{"doi":"10.3389/fcvm.2021.633212","title":"PEGylated Serp-1 Markedly Reduces Pristane-Induced Experimental Diffuse Alveolar Hemorrhage, Altering uPAR Distribution, and Macrophage Invasion","abstract":"Diffuse alveolar hemorrhage (DAH) is one of the most serious clinical complications of systemic lupus erythematosus (SLE). The prevalence of DAH is reported to range from 1 to 5%, but while DAH is considered a rare complication there is a reported 50–80% mortality. There is at present no proven effective treatment for DAH and the therapeutics that have been tested have significant side effects. There is a clear necessity to discover new drugs to improve outcomes in DAH. Ser ine p rotease in hibitors, serpins , regulate thrombotic and thrombolytic protease cascades. We are investigating a Myxomavirus derived immune modulating serpin, Serp-1, as a new class of immune modulating therapeutics for vasculopathy and lung hemorrhage. Serp-1 has proven efficacy in models of herpes virus-induced arterial inflammation (vasculitis) and lung hemorrhage and has also proved safe in a clinical trial in patients with unstable coronary syndromes and stent implant. Here, we examine Serp-1, both as a native secreted protein expressed by CHO cells and as a polyethylene glycol modified (PEGylated) variant (Serp-1m5), for potential therapy in DAH. DAH was induced by intraperitoneal (IP) injection of pristane in C57BL/6J (B6) mice. Mice were treated with 100 ng/g bodyweight of either Serp-1 as native 55 kDa secreted glycoprotein, or as Serp-1m5, or saline controls after inducing DAH. Treatments were repeated daily for 14 days (6 mice/group). Serp-1 partially and Serp-1m5 significantly reduced pristane-induced DAH when compared with saline as assessed by gross pathology and H&E staining (Serp-1, p = 0.2172; Serp-1m5, p = 0.0252). Both Serp-1m5 and Serp-1 treatment reduced perivascular inflammation and reduced M1 macrophage (Serp-1, p = 0.0350; Serp-1m5, p = 0.0053), hemosiderin-laden macrophage (Serp-1, p = 0.0370; Serp-1m5, p = 0.0424) invasion, and complement C5b/9 staining. Extracellular urokinase-type plasminogen activator receptor positive (uPAR+) clusters were significantly reduced (Serp-1, p = 0.0172; Serp-1m5, p = 0.0025). Serp-1m5 also increased intact uPAR+ alveoli in the lung ( p = 0.0091). In conclusion, Serp-1m5 significantly reduces lung damage and hemorrhage in a pristane model of SLE DAH, providing a new potential therapeutic approach.","journal":"Frontiers in Cardiovascular Medicine","year":2021,"id":187662,"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":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9503,"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":392469,"name":"Jordan R. Yaron","orcid":"0000-0002-4133-474X","position":1,"is_corresponding":false},{"id":747794,"name":"J W Wallen","orcid":null,"position":2,"is_corresponding":false},{"id":747795,"name":"Kyle Browder","orcid":null,"position":3,"is_corresponding":false},{"id":747290,"name":"Ryan J. Boyd","orcid":"0000-0002-6704-8696","position":4,"is_corresponding":false},{"id":712827,"name":"Tien L. Olson","orcid":"0000-0002-2383-0862","position":5,"is_corresponding":false},{"id":392471,"name":"Michelle Burgin","orcid":"0000-0002-8596-9683","position":6,"is_corresponding":false},{"id":747796,"name":"Peaches Ulrich","orcid":null,"position":7,"is_corresponding":false},{"id":747797,"name":"Emily Aliskevich","orcid":null,"position":8,"is_corresponding":false},{"id":393958,"name":"Lauren N. Schutz","orcid":null,"position":9,"is_corresponding":false},{"id":439979,"name":"Petra Fromme","orcid":"0000-0003-0953-4909","position":10,"is_corresponding":false},{"id":485394,"name":"Liqiang Zhang","orcid":"0000-0002-4175-7590","position":11,"is_corresponding":false},{"id":747291,"name":"Alexandra Lucas","orcid":"0000-0002-5195-1442","position":12,"is_corresponding":false},{"id":393957,"name":"Qiuyun Guo","orcid":null,"position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-18T23:48:55.420619Z","pmid":"33665212","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":[]}