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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Song, Wen-Chao Sato, Sayaka Gullipalli, Damodar Miwa, Takashi Nangaku, Masaomi |
| Description | Country affiliation: United States Author Affiliation: Miwa T ( Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.) |
| Abstract | Complement is implicated in the pathogenesis of ischemia-reperfusion injury (IRI). The activation pathway(s) and effector(s) of complement in IRI may be organ specific and remain to be fully characterized. We previously developed a renal IRI model in decay-accelerating factor (DAF) and CD59 double-knockout (DAF(-/-)CD59(-/-)) mice. In this study, we used this model to dissect the pathway(s) by which complement is activated in renal IRI and to evaluate whether C3aR- or C5aR-mediated inflammation or the membrane attack complex was pathogenic. We crossed DAF(-/-)CD59(-/-) mice with mice deficient in various complement components or receptors including C3, C4, factor B (fB), factor properdin (fP), mannose-binding lectin, C3aR, C5aR, or Ig and assessed renal IRI in the resulting mutant strains. We found that deletion of C3, fB, fP, C3aR, or C5aR significantly ameliorated renal IRI in DAF(-/-)CD59(-/-) mice, whereas deficiency of C4, Ig, or mannose-binding lectin had no effect. Treatment of DAF(-/-)CD59(-/-) mice with an anti-C5 mAb reduced renal IRI to a greater degree than did C5aR deficiency. We also generated and tested a function-blocking anti-mouse fP mAb and showed it to ameliorate renal IRI when given to DAF(-/-)CD59(-/-) mice 24 h before, but not 4 or 8 h after, ischemia/reperfusion. These results suggest that complement is activated via the alternative pathway during the early phase of reperfusion, and both anaphylatoxin-mediated inflammation and the membrane attack complex contribute to tissue injury. Further, they demonstrate a critical role for properdin and support its therapeutic targeting in renal IRI. |
| ISSN | 00221767 |
| e-ISSN | 15506606 |
| DOI | 10.4049/jimmunol.1202275 |
| Journal | The Journal of Immunology |
| Issue Number | 7 |
| Volume Number | 190 |
| Language | English |
| Publisher | The American Association of Immunologists |
| Publisher Date | 2013-04-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Antigens, Cd55 Genetics Antigens, Cd59 Kidney Blood Supply Properdin Antagonists & Inhibitors Receptor, Anaphylatoxin C5a Reperfusion Injury Immunology Animals Antibodies, Monoclonal Pharmacology Complement C3 Deficiency Complement C3 Convertase, Alternative Pathway Complement Factor B Disease Models, Animal Pathology Mice Mice, Knockout Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Discipline Immunology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Immunology and Allergy Immunology |
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