Physiology in medicinePhagocytes and oxidative stress☆
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A short history of oxidants and phagocytes
The role of phagocytes in host defense was discovered late in the nineteenth century by Elie Metchnikoff (1), who noted that these cells crowded around sharp thorns with which he had pierced transparent starfish larvae. Metchnikoff concluded that these “wandering cells,” as he called them, were somehow involved in defending the starfish larvae against the damage inflicted by the thorns. The following 50 years saw a protracted war between those who said that host defense was the responsibility
The enzymes
Phagocytes manufacture a stupendous battery of reactive oxidants that they use for the destruction of invading microorganisms. These oxidants are generated by four enzymes: NADPH oxidase, superoxide dismutase, nitric oxide synthase, and myeloperoxidase (in the case of eosinophils, eosinophil peroxidase).
The oxidants
The actions of the enzymes described above give rise to four products: O2−, H2O2, NO, and HOCl. All the myriad oxidants produced by phagocytes arise from nonenzymatic reactions involving those four compounds (Figure 3).
Emphysema
Neutrophils contain three neutral proteases, cathepsin G, elastase, and proteinase 3, which reside in their azurophil granules. They are called neutral proteases because, unlike lysosomal proteases, which are most active in acidic environments, these proteases operate best at neutral pH, that is, the pH of normal tissues. These proteases are employed chiefly to degrade substances that neutrophils have ingested, but because the contents of azurophil granules are sometimes released into the
Conclusion
It is clear from the foregoing that reactive oxidizing species produced from phagocytes are important in the pathogenesis of many conditions. It may be that the development of drugs to antagonize these oxidizing species can prevent at least some of the damage inflicted on tissues by these very reactive agents. (Figure 8)
References (108)
- et al.
The biochemical basis of phagocytosis. I. Metabolic changes during the ingestion of particles by polymorphonuclear leukocytes
J Biol Chem
(1959) NADPH oxidasean update
Blood
(1999)- et al.
Molecular basis of chronic granulomatous disease
Blood
(1991) - et al.
Superoxide dismutase. An enzymic function for erythrocuprein
J Biol Chem
(1969) - et al.
Leukemia inhibitory factor and tumor necrosis factor induce manganese superoxide dismutase and protect rabbit hearts from reperfusion injury
J Mol Cell Cardiol
(1995) Nitric oxide synthaseaspects concerning structure and catalysis
Cell
(1994)Regulation of cytosolic guanylyl cyclase by nitric oxidethe NO-cyclic GMP signal transduction system
Adv Pharmacol
(1994)- et al.
Purification of the inducible murine macrophage nitric oxide synthase
J Biol Chem
(1991) - et al.
Human mononuclear phagocyte inducible nitric oxide synthase (iNOS)analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages
Blood
(1995) - et al.
Inside the neutrophil phagosomeoxidants, myeloperoxidase, and bacterial killing
Blood
(1998)
Structure of the green heme in myeloperoxidase
Arch Biochem Biophys
Eosinophils preferentially use bromide to generate halogenating agents
J Biol Chem
Thiocyanate is the major substrate for eosinophil peroxidase in physiologic fluids. Implications for cytotoxicity
J Biol Chem
Iron and free radical reactionstwo aspects of antioxidant protection
Trends Biochem Sci
Chlorination of endogenous amines by isolated neutrophils. Ammonia-dependent bactericidal, cytotoxic, and cytolytic activities of the chloramines
J Biol Chem
Antioxidant role and subcellular location of hypotaurine and taurine in human neutrophils
Biochim Biophys Acta Gen Subj
Superoxide-dependent hydroxylation by myeloperoxidase
J Biol Chem
Intracellular singlet oxygen generation by phagocytosing neutrophils in response to particles coated with a chemical trap
J Biol Chem
Peroxynitrite reaction with carbon dioxide/bicarbonatekinetics and influence on peroxynitrite-mediated oxidations
Arch Biochem Biophys
Formation of nitrating and chlorinating species by reaction of nitrite with hypochlorous acid. A novel mechanism for nitric oxide-mediated protein modification
J Biol Chem
Myeloperoxidase-catalyzed inactivation of alpha 1-protease inhibitor by human neutrophils
J Biol Chem
Low density lipoprotein oxidation and its pathobiological significance
J Biol Chem
Oxidative modification of low-density lipoprotein by human polymorphonuclear leucocytes to a form recognised by the lipoprotein scavenger pathway
Biochim Biophys Acta Lipids Lipid Metab
Human macrophage metabolism of low density lipoprotein oxidized by stimulated neutrophils and ferritin
Atherosclerosis
Mechanisms of myocardial reperfusion injury
Ann Thorac Surg
The effects of calcium channel antagonist treatment and oxygen radical scavenging on infarct size and the no-reflow phenomenon in reperfused hearts
Am Heart J
Role of selectins in myocardial ischemia-reperfusion injury
Ann Thorac Surg
Role of the b2-integrins and immunoglobulin superfamily members in myocardial ischemia-reperfusion
Ann Thorac Surg
Evidence for nitric oxide-mediated oxidative damage in chronic inflammation. Nitrotyrosine in serum and synovial fluid from rheumatoid patients
FEBS Lett
The extra respiration of phagocytosis
Am J Physiol
Biochemical aspects of phagocytosis
Nature
A peroxidase-mediated antimicrobial system in leukocytes
J Clin Invest
Biological defense mechanismsthe production by leukocytes of superoxide, a potential bactericidal agent
J Clin Invest
Purified cytochrome b from human granulocyte plasma membrane is comprised of two polypeptides with relative molecular weights of 91,000 and 22,000
J Clin Invest
Regulation of phagocyte oxygen radical production by the GTP-binding protein Rac 2
Science
Identification of a highly mobilizable subset of human neutrophil intracellular vesicles that contains tetranectin and latent alkaline phosphatase
J Clin Invest
Neutrophil nicotinamide adenine dinucleotide phosphate oxidase assembly. Translocation of p47-phox and p67-phox requires interaction between p47-phox and cytochrome b558
J Clin Invest
Identification of intracellular sites of superoxide production in stimulated neutrophils
J Cell Sci
Superoxide radical and superoxide dismutases
Annu Rev Biochem
Antioxidant enzyme expression in rat lungs during hyperoxia
Am J Physiol Lung Cell Mol Physiol
Reexamination of the mechanism of hydroxyl radical adducts formed from the reaction between familial amyotrophic lateral sclerosis-associated Cu,Zn superoxide dismutase mutants and H2O2
Proc Natl Acad Sci U S A
Macrophage microbicidal mechanisms in vivoreactive nitrogen versus oxygen intermediates in the killing of intracellular visceral Leishmania donovani
J Exp Med
Reaction of myeloperoxidase compound I with chloride, bromide, iodide, and thiocyanate
Biochemistry
Myeloperoxidase (MPO) gene mutation in hereditary MPO deficiency
Blood
Leukocyte myeloperoxidase deficiency and disseminated candidasisthe role of myeloperoxidase in resistance to Candida infection
J Clin Invest
Clinical manifestation of myeloperoxidase deficiency
J Mol Med
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