The DAMP Awakens: The Role of Heme and Heme Oxygenase-1 in Organ Transplantation

Ischemia-reperfusion injury (IRI) determines early and delayed graft function and long-term allograft survival in solid organ transplantation and is one determinant of outcome that remains modifiable in the operating room. Cell-free heme, a Danger-Associated Molecular Pattern (DAMP), is liberated from hemoproteins as a result of IRI, and overwhelms the haptoglobin, hemopexin scavenging systems. As such, it then intercalates into cell membranes, drives Fenton chemistry, and acts as a DAMP that engages TLR4/MD2, precipitating cell death. Heme also triggers its own clearance through NRF2 and BACH1, which regulate expression of heme oxygenase-1 (HO-1, Hmox1), that degrades heme into the bioactive molecules, carbon monoxide (CO), biliverdin and ferrous iron. CO modulates inflammation, inhibits cell death pathways and preserves the microcirculation. Biliverdin and bilirubin act as potent antioxidants, and ferritin sequesters labile, highly reactive iron. The role of heme and HO-1 has been well-studied in models of kidney transplantation where HO-1 induction and, independently, exogenous CO treatment have been shown to attenuate transplant-induced IRI and chronic rejection. Importantly, human HO-1 is a critical component of the multi-transgenic donor pig organs that are being tested in ongoing clinical trials. This review discusses the current state of HO-1 in transplantation, including mechanisms of action, preclinical modeling, and clinical applications.