Targeting PAR1 biased signaling with parmodulin reduces thromboinflammation and acute lung injury in sickle cell disease
Year: 2026
Type: article
Abstract: ABSTRACT: Protease activated receptor 1 (PAR1) is expressed by numerous cell types, including endothelial cells. Thrombin cleaves PAR1 at Arg41 and activates proinflammatory and barrier disruptive signaling. Alternatively, PAR1 is cleaved at Arg46 by activated protein C (APC) that is bound to endothelial protein C receptor (ECPR), which induces anti-inflammatory and barrier protective signaling. In sickle cell disease (SCD), we showed that thrombin-PAR1 signaling contributes to vascular stasis and, more recently, that PAR1-R41-biased signaling enhances inflammation, whereas PAR1-R46 signaling reduces thrombo-inflammation. We hypothesized that ECPR-PAR1-R46-biased signaling protects sickle mice from thrombo-inflammation. To test this hypothesis, Townes sickle mice were treated with parmodulin (parmodulin 2 [PM2, aka ML161] or NRD-21) to promote protective, anti-inflammatory PAR1-biased signaling. We found that PM2 significantly attenuated thrombin generation, inflammation, and endothelial activation and protected sickle mice from a model of lethal acute chest syndrome. These results suggest that using PM2 to block thrombin-PAR1 signaling while inducing APC-like signaling can promote cytoprotective, anti-inflammatory effects in mouse models of SCD.
Source: Blood Advances
Institution: University of North Carolina at Chapel Hill
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
Funders: European High Performance Computing Joint Undertaking, Ministry of Health, Ontario, International Centre for Advanced Materials, National Science Foundation, Alfred P. Sloan Foundation, Gordon and Betty Moore Foundation, American Heart Association, Pfizer, Alexander von Humboldt-Stiftung, University of Michigan, Fondazione Cassa di Risparmio di Padova e Rovigo, University of Utah, Japan Agency for Medical Research and Development, Jürgen Manchot Stiftung, Comunidad de Madrid, UK Research and Innovation, MathWorks, Innovative Research Group Project of the National Natural Science Foundation of China, Japanese Society of Hematology, Universidad San Jorge, Royal Society of Chemistry, University College London, University of Oxford, European Commission, University of Edinburgh, University College Dublin, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Swedish Foundation for International Cooperation in Research and Higher Education, Danmarks Grundforskningsfond, National Natural Science Foundation of China, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Bundesministerium für Bildung und Forschung, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, University of Toronto, Conselho Nacional de Desenvolvimento Científico e Tecnológico, National Research Foundation of Korea, Magyar Tudományos Akadémia, Ministry of Agriculture, Forestry and Fisheries, Vetenskapsrådet, Thüringer Aufbaubank, Ministerio de Ciencia e Innovación, Shanghai Jiao Tong University, Fundação de Amparo à Pesquisa do Estado de Goiás, Alexander S. Onassis Public Benefit Foundation, Kungliga Fysiografiska Sällskapet i Lund, Einstein Stiftung Berlin, National Center for Geriatrics and Gerontology, Shanghai Hospital Development Center, Yunnan Provincial Science and Technology Department, Novo Nordisk Fonden, Gobierno de Aragón, Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, Shanghai Rising-Star Program, Ministry of Science and ICT, South Korea, Region Uppsala, Shanghai Clinical Research Center, Natural Science Foundation of Sichuan Province, Ruijin Hospital, Agencia Nacional de Investigación y Desarrollo, National Institutes of Health, Animal and Plant Health Inspection Service, Horizon 2020 Framework Programme, Center for High Performance Computing, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Science and Technology Facilities Council, Christ's College, University of Cambridge, Churchill College, University of Cambridge, Australian Research Council, National Health and Medical Research Council, Japan Society for the Promotion of Science, Consejo Superior de Investigaciones Científicas, School of Medicine, Shanghai Jiao Tong University, Agencia Estatal de Investigación, National Key Research and Development Program of China, Key Science and Technology Program of Shaanxi Province, Vicerrectoría de Investigación y Extensión, Universidad Industrial de Santander, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Fogarty International Center, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, National Institute of Child Health and Human Development, Division of Information and Intelligent Systems, Division of Chemistry, Division of Biological Infrastructure, National Center for Advancing Translational Sciences, Hydrogen and Fuel Cell Technologies Office, Fondo Nacional de Desarrollo Científico y Tecnológico, Fondo de Fomento al Desarrollo Científico y Tecnológico, H2020 European Research Council, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, Institute of Biomedicine, University of Turku, Ministry of Long-Term Care, North Carolina Policy Collaboratory, Intramural Research Program
OpenAlex ID: W7127356407