Scientific Publications by FDA Staff
Antioxid Redox Signal 2008 Aug;10(8):1449-62
Structural stabilization in tetrameric or polymeric hemoglobin determines its interaction with endogenous antioxidant scavenger pathways.
Buehler PW, Vallelian F, Mikolajczyk MG, Schoedon G, Schweizer T, Alayash AI, Schaer DJ
Schaer, DJ (reprint author), Univ Hosp, Med Clin Res Unit, CH-8091 Zurich, Switzerland US FDA, CBER, Div Hematol, Lab Biochem & Vasc Biol, Rockville, MD USA ETH, Dept Mat, Zurich, Switzerland Univ Zurich, Med Clin Res Unit, CH-8006 Zurich, Switzerland
Hemoglobin (Hb) released into the circulation during hemolysis and chemically modified Hb proposed for use as oxygen therapeutics exert toxic effects that are partially attributable to heme's oxidant activity. Native extracellular Hb is scavenged by haptoglobin (Hp) after alphabeta-subunit dimerization. In the absence of Hp, monocyte/macrophage cell-surface CD163 binds and clears Hb. We evaluated several chemically modified Hbs to establish the role of chemical cross-linking patterns and molecular sizes on binding and clearance by each pathway. We found that Hbs possessing beta-globin cross-linking, irrespective of polymerization, demonstrate increased Hp affinity compared with alpha-globin-stabilized Hbs. These data suggest that Hb alpha-subunit accessibility is critical for Hp binding in the absence of dimerization. beta-Globin chain cross-linked tetramers/polymers displayed strong polyvalent Hp binding with increased viscosity and formation of visible gel matrices. Modified Hb interaction with CD163 and cellular uptake demonstrated an inverse relation with molecular size, irrespective of alpha and beta cross-linking. These findings were confirmed by HO-1 induction and intracellular ferritin accumulation in CD163-expressing HEK293 cells. Based on these results, a rational and systematic approach to HBOC design may be used to optimize interaction with endogenous Hb clearance and detoxification pathways.
|Category: Journal Article|
|PubMed ID: #18522492|
|Includes FDA Authors from Scientific Area(s): Biologics|
|Entry Created: 2011-10-04||Entry Last Modified: 2012-08-29|