{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T12:12:09Z","timestamp":1793275929107,"version":"4.5.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2017,8,1]],"date-time":"2017-08-01T00:00:00Z","timestamp":1501545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive nucleotide-binding oligomerization domain\u2013like receptor family, pyrin domain\u2013containing 3 (NLRP3) inflammasome and concomitant IL-1\u03b2 responses occur in chronic obstructive pulmonary disease, respiratory infections, and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved, and potential for therapeutic targeting remain poorly understood, and are unknown in severe, steroid-resistant asthma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1\u03b2 in severe, steroid-resistant asthma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We developed mouse models of Chlamydia and Haemophilus respiratory infection\u2013mediated, ovalbumin-induced severe, steroid-resistant allergic airway disease. These models share the hallmark features of human disease, including elevated airway neutrophils, and NLRP3 inflammasome and IL-1\u03b2 responses. The roles and potential for targeting of NLRP3 inflammasome, caspase-1, and IL-1\u03b2 responses in experimental severe, steroid-resistant asthma were examined using a highly selective NLRP3 inhibitor, MCC950; the specific caspase-1 inhibitor Ac-YVAD-cho; and neutralizing anti\u2013IL-1\u03b2 antibody. Roles for IL-1\u03b2\u2013induced neutrophilic inflammation were examined using IL-1\u03b2 and anti-Ly6G.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1\u03b2 responses that drive steroid-resistant neutrophilic inflammation and airway hyperresponsiveness. Neutrophilic airway inflammation, disease severity, and steroid resistance in human asthma correlate with NLRP3 and IL-1\u03b2 expression. Treatment with anti\u2013IL-1\u03b2, Ac-YVAD-cho, and MCC950 suppressed IL-1\u03b2 responses and the important steroid-resistant features of disease in mice, whereas IL-1\u03b2 administration recapitulated these features. Neutrophil depletion suppressed IL-1\u03b2\u2013induced steroid-resistant airway hyperresponsiveness.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201609-1830oc","type":"journal-article","created":{"date-parts":[[2017,3,2]],"date-time":"2017-03-02T11:03:20Z","timestamp":1488452600000},"page":"283-297","source":"Crossref","is-referenced-by-count":423,"title":["Role for NLRP3 Inflammasome\u2013mediated, IL-1\u03b2\u2013Dependent Responses in Severe, Steroid-Resistant Asthma"],"prefix":"10.1093","volume":"196","author":[{"given":"Richard Y.","family":"Kim","sequence":"first","affiliation":[{"name":"Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W.","family":"Pinkerton","sequence":"additional","affiliation":[{"name":"Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ama T.","family":"Essilfie","sequence":"additional","affiliation":[{"name":"Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avril A. 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