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Targeting complement component 5a promotes vascular integrity and limits airway remodeling.

ABSTRACT: 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.

SUBMITTER: Khan MA

PROVIDER: S-EPMC3625314 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Targeting complement component 5a promotes vascular integrity and limits airway remodeling.

Khan Mohammad A MA Maasch Christian C Vater Axel A Klussmann Sven S Morser John J Leung Lawrence L LL Atkinson Carl C Tomlinson Stephen S Heeger Peter S PS Nicolls Mark R MR

Proceedings of the National Academy of Sciences of the United States of America 20130325 15

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 ...[more]

PMID: 23530212

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Targeting complement component 5a promotes vascular integrity and limits airway remodeling.

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Targeting complement component 5a promotes vascular integrity and limits airway remodeling.

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