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In this work, we studied the activation of inflammasomes in the airways of critically ill COVID-19 patients and the effects of N-acetylcysteine (NAC) on inflammasomes. Tracheal biopsies were obtained from critically ill patients without COVID-19 and no respiratory disease (control, n = 32), SARS-CoV-2 B.1 variant (n = 31), and B.1.1.7 VOC alpha variant (n = 20) patients. Gene expression and protein expression were measured by RT-qPCR and immunohistochemistry. Macrophages and bronchial epithelial cells were stimulated with different S, E, M, and N SARS-CoV-2 recombinant proteins in the presence or absence of NAC. NLRP3 inflammasome complex was over-expressed and activated in the COVID-19 B.1.1.7 VOC variant and associated with systemic inflammation and 28-day mortality. TLR2\/MyD88 and redox NOX4\/Nrf2 ratio were also over-expressed in the COVID-19 B.1.1.7 VOC variant. The combination of S-E-M SARS-CoV-2 recombinant proteins increased cytokine release in macrophages and bronchial epithelial cells through the activation of TLR2. NAC inhibited SARS-CoV-2 mosaic (S-E-M)-induced cytokine release and inflammasome activation. In summary, inflammasome is over-activated in severe COVID-19 and increased in B.1.1.7 VOC variant. In addition, NAC can reduce inflammasome activation induced by SARS-CoV-2 in vitro, which may be of potential translational value in COVID-19 patients.<\/jats:p>","DOI":"10.3390\/ijms232314518","type":"journal-article","created":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T08:25:28Z","timestamp":1669105528000},"page":"14518","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["N-acetylcysteine Reduces Inflammasome Activation Induced by SARS-CoV-2 Proteins In Vitro"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6033-4211","authenticated-orcid":false,"given":"Javier","family":"Milara","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Valencia, 46014 Valencia, Spain"},{"name":"Pharmacy Unit, University General Hospital Consortium, 46014 Valencia, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Respiratorias (CIBERES), Health Institute Carlos III, 46014 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Mart\u00ednez-Exp\u00f3sito","sequence":"additional","affiliation":[{"name":"ENT Department, Consorci Hospital General Universitari de Valencia, 46014 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5929-5486","authenticated-orcid":false,"given":"Paula","family":"Montero","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Valencia, 46014 Valencia, Spain"},{"name":"Faculty of Health Sciences, Universidad Europea de Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e9s","family":"Roger","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Valencia, 46014 Valencia, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Respiratorias (CIBERES), Health Institute Carlos III, 46014 Valencia, Spain"},{"name":"Faculty of Health Sciences, Universidad Europea de Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Amparo","family":"Bayarri","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Valencia, 46014 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2883-5611","authenticated-orcid":false,"given":"Pilar","family":"Ribera","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Valencia, 46014 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam Natsuki","family":"Oishi-Konari","sequence":"additional","affiliation":[{"name":"ENT Department, Consorci Hospital General Universitari de Valencia, 46014 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Ram\u00f3n","family":"Alba-Garc\u00eda","sequence":"additional","affiliation":[{"name":"ENT Department, Consorci Hospital General Universitari de Valencia, 46014 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique","family":"Zapater","sequence":"additional","affiliation":[{"name":"ENT Department, Consorci Hospital General Universitari de Valencia, 46014 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Cortijo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Valencia, 46014 Valencia, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Respiratorias (CIBERES), Health Institute Carlos III, 46014 Valencia, Spain"},{"name":"Research and Teaching Unit, University General Hospital Consortium, 46014 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1056\/NEJMcp2009575","article-title":"Severe Covid-19","volume":"383","author":"Berlin","year":"2020","journal-title":"N. 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