Hemoglobin-based oxygen carrier induces heme oxygenase-1 in the heart and lung but not brain.
BACKGROUND
The clinical sequel of ischemia and reperfusion remains a challenge in several clinical areas. Overexpression of heme oxygenase-1 (HO-1), using viral vectors, endotoxemia, and hypoxia, provides protection against ischemia and reperfusion injury. To date, however, no clinically viable therapy exists to safely induce HO-1. We have recently observed that administration of a hemoglobin-based oxygen carrier (HBOC) attenuates postinjury systemic inflammation. We have further demonstrated that an HBOC can induce HO-1 in vitro. We now explore the tissue-specific induction of heme oxygenase-1 after administration of an HBOC.


METHODS
Rats were infused with doses of HBOC or saline through femoral vein injection (n=5 per group). Animals were sacrificed and organs were flushed. Heart, lung, and brain samples were taken for evaluation of total organ levels of HO-1 induction and for histologic localization of the cellular expression of the HO-1. Heat shock protein 72 levels were also analyzed to determine whether HO-1 induction was a generalized stress response.


RESULTS
Both the heart and lung demonstrated a dose-dependent induction of total organ HO-1. Interestingly, brain tissue did not have any significant amount of HO-1, either at baseline or after HBOC therapy. The cellular localization of HO-1 between organs was also specific, predominantly occurring in the cardiac myocyte and alveolar macrophages. Heat shock protein 72 levels were not significantly changed in any group examined, suggesting the induction of HO-1 is specific.


CONCLUSIONS
This study demonstrates that a clinically accessible product, HBOC, can specifically and selectively induce the expression of the protective enzyme HO-1 in vivo. These findings begin to characterize which organ systems may benefit by preischemic treatments with HBOC and further expand potential clinical applications of HBOCs.
Damle
Sagar S
SS
Department of Surgery, University of Colorado at Denver and Health Sciences Center, Denver, CO 80204, USA.
Moore
Ernest E
EE
Babu
Ashok N
AN
Meng
Xianzhong
X
Fullerton
David A
DA
Banerjee
Anirban
A
D000818:Animals; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006454:Hemoglobins / Q000008:administration & dosage / Q000494:pharmacology*; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008168:Lung / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley
D006454:Hemoglobins; C509893:PolyHeme; D051547:Heme Oxygenase-1