Oxygen radicals in ulcerative colitis

doi:10.1016/0891-5849(92)90079-V

Free Radical Biology and Medicine

Volume 13, Issue 2, August 1992, Pages 169-181

https://doi.org/10.1016/0891-5849(92)90079-V Get rights and content

Abstract

This article reviews the pathophysiologic concept that superoxide and hydrogen peroxide, generated by activated leukocytes, together with low-molecular-weight chelate iron derived from fecal sources and from denatured hemoglobin, amplify the inflammotory response and subsequent mucosal damage in patients with active episodes of ulcerative colitis. The putative pathogenic mechanisms reviewed are as follows: (1) Dietary iron is concentrated in fecal material owing to normally limited iron absorption. (2) Mucosal bleeding, characteristic of ulcerative colitis, as well as supplemental oral iron therapy for chronic anemia, further conspire to maintain or elevate mucosal iron concentration in colitis. (3) Fenton chemistry, driven especially by leukocyte-generated superoxide and hydrogen peroxide, leads to formation of hydroxyl radicals. (4) The resultant oxidative stress leads to the extension and propagation of crypt abscesses, either through direct membrane disruption by lipid peroxidation or through generation of secondary toxic oxidants such as chloramines. (5) Chemotactic products of lipid peroxidation, including 4-hydroxynonenal, provide positive feedback to accelerate this inflammatory/oxidative process, leading to acute exacerbations of the disease. (6) Other oxidized products, such as oxidized tryptophan metabolites, created by free radical mechanisms in or near the mucosa, may act as carcinogens or tumor promotors that contribute to the exceedingly high incidence of colon carcinoma in patients suffering from chronic ulcerative colitis. In this way, self-sustaining cycles of oxidant formation may amplify flare-ups of inflammation and mucosal injury in ulcerative colitis. This concept, if proved correct by subsequent research, would provide a rationale for several novel clinical approaches to the management of ulcerative colitis, including use of SOD mimetics, iron chelators, and chain-breaking antioxidants.

References (88)

S.D. Aust et al.
The role of iron in enzymatic lipid peroxidation
L.J. Marnett et al.
Prostaglandin synthetase dependent activation of 7,8-dihydro-7,8-dihydroxy-benzo(A)pyrene to mutagenic derivatives
Biochem. Biophys. Res. Commun.
(1978)
C.F. Babbs
Hypothesis paper: Free radicals and the etiology of colon cancer
Free Rad. Biol. Med.
(1990)
S.J. Weiss
The role of superoxide in the destruction of erythrocyte targets by human neutrophils
J. Biol. Chem.
(1980)
J.R. Bucher et al.
The requirement for ferric in the initiation of lipid peroxidation by chelated ferrous iron
Biochem. Biophys. Res. Commun.
(1983)
E.L. Thomas et al.
Evidence for a role of taurine in the in vitro oxidative toxicity of neutrophils toward erythrocytes
J. Biol. Chem.
(1985)
M.B. Grisham et al.
Chlorination of endogenous amines by isolated neutrophils
J. Biol. Chem.
(1984)
M. Markert et al.
Measurement of superoxide production by human neutrophils. The preparation and assay of NADPH oxidase-containing particles from human neutrophils
Meth. Enzymology
(1984)
M.C.M. Vissers et al.
Neutrophils adherent to a nonphagocytosable surface (glomerular basement membrane) produce oxidants only at the site of attachment
Blood
(1985)
D.A. Parks et al.
Ischemic injury in the cat small intestine, role of superoxide radicals
Gasteroenterology
(1982)

S.M. Smith et al.

Gastric mucosal injury in the rat-role of iron and xanthine oxidase

Gastroenterology

(1987)

I. Fridovich

Quantitative aspects of the production of superoxide anion radical by milk xanthine oxidase

J. Biol. Chem.

(1970)

H.M. Hassan et al.

Paraquat and Escherichia coli: Mechanism of production of extracellular superoxide radical

J. Biol. Chem.

(1979)

J.M. McCord et al.

Superoxide dismutase: An enzymic function for erythrocuprein (hemocuprein)

J. Biol. Chem.

(1969)

G.S. Krause et al.

Cardiac arrest and resuscitation: Brain iron delocalization during reperfusion

Ann. Emerg. Med.

(1985)

S. Holt et al.

Myocardial tissue iron delocalization and evidence for lipid peroxidation after two hours of isichemia

Ann. Emerg. Med.

(1986)

S.C. Salaris et al.

The effect of oxygen concentration on the formation of malondialdehyde-like material in a model of tissue ischemia and reoxygenation

Free Rad. Biol. Med.

(1989)

J.M.C. Gutteridge et al.

Iron-dependent free radical damage to DNA and deoxyribose. Separation of TBA-reactive intermediates

Int. J. Biochem.

(1982)

J. Emerit et al.

Phase II trial of coper zinc superoxide dismutase (CuZn SOD) in the treatment of crohn's disease

Free Rad. Biol. Med.

(1989)

H. Esterbauer et al.

Chemistry and biochemistry of 4-hydroxynonenal, malondialdehyde and related aldehydes

Free Rad. Biol. Med.

(1991)

C.F. Babbs et al.

Simulation of free radical reactions in biology and medicine: A new two-compartment kinetic model of intracellular lipid peroxidation

Free Rad. Biol. Med.

(1990)

Y.S. Kim et al.

Ulcerative colitis: A specific mucin defect?

Gastroenterology

(1984)

M. Katrantzis et al.

The oxidant hypochlorite (OCI⁻), a product of the myeloperoxidase system, degrades articular cartilage proteoglycan aggregate

Free Rad. Biol. Med.

(1991)

M.A. Peppercorn et al.

Distribution studies of salicylosulfapyridine and its metabolites

Gastroenterology

(1973)

C.F. Babbs et al.

Scatchard analysis of methane sulfinic acid production from dimethyl sulfoxide: A method to quantify hydroxyl radical formation in physiologic systems

Free Rad. Biol. Med.

(1989)

M.B. Grisham

Effect of 5-aminosalicylic acid on ferrous sulfate-mediated damage to deoxyribose

Biochem. Pharmacol.

(1990)

R.S. Cotran et al.

Robbins pathologic basis of disease

J.C. Houston et al.

F. Shanahan et al.

Inflammatory bowel disease

J.V. Carbone et al.

Alimentary tract & liver

J.M. Richter

Management of inflammatory bowel disease

J.B. Smith et al.

Quantitative effects of iron chelators on hydroxyl radical production by the superoxide-driven Fenton reaction

Free Rad. Res. Commun.

(1990)

W.S. Caughey et al.

Oxy radical and peroxide formation by hemoglobin

M.B. Grisham et al.

Neutrophil-mediated mucosal injury—role of reactive oxygen metabolites

Diges. Dis. Sciences

(1988)

H. Esterbauer et al.

Hydroxyalkenals: Cytotoxic products of lipid peroxidation

ISI Atlas of Science—BioChemistry

(1988)

M. Curzio et al.

Chemotactic activity of the lipid peroxidation product 4-hydroxynonenal and homologous hydroxyalkenals

Biol. Chem. Hoppe Seyler

(1986)

S.D. Aust et al.

Evidence for the initiation of lipid peroxidation by a ferrous-dioxygen-ferric chelate complex

M.B. Grisham et al.

Effects of neutrophil-derived oxidants on intestinal permeability, electrolyte transport, and epithelial cell viability

Inflammation

(1990)

J.C. Fantone et al.

Role of oxygen derived free radicals and metabolites in leukocyte dependent inflammatory reactions

Am. J. Path.

(1982)

B.D. Davis et al.

Microbiology

(1980)

E. Graf et al.

Dietary suppression of colonic cancer—fiber or phytate?

Cancer

(1985)

E. Cavalieri et al.

Multiple mechanisms of activation in aromatic hydrocarbon carcinogenesis

C. Nagata et al.

T.A. Dix et al.

Metabolism of polycyclic aromatic hydrocarbon derivatives to ultimate carcinogens during lipid perioxidation

Science

(1983)

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Hypothesis paperOxygen radicals in ulcerative colitis

Abstract

Biochem. Biophys. Res. Commun.

Free Rad. Biol. Med.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Meth. Enzymology

Blood

Gasteroenterology

Gastroenterology

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Ann. Emerg. Med.

Ann. Emerg. Med.

Free Rad. Biol. Med.

Int. J. Biochem.

Free Rad. Biol. Med.

Free Rad. Biol. Med.

Free Rad. Biol. Med.

Gastroenterology

Free Rad. Biol. Med.

Gastroenterology

Free Rad. Biol. Med.

Biochem. Pharmacol.

Robbins pathologic basis of disease

Inflammatory bowel disease

Alimentary tract & liver

Management of inflammatory bowel disease

Quantitative effects of iron chelators on hydroxyl radical production by the superoxide-driven Fenton reaction

Free Rad. Res. Commun.

Oxy radical and peroxide formation by hemoglobin

Neutrophil-mediated mucosal injury—role of reactive oxygen metabolites

Diges. Dis. Sciences

Hydroxyalkenals: Cytotoxic products of lipid peroxidation

ISI Atlas of Science—BioChemistry

Chemotactic activity of the lipid peroxidation product 4-hydroxynonenal and homologous hydroxyalkenals

Biol. Chem. Hoppe Seyler

Evidence for the initiation of lipid peroxidation by a ferrous-dioxygen-ferric chelate complex

Effects of neutrophil-derived oxidants on intestinal permeability, electrolyte transport, and epithelial cell viability

Inflammation

Role of oxygen derived free radicals and metabolites in leukocyte dependent inflammatory reactions

Am. J. Path.

Microbiology

Dietary suppression of colonic cancer—fiber or phytate?

Cancer

Multiple mechanisms of activation in aromatic hydrocarbon carcinogenesis

Metabolism of polycyclic aromatic hydrocarbon derivatives to ultimate carcinogens during lipid perioxidation

Science

Hypothesis paper
Oxygen radicals in ulcerative colitis