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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-04, Vol.110 (15), p.6061-6066
• Main Authors: Khan, Mohammad A., Maasch, Christian, Vater, Axel, Klussmann, Sven, Morser, John, Leung, Lawrence L., Atkinson, Carl, Tomlinson, Stephen, Heeger, Peter S., Nicolls, Mark R.
• Format: Article
• Language: English
• Subjects: Airway management; Airway Remodeling; Animals; Biological Sciences; Blood; Blood vessels; Bronchiolitis Obliterans - diagnosis; Collagens; Complement C3 - genetics; Complement C5a - antagonists & inhibitors; Complement C5a - genetics; Fibrosis; Graft Rejection; Homologous transplantation; Hypoxia; Immunology; Immunosuppressive Agents - therapeutic use; Ischemia; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Microcirculation; Microvessels; Oxygen - metabolism; Perfusion; Permeability; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Thrombin - metabolism; Tissue grafting; Tissue transplantation; Transplantation; Transplantation, Homologous; Transplants & implants
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1217991110

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.