Alpha-1-microglobulin: Innate defence against pathological oxidation

Sammanfattning: Oxidative stress has been implicated as an important factor in the progression of many diseases. An imbalance in the redox-system may cause oxidation of cells and molecules, which might subsequently lead to tissue damage. The research presented in this thesis has focused on elucidating a possible involvement of the human protein alpha-1-microglobulin in the defence against pathological oxidation. alpha-1-microglobulin is a ubiquitous plasma and tissue protein mainly synthesized in the liver. It binds and degrades heme, is a radical scavenger and has reductase properties. Results in this thesis show that oxidatively challenged cells have the ability to up-regulate their alpha-1-microglobulin de novo synthesis, i.e. human hepatoma and blood cells can up-regulate both their mRNA expression and protein synthesis when exposed to hemoglobin, heme and reactive oxygen species. Furthermore, alpha-1-microglobulin was shown to exert potent cytoprotective properties against hemoglobin-, heme-, radiation- and reactive oxygen-induced oxidative stress. For instance, alpha-1-microglobulin could reduce cytosol oxidation and formation of molecular oxidation markers in hepatoma cells, blood cells and keratinocytes. Moreover, results show that alpha-1-microglobulin inhibits induction of cellular necrosis and apoptosis. Finally, hemoglobin, oxidation and alpha-1-microglobulin have been investigated in preeclampsia, a pregnancy-related disease. They were all shown to be elevated, and results suggest that hemoglobin contributes to the oxidative stress seen in preeclampsia. In conclusion, results presented in this thesis show, for the first time, that alpha-1-microglobulin is involved in the cellular defence against pathological oxidation caused by hemoglobin, heme, radiation and reactive oxygen species.