Blood Substitutes and the Intestinal Microcirculation: Extravasation and Ultrastructural Alterations
Three necessary requirements for hemoglobin (Hb)-based blood substitutes are (i) that they remain in the circulation for an appropriate time period, (ii) that they do not alter the mechanisms of macromolecular exchange between blood and tissue, and (iii) that they do not cause tissue damage. A problem with hemoglobin-based blood substitutes is that they may leave the circulation and produce cytotoxic side effects. One vital organ which is particularly adversely affected during hemorrhagic shock is the intestine. Shock results in loss of gut mucosal integrity, allowing translocation of bacteria and endotoxins into the circulation, resulting in a systemic inflammatory response. The intestine is also important with respect to the immune system because the mucosa contains Peyer’s patches, or organized aggregates of lymphoid tissue in between the villi. Peyer’s patches play a key role in the initiation and expression of mucosal immunity. For these reasons we decided to focus on the intestine with respect to its responses to blood substitutes.
KeywordsIschemia Superoxide Selenium Histamine Bicarbonate
Polymers for delivering peptides and proteins. Am. J. Hosp. Pharm.
51: 210–218, 1994.PubMedGoogle Scholar
Chang, T.M.S., and C. Lister.
A preclinical screening test for modified hemoglobin to bridge the gap between safety studies and use in humans. Biomat., Artif Cells, Immobil. Biotech.
20: 565–573, 1992.Google Scholar
Comair, Y.G., H.M. Schipper, and S. Brem.
The prevention of oxyhemoglobin-induced endothelial and smooth muscle cytoskeletal injury by deferoxamine. Neurosurgery
32: 58–64, 1993.PubMedCrossRefGoogle Scholar
D’Agnillo, F., and T.M. Chang.
Cross-linked hemoglobin-superoxide dismutase-catalase scavenges oxygen-derived free-radicals and prevents methemoglobin formation and iron release. Biomat., Artif. Cells, Immobil. Biotech.
21(5): 609–621, 1993.Google Scholar
Deitch, E.A., W. Bridges, L. Ma, R. Berg, R.D. Specian, and D.N. Granger.
Hemorrhagic shock-induced bacterial translocation: the role of neutrophils and hydroxyl radicals. J.Trauma
30: 942–952, 1990.PubMedCrossRefGoogle Scholar
Feola, M., J. Simoni, M. Dobke, and P.C. Canizaro.
Complement activation and the toxicity of stroma-free hemoglobin solutions in primates. Circ. Shock
25: 275–290, 1988.PubMedGoogle Scholar
Giulivi, C., and K.J.A. Davies.
A novel antioxidant role for hemoglobin: the comproportionation of ferryl hemoglobin with oxyhemoglobin. J. Biol. Chem.
265: 19453–19460, 1990.PubMedGoogle Scholar
Granger, D.N., G. Rutili, and J.M. McCord.
Superoxide radicals in feline intestinal ischemia. Gastroenterology
81: 22–29, 1981.PubMedGoogle Scholar
Halliwell, B., and J.M.C. Gutteridge.
Oxygen free radicals and iron in relation to biology and medicine: some problems and concepts. Arch. Biochem. Biophys.
246: 501–514, 1986.PubMedCrossRefGoogle Scholar
Kaca, W., and R. Roth.
Activation of complement by human hemoglobin and by mixtures of hemoglobin and bacterial endotoxin. Biochim. Biophys. Acta.
1245: 49–56, 1995.PubMedCrossRefGoogle Scholar
Milici, A.J., and P.W. Bankston.
Fetal and neonatal rat intestinal capillaries: permeability to carbon, ferritin, hemoglobin, and myoglobin. Am. J. Anat.
165: 165–186, 1982.PubMedCrossRefGoogle Scholar
Misra, H.P., and I. Fridovich.
The generation of superoxide radical during the autoxidation of hemoglobin. J. Biol. Chem.
247: 6960–6962, 1972.PubMedGoogle Scholar
Moore, R., J. Madri, S. Carlson, and J.L. Madara.
Collagens facilitate epithelial migration in restitution of native guinea pig intestinal epithelium. Gastroenterology
102: 119–130, 1992.PubMedGoogle Scholar
Hemoglobin-and myoglobin-induced acute renal failure in rats: role of iron in nephrotoxicity. Am
. J. Physiol.
255(Renal Fluid Electrolyte Physiol. 24): F539–F544, 1988.Google Scholar
Seibert, A.F., A.E. Taylor, J.B. Bass, and J. Haynes, Jr.
, Hemoglobin potentiates oxidant injury in isolated rat lungs. Am
. J. Physiol.
260 (Heart Circ. Physiol. 29): H1980–H1984, 1991.PubMedGoogle Scholar
Simoni, J., G. Simoni, E.L. Garcia, S.D. Prien, R.M. Tran, M. Feola, and G.T. Shires.
Protective effect of selenium on hemoglobin mediated lipid peroxidation in vivo. Art. Cells
23: 469–486, 1995.Google Scholar
Smith, C.D., S.T. Schuschereba, J.R. Hess, L. McKinney, D. Bunch, and P.D. Bowman.
Liver and kidney injury after administration of hemoglobin cross-linked with bis(3,5-dibromosalicyl) fumarate. Biomat., Artif Cells, Artif Org.
18: 251–261, 1990.Google Scholar
Szebeni J., N.M. Wassef, H. Spielberg, A.S. Rudolph, and C.R. Alving.
Complement activation in rats by liposomes and liposome-encapsulated hemoglobin: evidence for anti-lipid antibodies and alternative pathways activation. Biochem. Biophys. Res. Comm.
205: 255–263, 1994.PubMedCrossRefGoogle Scholar
Weyer, R., B. Oudega, and B.F. Van Gelder.
Generation of superoxide radicals during the autoxidation of mammalian oxyhemoglobin. Biochem. Biophys. Acta.
302: 475–478, 1973.CrossRefGoogle Scholar
© Springer Science+Business Media New York 1997