title: 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.
authors.affiliation: Medical Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Khan
authors.forename: Christian
authors.initials: C
authors.lastname: Maasch
authors.forename: Axel
authors.initials: A
authors.lastname: Vater
authors.forename: Sven
authors.initials: S
authors.lastname: Klussmann
authors.forename: John
authors.initials: J
authors.lastname: Morser
authors.forename: Lawrence L
authors.initials: LL
authors.lastname: Leung
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
authors.forename: Peter S
authors.initials: PS
authors.lastname: Heeger
authors.forename: Mark R
authors.initials: MR
authors.lastname: Nicolls
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D001989:Bronchiolitis Obliterans / Q000175:diagnosis; D003176:Complement C3 / Q000235:genetics; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000235:genetics*; D005355:Fibrosis; D006084:Graft Rejection; D000860:Hypoxia; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation; D010100:Oxygen / Q000378:metabolism; D010477:Perfusion; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*; D014184:Transplantation, Homologous
chemical_list: D003176:Complement C3; D007166:Immunosuppressive Agents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D015936:Complement C5a; D013917:Thrombin; D010100:Oxygen