Abstract
Abstract 2135
Circulating heme is scavenged by multiple plasma proteins and delivered to the liver for degradation. We have recently demonstrated that heme scavenging is variably impaired in transgenic mice with sickle cell disease (SCD). In this study, we tested the hypothesis that excess protein-free plasma heme (PFPH) in the blood circulation, and excess scavenged protein-bound plasma heme (PBPH) destined for degradation cause different types of organ damage in SCD. Transgenic mice expressing exclusively human sickle hemoglobin (SS) were intravenously injected with a dose of heme (25 micromoles/kg) to elevate PBPH only, or with a dose (70 micromoles/kg) sufficient to raise PFPH. In agreement with our previous findings, PFPH was associated with severe lung injury and 100% lethality within 2 hours. This phenomenon occurred independent of any liver involvement. Modest elevation of circulating heme sufficient to raise PBPH only, increased alanine aminotransferase and aspartate aminotranferase 3- to 4-fold (P<0.001) within 12 hours, caused 55% lethality by 72 hours, with severe liver damage but no lung involvement. There was no effect on lung and liver function in control AA and AS mice administered the same doses of heme given to the SS mice. Recombinant human hemopexin rescued SS mice from heme induced lung damage and sudden death, however, the same group of mice developed severe liver damage and succumbed 24–48 hours later. Finally, in a cohort of 27 patients with SCD, a sudden drop in hemoglobin of 0.5 to 4.0 g/dl was associated with a marked increase in ALT 3–7 days later (p=0.027). Collectively, these results show for the first time that acute elevation of circulating heme causes two distinct organ pathologies with different mortality profiles in SCD. Therapeutic strategies based solely on enhanced scavenging of excess heme may provide short-term pulmonary benefits with deleterious long-term effects on liver function.
Disclosures:
Ofori-Acquah: Emory University: Patents & Royalties.
Dietary supplementation with sulforaphane attenuates liver damage and heme overload in a sickle cell disease murine model