Inhibition of the lectin pathway of complement activation reduces LPS-induced acute respiratory distress syndrome in mice
Acute respiratory distress syndrome (ARDS) is a life-threatening disorder with a high rate of mortality. Complement activation in ARDS initiates a robust inflammatory reaction that can cause progressive endothelial injury in the lung. Here, we tested whether inhibition of the lectin pathway of compl...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-05-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1192767/full |
| _version_ | 1797816674657763328 |
|---|---|
| author | Youssif M. Ali Youssif M. Ali Nicholas J. Lynch Ahmed A. Shaaban Dina E. Rizk Shaymaa H. Abdel-Rahman Priyanka Khatri Munehisa Yabuki Sadam Yaseen Thomas Dudler Gregory Demopulos Wilhelm J. Schwaeble |
| author_facet | Youssif M. Ali Youssif M. Ali Nicholas J. Lynch Ahmed A. Shaaban Dina E. Rizk Shaymaa H. Abdel-Rahman Priyanka Khatri Munehisa Yabuki Sadam Yaseen Thomas Dudler Gregory Demopulos Wilhelm J. Schwaeble |
| author_sort | Youssif M. Ali |
| collection | DOAJ |
| description | Acute respiratory distress syndrome (ARDS) is a life-threatening disorder with a high rate of mortality. Complement activation in ARDS initiates a robust inflammatory reaction that can cause progressive endothelial injury in the lung. Here, we tested whether inhibition of the lectin pathway of complement could reduce the pathology and improve the outcomes in a murine model of LPS-induced lung injury that closely mimics ARDS in human. In vitro, LPS binds to murine and human collectin 11, human MBL and murine MBL-A, but not to C1q, the recognition subcomponent of the classical pathway. This binding initiates deposition of the complement activation products C3b, C4b and C5b-9 on LPS via the lectin pathway. HG-4, a monoclonal antibody that targets MASP-2, a key enzyme in the lectin pathway, inhibited lectin pathway functional activity in vitro, with an IC50 of circa 10nM. Administration of HG4 (5mg/kg) in mice led to almost complete inhibition of the lectin pathway activation for 48hrs, and 50% inhibition at 60hrs post administration. Inhibition of the lectin pathway in mice prior to LPS-induced lung injury improved all pathological markers tested. HG4 reduces the protein concentration in bronchoalveolar lavage fluid (p<0.0001) and levels of myeloid peroxide (p<0.0001), LDH (p<0.0001), TNFα and IL6 (both p<0.0001). Lung injury was significantly reduced (p<0.001) and the survival time of the mice increased (p<0.01). From the previous findings we concluded that inhibition of the lectin pathway has the potential to prevent ARDS pathology. |
| first_indexed | 2024-03-13T08:41:11Z |
| format | Article |
| id | doaj.art-892bed69f9b0470381a042c2abcca0b3 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-13T08:41:11Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-892bed69f9b0470381a042c2abcca0b32023-05-30T10:46:33ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-05-011410.3389/fimmu.2023.11927671192767Inhibition of the lectin pathway of complement activation reduces LPS-induced acute respiratory distress syndrome in miceYoussif M. Ali0Youssif M. Ali1Nicholas J. Lynch2Ahmed A. Shaaban3Dina E. Rizk4Shaymaa H. Abdel-Rahman5Priyanka Khatri6Munehisa Yabuki7Sadam Yaseen8Thomas Dudler9Gregory Demopulos10Wilhelm J. Schwaeble11Department of Veterinary Medicine, School of Biological Sciences, University of Cambridge, Cambridge, United KingdomDepartment of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, EgyptDepartment of Veterinary Medicine, School of Biological Sciences, University of Cambridge, Cambridge, United KingdomDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, EgyptDepartment of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, EgyptDepartment of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, EgyptDepartment of Veterinary Medicine, School of Biological Sciences, University of Cambridge, Cambridge, United KingdomOmeros Corporation, Seattle, WA, United StatesOmeros Corporation, Seattle, WA, United StatesOmeros Corporation, Seattle, WA, United StatesOmeros Corporation, Seattle, WA, United StatesDepartment of Veterinary Medicine, School of Biological Sciences, University of Cambridge, Cambridge, United KingdomAcute respiratory distress syndrome (ARDS) is a life-threatening disorder with a high rate of mortality. Complement activation in ARDS initiates a robust inflammatory reaction that can cause progressive endothelial injury in the lung. Here, we tested whether inhibition of the lectin pathway of complement could reduce the pathology and improve the outcomes in a murine model of LPS-induced lung injury that closely mimics ARDS in human. In vitro, LPS binds to murine and human collectin 11, human MBL and murine MBL-A, but not to C1q, the recognition subcomponent of the classical pathway. This binding initiates deposition of the complement activation products C3b, C4b and C5b-9 on LPS via the lectin pathway. HG-4, a monoclonal antibody that targets MASP-2, a key enzyme in the lectin pathway, inhibited lectin pathway functional activity in vitro, with an IC50 of circa 10nM. Administration of HG4 (5mg/kg) in mice led to almost complete inhibition of the lectin pathway activation for 48hrs, and 50% inhibition at 60hrs post administration. Inhibition of the lectin pathway in mice prior to LPS-induced lung injury improved all pathological markers tested. HG4 reduces the protein concentration in bronchoalveolar lavage fluid (p<0.0001) and levels of myeloid peroxide (p<0.0001), LDH (p<0.0001), TNFα and IL6 (both p<0.0001). Lung injury was significantly reduced (p<0.001) and the survival time of the mice increased (p<0.01). From the previous findings we concluded that inhibition of the lectin pathway has the potential to prevent ARDS pathology.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1192767/fullARDSlectin pathwaylung injurycomplement therapeuticsLPS |
| spellingShingle | Youssif M. Ali Youssif M. Ali Nicholas J. Lynch Ahmed A. Shaaban Dina E. Rizk Shaymaa H. Abdel-Rahman Priyanka Khatri Munehisa Yabuki Sadam Yaseen Thomas Dudler Gregory Demopulos Wilhelm J. Schwaeble Inhibition of the lectin pathway of complement activation reduces LPS-induced acute respiratory distress syndrome in mice Frontiers in Immunology ARDS lectin pathway lung injury complement therapeutics LPS |
| title | Inhibition of the lectin pathway of complement activation reduces LPS-induced acute respiratory distress syndrome in mice |
| title_full | Inhibition of the lectin pathway of complement activation reduces LPS-induced acute respiratory distress syndrome in mice |
| title_fullStr | Inhibition of the lectin pathway of complement activation reduces LPS-induced acute respiratory distress syndrome in mice |
| title_full_unstemmed | Inhibition of the lectin pathway of complement activation reduces LPS-induced acute respiratory distress syndrome in mice |
| title_short | Inhibition of the lectin pathway of complement activation reduces LPS-induced acute respiratory distress syndrome in mice |
| title_sort | inhibition of the lectin pathway of complement activation reduces lps induced acute respiratory distress syndrome in mice |
| topic | ARDS lectin pathway lung injury complement therapeutics LPS |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1192767/full |
| work_keys_str_mv | AT youssifmali inhibitionofthelectinpathwayofcomplementactivationreduceslpsinducedacuterespiratorydistresssyndromeinmice AT youssifmali inhibitionofthelectinpathwayofcomplementactivationreduceslpsinducedacuterespiratorydistresssyndromeinmice AT nicholasjlynch inhibitionofthelectinpathwayofcomplementactivationreduceslpsinducedacuterespiratorydistresssyndromeinmice AT ahmedashaaban inhibitionofthelectinpathwayofcomplementactivationreduceslpsinducedacuterespiratorydistresssyndromeinmice AT dinaerizk inhibitionofthelectinpathwayofcomplementactivationreduceslpsinducedacuterespiratorydistresssyndromeinmice AT shaymaahabdelrahman inhibitionofthelectinpathwayofcomplementactivationreduceslpsinducedacuterespiratorydistresssyndromeinmice AT priyankakhatri inhibitionofthelectinpathwayofcomplementactivationreduceslpsinducedacuterespiratorydistresssyndromeinmice AT munehisayabuki inhibitionofthelectinpathwayofcomplementactivationreduceslpsinducedacuterespiratorydistresssyndromeinmice AT sadamyaseen inhibitionofthelectinpathwayofcomplementactivationreduceslpsinducedacuterespiratorydistresssyndromeinmice AT thomasdudler inhibitionofthelectinpathwayofcomplementactivationreduceslpsinducedacuterespiratorydistresssyndromeinmice AT gregorydemopulos inhibitionofthelectinpathwayofcomplementactivationreduceslpsinducedacuterespiratorydistresssyndromeinmice AT wilhelmjschwaeble inhibitionofthelectinpathwayofcomplementactivationreduceslpsinducedacuterespiratorydistresssyndromeinmice |