All ETDs from UAB

Advisory Committee Chair

James F George

Advisory Committee Members

Sumanth D Prabhu

Roger C White

Louis B Justement

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in the catabolism of heme, which is released by necrotic cells in injured tissue. HO-1 expression is protective in cardiac and renal injury because it coordinates the degradation of pro-oxidant heme with the generation of equimolar quantities of iron (Fe2+) and the cytoprotective mole-cules carbon monoxide and biliverdin. While many studies have demonstrated that HO-1 expression is protective in numerous disease states, relatively few have examined the specific cellular compartment(s) through which HO-1 expression confers its protective effects. Our objective was to define the cellular compartments in which HO-1 expression is critical to protect against injury to the heart and kidney and to determine the cellular mechanisms by which HO-1 protects these cells, thus suppressing the formation of sig-nals that activate the immune response after tissue injury. We hypothesized that HO-1 expression in the tissue parenchyma is important in protecting cells from injury-induced death, thus preserving the structural and functional properties of the heart and kidney af-ter injury. We also hypothesized that HO-1 expression within myeloid cells of the innate immune system is critical in regulating their function, differentiation, and trafficking after injury to the tissue parenchyma. HO-1 expression protects cells within the heart and kid-ney from necrotic cell death after injury. This function was critical in limiting the infiltra-tion of neutrophils, a myeloid cell lineage known to propagate injury within a damaged organ. In addition, we found that cell-autonomous HO-1 expression in macrophages and dendritic cells regulates their ability to produce inflammatory cytokines and to traffic to the peripheral lymphoid organs after AKI. This effect of HO-1 on myeloid cells plays an important role in recovery from AKI. In addition, we demonstrated that HO-1 expression mediates its protective properties in cardiomyocytes through regulation of mitochondrial dynamics and mitophagy in doxorubicin-induced cardiac toxicity. Thus, HO-1 expression is a promising therapeutic target in cardiac and renal disease states because it prevents injury to the organ parenchyma, thus directly and indirectly regulating the ensuing in-flammatory response to injury.