yang","year":"2021","journal-title":"Drug design, development and therapy"},{"issue":"9","key":"pone.0286211.ref011","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1016\/S2213-2600(21)00310-6","article-title":"Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial","volume":"9","author":"C. C. Butler","year":"2021","journal-title":"The Lancet. Respiratory medicine"},{"key":"pone.0286211.ref012","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.pupt.2016.06.004","article-title":"Targeted drug delivery to emphysematous lungs: Inhibition of MMPs by doxycycline loaded nanoparticles","volume":"39","author":"V Parasaram","year":"2016","journal-title":"Pulm Pharmacol Ther"},{"issue":"9","key":"pone.0286211.ref013","doi-asserted-by":"crossref","first-page":"852","DOI":"10.3390\/ph14090852","article-title":"Doxycycline Attenuates Cancer Cell Growth by Suppressing NLRP3-Mediated Inflammation","volume":"14","author":"M. Alsaadi","year":"2021","journal-title":"Pharmaceuticals (Basel, Switzerland)"},{"key":"pone.0286211.ref014","unstructured":"Vyavahare, N.R., Rice, C, Nosoudi, N., Karamched S., Parasaram, V., International patent application, Anti-elastin antibodies and methods of use, https:\/\/patentscope.wipo.int\/search\/en\/detail.jsf?docId=US355368379&_cid=P10-L38VSB-11003-1"},{"issue":"1","key":"pone.0286211.ref015","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.bbrc.2018.03.100","article-title":"Pentagalloyl glucose increases elastin deposition, decreases reactive oxygen species and matrix metalloproteinase activity in pulmonary fibroblasts under inflammatory conditions","volume":"499","author":"V. Parasaram","year":"2018","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"pone.0286211.ref016","doi-asserted-by":"crossref","first-page":"8584","DOI":"10.1038\/s41598-021-88017-w","article-title":"Systemic delivery of targeted nanotherapeutic reverses angiotensin II-induced abdominal aortic aneurysms in mice","volume":"11","author":"X. Wang","year":"2021","journal-title":"Sci Rep"},{"issue":"123","key":"pone.0286211.ref017","first-page":"55398","article-title":"Bronchoalveolar Lavage of Murine Lungs to Analyze Inflammatory Cell Infiltration","author":"L. Van Hoecke","year":"2017","journal-title":"Journal of visualized experiments: JoVE"},{"issue":"1","key":"pone.0286211.ref018","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1006\/abio.1997.2170","article-title":"Zymography: a single-step staining method for quantitation of proteolytic activity on substrate gels","volume":"249","author":"T. M. Leber","year":"1997","journal-title":"Analytical biochemistry"},{"issue":"7","key":"pone.0286211.ref019","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.3390\/cells11071138","article-title":"Functional and Phenotypic Characterization of Siglec-6 on Human Mast Cells","volume":"11","author":"PA Robida","year":"2022","journal-title":"Cells"},{"key":"pone.0286211.ref020","doi-asserted-by":"crossref","first-page":"107462","DOI":"10.1016\/j.intimp.2021.107462","article-title":"Novaes, Doxycycline aggravates granulomatous inflammation and lung microstructural remodeling induced by Schistosoma mansoni infection","volume":"94","author":"P Margarida","year":"2021","journal-title":"International Immunopharmacology"},{"key":"pone.0286211.ref021","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.rmed.2015.10.009","article-title":"Effects of Doxycycline on local and systemic inflammation in stable COPD patients, a randomized clinical trial","volume":"110","author":"H. J. Prins","year":"2016","journal-title":"Respiratory medicine"},{"issue":"7","key":"pone.0286211.ref022","doi-asserted-by":"crossref","first-page":"503","DOI":"10.3109\/07853890.2011.577093","article-title":"Interleukin-23: a key cytokine in inflammatory diseases","volume":"43","author":"E. Duvallet","year":"2011","journal-title":"Annals of medicine"},{"issue":"1","key":"pone.0286211.ref023","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1165\/rcmb.2022-0117OC","article-title":"IFN-\u03b3 Is Protective in Cytokine Release Syndrome-associated Extrapulmonary Acute Lung Injury","volume":"68","author":"Y Sun","year":"2023","journal-title":"Am J Respir Cell Mol Biol"},{"issue":"5","key":"pone.0286211.ref024","doi-asserted-by":"crossref","first-page":"e33","DOI":"10.4110\/in.2018.18.e33","article-title":"Direct Antiviral Mechanisms of Interferon-Gamma","volume":"18","author":"S Kang","year":"2018","journal-title":"Immune Netw"},{"issue":"3","key":"pone.0286211.ref025","first-page":"87","article-title":"Interferon-gamma (r-IFN-gamma) induces activation of alveolar macrophages (AM) from anergic patients with chronic obstructive pulmonary disease (COPD)","volume":"6","author":"T. Todisco","year":"1992","journal-title":"Journal of biological regulators and homeostatic agents"},{"key":"pone.0286211.ref026","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/1465-9921-7-125","article-title":"Role of TNF\u03b1 in pulmonary pathophysiology","volume":"7","author":"S. Mukhopadhyay","year":"2006","journal-title":"Respir Res"},{"issue":"Suppl 1","key":"pone.0286211.ref027","doi-asserted-by":"crossref","first-page":"60","DOI":"10.3109\/15412555.2013.764403","article-title":"Neutrophil elastase-mediated lung disease","volume":"10","author":"R. A. Sandhaus","year":"2013","journal-title":"COPD"},{"issue":"5","key":"pone.0286211.ref028","doi-asserted-by":"crossref","first-page":"L931","DOI":"10.1152\/ajplung.00150.2009","article-title":"Elastase- and LPS-exposed mice display altered responses to rhinovirus infection","volume":"297","author":"U Sajjan","year":"2009","journal-title":"American journal of physiology. Lung cellular and molecular physiology"},{"issue":"1","key":"pone.0286211.ref029","first-page":"61","volume":"180","author":"S. Ganesan","year":"2012","journal-title":"Elastase\/LPS-Exposed Mice Exhibit Impaired Innate Immune Responses to Bacterial Challenge: Role of Scavenger Receptor A, The American Journal of Pathology"},{"key":"pone.0286211.ref030","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/1465-9921-11-131","article-title":"Quercetin prevents progression of disease in elastase\/LPS-exposed mice by negatively regulating MMP expression","volume":"11","author":"S. Ganesan","year":"2010","journal-title":"Respir Res"},{"key":"pone.0286211.ref031","article-title":"Front","volume":"28","author":"M.N. De Olivers","year":"2019","journal-title":"Physiol."},{"issue":"4","key":"pone.0286211.ref032","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1111\/imm.13121","article-title":"Siglec-F is induced by granulocyte-macrophage colony-stimulating factor and enhances interleukin-4-induced expression of arginase-1 in mouse macrophages","volume":"158","author":"H Tateyama","year":"2019","journal-title":"Immunology"},{"issue":"17","key":"pone.0286211.ref033","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1056\/NEJMoa1708208","article-title":"Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease","volume":"377","author":"I. D. Pavord","year":"2017","journal-title":"The New England journal of medicine"},{"issue":"7","key":"pone.0286211.ref034","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1056\/NEJMc1715454","article-title":"Mepolizumab for Eosinophilic COPD","volume":"378","author":"Y. Xia","year":"2018","journal-title":"The New England journal of medicine"},{"key":"pone.0286211.ref035","doi-asserted-by":"crossref","first-page":"329418","DOI":"10.1155\/2015\/329418","article-title":"Anti-inflammatory properties of low and high doxycycline doses: an in vitro study","volume":"2015","author":"R. Di Caprio","year":"2015","journal-title":"Mediators of inflammation"},{"key":"pone.0286211.ref036","doi-asserted-by":"crossref","first-page":"221","DOI":"10.4103\/1817-1737.84777","article-title":"Effect of Doxycycline in patients of moderate to severe chronic obstructive pulmonary disease with stable symptoms","volume":"6","author":"P.S. Dalvi","year":"2011","journal-title":"Ann Thorac Med"},{"key":"pone.0286211.ref037","doi-asserted-by":"crossref","first-page":"116163","DOI":"10.1016\/j.carbpol.2020.116163","article-title":"The effect of doxycycline-containing chitosan\/carboxymethyl chitosan nanoparticles on NLRP3 inflammasome in periodontal disease","volume":"237","author":"S. Xu","year":"2020","journal-title":"Carbohydrate polymers"},{"issue":"10","key":"pone.0286211.ref038","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.3390\/jcm8101615","article-title":"Targeting NLRP3 Inflammasome Activation in Severe Asthma","volume":"8","author":"E. Theofani","year":"2019","journal-title":"Journal of clinical medicine"},{"issue":"3","key":"pone.0286211.ref039","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1016\/j.jaci.2020.01.009","article-title":"Activated pyrin domain containing 3 (NLRP3) inflammasome in neutrophilic chronic rhinosinusitis with nasal polyps (CRSwNP)","volume":"145","author":"Y. Wei","year":"2020","journal-title":"The Journal of allergy and clinical immunology"},{"issue":"6","key":"pone.0286211.ref040","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1007\/s10753-016-0442-z","article-title":"Role of NLRP3 Inflammasome in Eosinophilic and Non-eosinophilic Chronic Rhinosinusitis with Nasal Polyps","volume":"39","author":"H. 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