Cargando…

PEGylated Serp-1 Markedly Reduces Pristane-Induced Experimental Diffuse Alveolar Hemorrhage, Altering uPAR Distribution, and Macrophage Invasion

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 effe...

Descripción completa

Detalles Bibliográficos
Autores principales: Guo, Qiuyun, Yaron, Jordan R., Wallen, John W., Browder, Kyle F., Boyd, Ryan, Olson, Tien L., Burgin, Michelle, Ulrich, Peaches, Aliskevich, Emily, Schutz, Lauren N., Fromme, Petra, Zhang, Liqiang, Lucas, Alexandra R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921738/
https://www.ncbi.nlm.nih.gov/pubmed/33665212
http://dx.doi.org/10.3389/fcvm.2021.633212
_version_ 1783658529662435328
author Guo, Qiuyun
Yaron, Jordan R.
Wallen, John W.
Browder, Kyle F.
Boyd, Ryan
Olson, Tien L.
Burgin, Michelle
Ulrich, Peaches
Aliskevich, Emily
Schutz, Lauren N.
Fromme, Petra
Zhang, Liqiang
Lucas, Alexandra R.
author_facet Guo, Qiuyun
Yaron, Jordan R.
Wallen, John W.
Browder, Kyle F.
Boyd, Ryan
Olson, Tien L.
Burgin, Michelle
Ulrich, Peaches
Aliskevich, Emily
Schutz, Lauren N.
Fromme, Petra
Zhang, Liqiang
Lucas, Alexandra R.
author_sort Guo, Qiuyun
collection PubMed
description 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. Serine protease inhibitors, 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.
format Online
Article
Text
id pubmed-7921738
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-79217382021-03-03 PEGylated Serp-1 Markedly Reduces Pristane-Induced Experimental Diffuse Alveolar Hemorrhage, Altering uPAR Distribution, and Macrophage Invasion Guo, Qiuyun Yaron, Jordan R. Wallen, John W. Browder, Kyle F. Boyd, Ryan Olson, Tien L. Burgin, Michelle Ulrich, Peaches Aliskevich, Emily Schutz, Lauren N. Fromme, Petra Zhang, Liqiang Lucas, Alexandra R. Front Cardiovasc Med Cardiovascular Medicine 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. Serine protease inhibitors, 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. Frontiers Media S.A. 2021-02-16 /pmc/articles/PMC7921738/ /pubmed/33665212 http://dx.doi.org/10.3389/fcvm.2021.633212 Text en Copyright © 2021 Guo, Yaron, Wallen, Browder, Boyd, Olson, Burgin, Ulrich, Aliskevich, Schutz, Fromme, Zhang and Lucas. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cardiovascular Medicine
Guo, Qiuyun
Yaron, Jordan R.
Wallen, John W.
Browder, Kyle F.
Boyd, Ryan
Olson, Tien L.
Burgin, Michelle
Ulrich, Peaches
Aliskevich, Emily
Schutz, Lauren N.
Fromme, Petra
Zhang, Liqiang
Lucas, Alexandra R.
PEGylated Serp-1 Markedly Reduces Pristane-Induced Experimental Diffuse Alveolar Hemorrhage, Altering uPAR Distribution, and Macrophage Invasion
title PEGylated Serp-1 Markedly Reduces Pristane-Induced Experimental Diffuse Alveolar Hemorrhage, Altering uPAR Distribution, and Macrophage Invasion
title_full PEGylated Serp-1 Markedly Reduces Pristane-Induced Experimental Diffuse Alveolar Hemorrhage, Altering uPAR Distribution, and Macrophage Invasion
title_fullStr PEGylated Serp-1 Markedly Reduces Pristane-Induced Experimental Diffuse Alveolar Hemorrhage, Altering uPAR Distribution, and Macrophage Invasion
title_full_unstemmed PEGylated Serp-1 Markedly Reduces Pristane-Induced Experimental Diffuse Alveolar Hemorrhage, Altering uPAR Distribution, and Macrophage Invasion
title_short PEGylated Serp-1 Markedly Reduces Pristane-Induced Experimental Diffuse Alveolar Hemorrhage, Altering uPAR Distribution, and Macrophage Invasion
title_sort pegylated serp-1 markedly reduces pristane-induced experimental diffuse alveolar hemorrhage, altering upar distribution, and macrophage invasion
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921738/
https://www.ncbi.nlm.nih.gov/pubmed/33665212
http://dx.doi.org/10.3389/fcvm.2021.633212
work_keys_str_mv AT guoqiuyun pegylatedserp1markedlyreducespristaneinducedexperimentaldiffusealveolarhemorrhagealteringupardistributionandmacrophageinvasion
AT yaronjordanr pegylatedserp1markedlyreducespristaneinducedexperimentaldiffusealveolarhemorrhagealteringupardistributionandmacrophageinvasion
AT wallenjohnw pegylatedserp1markedlyreducespristaneinducedexperimentaldiffusealveolarhemorrhagealteringupardistributionandmacrophageinvasion
AT browderkylef pegylatedserp1markedlyreducespristaneinducedexperimentaldiffusealveolarhemorrhagealteringupardistributionandmacrophageinvasion
AT boydryan pegylatedserp1markedlyreducespristaneinducedexperimentaldiffusealveolarhemorrhagealteringupardistributionandmacrophageinvasion
AT olsontienl pegylatedserp1markedlyreducespristaneinducedexperimentaldiffusealveolarhemorrhagealteringupardistributionandmacrophageinvasion
AT burginmichelle pegylatedserp1markedlyreducespristaneinducedexperimentaldiffusealveolarhemorrhagealteringupardistributionandmacrophageinvasion
AT ulrichpeaches pegylatedserp1markedlyreducespristaneinducedexperimentaldiffusealveolarhemorrhagealteringupardistributionandmacrophageinvasion
AT aliskevichemily pegylatedserp1markedlyreducespristaneinducedexperimentaldiffusealveolarhemorrhagealteringupardistributionandmacrophageinvasion
AT schutzlaurenn pegylatedserp1markedlyreducespristaneinducedexperimentaldiffusealveolarhemorrhagealteringupardistributionandmacrophageinvasion
AT frommepetra pegylatedserp1markedlyreducespristaneinducedexperimentaldiffusealveolarhemorrhagealteringupardistributionandmacrophageinvasion
AT zhangliqiang pegylatedserp1markedlyreducespristaneinducedexperimentaldiffusealveolarhemorrhagealteringupardistributionandmacrophageinvasion
AT lucasalexandrar pegylatedserp1markedlyreducespristaneinducedexperimentaldiffusealveolarhemorrhagealteringupardistributionandmacrophageinvasion