Hypoxia-induced complement dysregulation is associated with microvascular impairments in mouse tracheal transplants

Complement Regulatory Proteins (CRPs), especially CD55 primarily negate complement factor 3-mediated injuries and maintain tissue homeostasis during complement cascade activation. Complement activation and regulation during alloimmune inflammation contribute to allograft injury and therefore we proposed to investigate a crucial pathological link between vascular expression of CD55, active-C3, T cell immunity and associated microvascular tissue injuries during allograft rejection.

Balb/c→C57BL/6 allografts were examined for microvascular deposition of CD55, C3d, T cells, and associated tissue microvascular impairments during rejection in mouse orthotopic tracheal transplantation.

Our findings demonstrated that hypoxia-induced early activation of HIF-1α favors a cell-mediated inflammation (CD4⁺, CD8⁺, and associated proinflammatory cytokines, IL-2 and TNF-α), which proportionally triggers the downregulation of CRP-CD55, and thereby augments the uncontrolled release of active-C3, and Caspase-3 deposition on CD31⁺ graft vascular endothelial cells. These molecular changes are pathologically associated with microvascular deterioration (low tissue O₂ and Blood flow) and subsequent airway epithelial injuries of rejecting allografts as compared to non-rejecting syngrafts.

Together, these findings establish a pathological correlation between complement dysregulation, T cell immunity, and microvascular associated injuries during alloimmune inflammation in transplantation.