{"doi":"10.1161/atvbaha.121.316925","title":"Interleukin-1RA Mitigates SARS-CoV-2–Induced Inflammatory Lung Vascular Leakage and Mortality in Humanized K18-hACE-2 Mice","abstract":"Objective: SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is a major cause of morbidity and mortality, often as a result of acute respiratory distress syndrome. Respiratory failure is characterized by a hyperinflammatory immune response, lung vascular injury, and edema formation. The potential for immunomodulatory therapy to prevent lung vascular injury and edema formation is not well understood. Approach and Results: We show that SARS-CoV-2 infection in humanized K18-hACE-2 mice activated inflammatory NLRP3 (NLR family pyrin domain containing 3)–caspase-1 pyroptotic signaling in lungs, release of IL (interleukin)-1β, and downregulation of the lung endothelial adherens junction protein VE (vascular endothelial)-cadherin. Primary human lung microvascular endothelial cells were susceptible to SARS-CoV-2 infection and displayed pyroptosis-like injury. We observed profound lung vascular injury post–SARS-CoV-2 infection and resultant protein-rich lung edema formation. Selective blockade of IL-1 receptor signaling by IL-1RA (IL-1 receptor antagonist) anakinra prevented downregulation of VE-cadherin, as well as accompanying lung vascular hyperpermeability. IL-1RA also significantly increased survival. Conclusions: These results provide insights into the central role of NLRP3–caspase-1 pyroptotic innate immune signaling and loss of lung endothelial adherens junctions in the mechanism of acute respiratory distress syndrome induced by SARS-CoV-2. Our data show that treatment with IL-1RA during activation of inflammasome provides the ideal scenario for preventing lung vascular injury and respiratory failure in coronavirus disease 2019 (COVID-19). Graphic Abstract: A graphic abstract is available for this article.","journal":"Arteriosclerosis Thrombosis and Vascular Biology","year":2021,"id":159281,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":42,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9597,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":235199,"name":"Lianghui Zhang","orcid":"0000-0003-3037-9173","position":1,"is_corresponding":false},{"id":669706,"name":"Abdul Qadir","orcid":"0000-0002-9133-2558","position":2,"is_corresponding":false},{"id":484769,"name":"Justin M. Richner","orcid":"0000-0002-5344-118X","position":3,"is_corresponding":false},{"id":484768,"name":"Jacob Class","orcid":"0000-0003-1928-5950","position":4,"is_corresponding":false},{"id":235204,"name":"Jalees Rehman","orcid":"0000-0002-2787-9292","position":5,"is_corresponding":false},{"id":235203,"name":"Asrar B. Malik","orcid":"0000-0002-8205-7128","position":6,"is_corresponding":false},{"id":243862,"name":"Shiqin Xiong","orcid":null,"position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-18T23:44:35.165422Z","pmid":"34496633","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}