دورية أكاديمية
Targeting complement component 5a promotes vascular integrity and limits airway remodeling.
| العنوان: | Targeting complement component 5a promotes vascular integrity and limits airway remodeling. |
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| المؤلفون: | Khan MA; Medical Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA., Maasch C, Vater A, Klussmann S, Morser J, Leung LL, Atkinson C, Tomlinson S, Heeger PS, Nicolls MR |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2013 Apr 09; Vol. 110 (15), pp. 6061-6. Date of Electronic Publication: 2013 Mar 25. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : National Academy of Sciences |
| مواضيع طبية MeSH: | Airway Remodeling* , Graft Rejection*, Complement C5a/*genetics , Thrombin/*metabolism, Animals ; Bronchiolitis Obliterans/diagnosis ; Complement C3/genetics ; Complement C5a/antagonists & inhibitors ; Fibrosis ; Hypoxia ; Immunosuppressive Agents/therapeutic use ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Microcirculation ; Oxygen/metabolism ; Perfusion ; Platelet Endothelial Cell Adhesion Molecule-1/metabolism ; Transplantation, Homologous |
| مستخلص: | Increased microvascular dilatation and permeability is observed during allograft rejection. Because vascular integrity is an important indicator of transplant health, we have sought to limit injury to blood vessels by blocking complement activation. Although complement component 3 (C3) inhibition is known to be vasculoprotective in transplantation studies, we recently demonstrated the paradoxical finding that, early in rejection, C3(-/-) transplant recipients actually exhibit worse microvascular injury than controls. In the genetic absence of C3, thrombin-mediated complement component 5 (C5) convertase activity leads to the generation of C5a (anaphylatoxin), a promoter of vasodilatation and permeability. In the current study, we demonstrated that microvessel thrombin deposition is significantly increased in C3(-/-) recipients during acute rejection. Thrombin colocalization with microvessels is closely associated with remarkably elevated plasma levels of C5a, vasodilatation, and increased vascular permeability. Administration of NOX-D19, a specific C5a inhibitor, to C3(-/-) recipients of airway transplants significantly improved tissue oxygenation, limited microvascular leakiness, and prevented airway ischemia, even in the absence of conventional T-cell-directed immunosuppression. As C3 inhibitors enter the clinics, the simultaneous targeting of this thrombin-mediated complement activation pathway and/or C5a itself may confer significant clinical benefit. |
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| معلومات مُعتمدة: | R01 HL095686 United States HL NHLBI NIH HHS; R01 AI071185 United States AI NIAID NIH HHS; P01 HL108797 United States HL NHLBI NIH HHS; I01 BX000509 United States BX BLRD VA; HL095686 United States HL NHLBI NIH HHS |
| المشرفين على المادة: | 0 (Complement C3) 0 (Immunosuppressive Agents) 0 (Platelet Endothelial Cell Adhesion Molecule-1) 80295-54-1 (Complement C5a) EC 3.4.21.5 (Thrombin) S88TT14065 (Oxygen) |
| تواريخ الأحداث: | Date Created: 20130327 Date Completed: 20130712 Latest Revision: 20211021 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC3625314 |
| DOI: | 10.1073/pnas.1217991110 |
| PMID: | 23530212 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1091-6490 |
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| DOI: | 10.1073/pnas.1217991110 |