The oxygen consumption and 02 production that occur during the respiratory burst are accounted for entirely by this reaction. H202 is produced by the reaction of O with itself, a dismutation in which one molecule of 02 is oxidized by the other20: Glucose oxidation through the HMP shunt accelerates because of an increase in the rate of production of NADP, the availability ofwhich limits the activity of the HMP shunt.2’ NADP production increases dur- ing the respiratory burst through the actions of (a) the 02-forming enzyme and (b) a glutathione-dependent system that uses NADPH to detoxify H202 by reduc- ing it to water22’23: 2 GSH + H2O2 p GSSG + 2 H20 glutathione peroxidase GSSG+NADPH . -‘2GSH+NADP glutathione reductase glucose-6-P dehydrogenase Each glucose that is metabolized via the HMP shunt reduces two molecules of NADP to NADPH, thus replenishing the supply of reducing agent necessary for the continued operation of the respiratory burst: Glucose-6-P + NADP 6-Phosphogluconate + NADPH -p Ribulose-5-P + CO2 + NADPH From the Blood Research Laboratory and the Department of Medicine. Tufts-New England Medical Center. Boston. Supported in part by US Public Health Service grant No. AJ-11827 and by grant No. I349from the Councilfor Tobacco Research-USA. Inc. Submitted March 26, 1984; accepted July 10, 1984. Address reprint requests to Dr Bernard M. Babior. Blood Research Laboratory, Department of Medicine. Tufts-New England Medical Center. Boston. MA 02/1/. in I 984 by Grune & Stratton. Inc. 0006-4971/84/6405--tX103/$03.0O/0 Blood, Vol 64, No 5 (November). 1984: pp 959-966 959 REVIEW Oxidants From Phagocytes: Agents of Defense and Destruction By Bernard M. Babior 0 F THE SYSTEMS that defend the host against invading microorganisms, the professional pha- gocytes (neutrophils, eosinophils, and mononuclear phagocytes) act in the most primitive fashion. Unlike cytotoxic lymphocytes and the complement system, which destroy their targets with a drop of poison,”2 the professional phagocytes kill like Attila the Hun, deploying a battery of weapons that lay waste to both the targets and the nearby landscape with the subtlety of an artillery barrage. Among the most powerful of these weapons is a group of oxidizing agents that are produced by the phagocytes when they encounter invading microorganisms or other appropriate stimuli. These oxidants are reactive enough to destroy most biologic molecules and are responsible for much of the damage inflicted by phagocytes on both microorga- nisms and surrounding tissues at sites of infection or inflammation. In this article, I briefly review the nature of these oxidants, their mode of production, and their biologic effects, both good and bad. THE REACTIVE OXIDANTS Reactive oxidants are produced from oxygen through a special metabolic pathway that, as far as is known, is unique to phagocytes. The consumption of oxygen through this pathway is initiated by the expo- sure of the cells to any one of a large number of stimuli, among the most effective of which are several that are likely to be present at sites of inflammation: opsonized microorganisms,3 the complement fragment C5a,4’5 leukotriene B4 (produced by stimulated phagocytes),6’7 and N-formylated oligopeptides of bacterial origin4’8 that are actively secreted or are released by lysis of dead organisms. Activation of the pathway occurs within a few seconds after stimulation9’1#{176}and is charac- terized by an abrupt increase in oxygen uptake together with the onset of production of a series of compounds formed from this oxygen: superoxide (Ok), hydrogen peroxide (H2O2), and a number of additional oxygen-containing compounds, all of which are highly reactive. In addition, there is a large increase in the oxidation of glucose via the hexosemonophosphate (HMP) shunt. These changes in oxidative metabolism are collectively known as the “respiratory burst,” a name derived from the sudden increase in oxygen uptake that is one of its invariable features.’ The biochemical basis for the respiratory burst is the activation of an enzyme, dormant in resting cells, that catalyzes the one-electron reduction of oxygen to 02 at the expense of NADPH9: 202 + NADPH-2O2 + NADP + H. 02 + 02 + 2 H - H202 + 02. Net: NADPH + H2O2 -‘ NADP + 2 H2O. 6-Phosphogluconate + NADP 6-phosphogluconate dehydrogenase For personal use only. on October 30, 2017. by guest www.bloodjournal.org From
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Transcript
The oxygen consumption and 02 production that
occur during the respiratory burst are accounted forentirely by this reaction. H202 is produced by the
reaction of O� with itself, a dismutation in which one
molecule of 02 is oxidized by the other20:
Glucose oxidation through the HMP shunt accelerates
because of an increase in the rate of production of
NADP�, the availability ofwhich limits the activity of
the HMP shunt.2’ NADP� production increases dur-ing the respiratory burst through the actions of (a) the
02-forming enzyme and (b) a glutathione-dependent
system that uses NADPH to detoxify H202 by reduc-
ing it to water22’23:
2 GSH + H2O2 p GSSG + 2 H20glutathioneperoxidase
GSSG+NADPH . -‘2GSH+NADPglutathione
reductase
glucose-6-P dehydrogenase
Each glucose that is metabolized via the HMP shuntreduces two molecules of NADP to NADPH, thus
replenishing the supply of reducing agent necessary for
the continued operation of the respiratory burst:
Glucose-6-P + NADP
6-Phosphogluconate
+ NADPH
-p Ribulose-5-P
+ CO2 + NADPH
From the Blood Research Laboratory and the Department of
Medicine. Tufts-New England Medical Center. Boston.
Supported in part by US Public Health Service grant No.
AJ-11827 and by grant No. I349from the Councilfor Tobacco
Research-USA. Inc.
Submitted March 26, 1984; accepted July 10, 1984.
Address reprint requests to Dr Bernard M. Babior. Blood
Research Laboratory, Department of Medicine. Tufts-New
England Medical Center. Boston. MA 02/1/.in I 984 by Grune & Stratton. Inc.
0006-4971/84/6405--tX103/$03.0O/0
Blood, Vol 64, No 5 (November). 1984: pp 959-966 959
REVIEW
Oxidants From Phagocytes: Agents of Defense and Destruction
By Bernard M. Babior
0 F THE SYSTEMS that defend the host against
invading microorganisms, the professional pha-
gocytes (neutrophils, eosinophils, and mononuclear
phagocytes) act in the most primitive fashion. Unlike
cytotoxic lymphocytes and the complement system,which destroy their targets with a drop of poison,”2 the
professional phagocytes kill like Attila the Hun,deploying a battery of weapons that lay waste to boththe targets and the nearby landscape with the subtlety
of an artillery barrage. Among the most powerful ofthese weapons is a group of oxidizing agents that are
produced by the phagocytes when they encounter
invading microorganisms or other appropriate stimuli.These oxidants are reactive enough to destroy most
biologic molecules and are responsible for much of thedamage inflicted by phagocytes on both microorga-
nisms and surrounding tissues at sites of infection or
inflammation. In this article, I briefly review thenature of these oxidants, their mode of production, andtheir biologic effects, both good and bad.
THE REACTIVE OXIDANTS
Reactive oxidants are produced from oxygen
through a special metabolic pathway that, as far as isknown, is unique to phagocytes. The consumption ofoxygen through this pathway is initiated by the expo-sure of the cells to any one of a large number of stimuli,
among the most effective of which are several that are
likely to be present at sites of inflammation: opsonizedmicroorganisms,3 the complement fragment C5a,4’5
leukotriene B4 (produced by stimulated phagocytes),6’7
and N-formylated oligopeptides of bacterial origin4’8that are actively secreted or are released by lysis of
dead organisms. Activation of the pathway occurs
within a few seconds after stimulation9’1#{176}and is charac-
terized by an abrupt increase in oxygen uptaketogether with the onset of production of a series ofcompounds formed from this oxygen: superoxide (Ok),
hydrogen peroxide (H2O2), and a number of additional
oxygen-containing compounds, all of which are highly
reactive. In addition, there is a large increase in the
oxidation of glucose via the hexosemonophosphate
(HMP) shunt. These changes in oxidative metabolism
are collectively known as the “respiratory burst,” a
name derived from the sudden increase in oxygenuptake that is one of its invariable features.’
The biochemical basis for the respiratory burst is the
activation of an enzyme, dormant in resting cells, that
catalyzes the one-electron reduction of oxygen to 02 at
the expense of NADPH�9:
202 + NADPH-�2O2 + NADP� + H�.
02 + 02 + 2 H� -� H202 + 02.
Net: NADPH + H2O2 -‘ NADP + 2 H2O.
6-Phosphogluconate + NADP
6-phosphogluconate dehydrogenase
For personal use only.on October 30, 2017. by guest www.bloodjournal.orgFrom
Of-forming oxidase, because from this location the
enzyme is able to deliver oxidants onto the target with
maximum efficiency.The phagocyte is also susceptible to damage by
these reactive oxidants, so attacks by at least some
kinds of phagocytes (for example, neutrophils) are
kamikaze assaults in which the attacker dies along
with the target. However, phagocytes are able to
defend themselves against their oxidants, at least to alimited extent. The antioxidant systems of the phago-
cytes include superoxide dismutase,87 which converts
Oi to oxygen and H2O2; catalase88 and the gluta-thione-dependent H2O2-detoxifying system referred to
above, both of which reduce H2O2 to water; taurine,89which may detoxify HOC1 (see above); and assorted
other antioxidants, such as a-tocopherol�#{176} and ascorbic
acid.9’ These may not preserve the life of the activated
phagocyte forever, but they permit it to survive long
enough to fire a lethal volley of oxidants at its target.Work has recently begun on the biochemical lesions
inflicted on living systems by the lethal oxidants of
phagocytes. HOC1, recognized for some time as a
highly potent microbicidal agent, has been shown to
oxidize -SH groups to disulfides and higher sulfuroxides,92’93 to convert thioethers to sulfoxides,94 and to
oxidize amino compounds to chloramines and dichlor-amines95 (see above). Halogenation of pyridine nucleo-
tides has been demonstrated,96 as has the destruction of
the biologic activity of nucleotides such as adenosine
triphosphate (ATP).97 In addition, HOC1 has been
shown to inactivate certain redox enzymes, including
heme-containing enzymes and iron-sulfur proteins, but
not flavoproteins.97 The inactivation of iron-sulfur pro-
teins is a particularly rapid reaction. The hydroxyl
radical (OH) as an isolated oxidant of biologic sys-
tems has not been studied nearly as thoroughly, butimportant information as to its effects can be inferred
from the extensive work that has been carried out withionizing radiation, most of the biologic actions ofwhich are mediated through OH. Particularly impor-
tant in this regard are studies that have been carried
out on the effects of ionizing radiation on DNA. Thesestudies have shown oxidative alterations of bases,
perhaps the most characteristic of which is the oxida-
tion of thymine to dihydrothymine glycol,98 as well as
the introduction of strand breaks in the DNA chain,some resulting from the action of excision repair
enzymes� and some caused by direct damage to thedeoxyribose moieties ofthe DNA chain.’#{176}#{176}Despite this
mass of information, the identity of the lesion(s)
immediately responsible for the death of an organism
attacked by these lethal oxidants has not yet beenestablished. My own guess is that the fatal lesion willultimately be shown to involve the membrane of the
microorganism under attack and will result in a loss of
permselectivity such that the organism is no longer
able to control its internal environment. If this shouldprove correct, tHen the mechanism of killing by oxi-dants will be similar to the mechanism of complement-
mediated killing, at least in the most general sense.
Though the phagocyte seems to be designed to
restrict oxidant production to the smallest possible
region (there is evidence, for example, that the O�-
forming oxidase is activated only in that region ofmembrane that is in contact with the target),’#{176}’ some
of the reactive oxidants inevitably leak into the sur-
rounding tissues, where they have the capacity toinflict considerable damage. The organ where this
damage has been best documented is the lung, in which
phagocyte-generated oxidants have been implicated in
the pathogenesis of both acute and chronic disease.Acutely, these oxidants may be responsible for much of
the alveolar damage and pulmonary edema seen in the
adult respiratory distress syndrome (ARDS; shocklung). One explanation for the pathogenesis of shock
lung involves a train of events in which the release of
the complement-derived anaphyllatoxin C5a into the
blood stream causes neutrophils to aggregate and to
begin producing O� ; these Of-generating neutrophil
aggregates become trapped in the lungs, where the
liberated oxidants destroy the pulmonary capillary
endothelium, permitting plasma to exude into the
alveoli.’#{176}2’#{176}5This explanation is supported by animal
and organ perfusion models of shock lung in which the
pulmonary damage induced by the inciting agent is
prevented if the neutrophils in the model system are
unable to manufacture reactive oxidants or are elimi-
nated entirely.’#{176}�”#{176}7Furthermore, recent studies in
patients with ARDS have provided unequivocal cvi-
dence for the release of oxidants into the pulmonarytissues of affected individuals, but not normal con-
trols.’#{176}�On the other hand, the foregoing train ofevents cannot be the only route to ARDS, because thiscondition can occur in patients with neutropenias so
severe that pathogenetically significant neutrophil
aggregates probably cannot be formed.A role for phagocyte-generated oxidants has also
been proposed in the pathogenesis of chronic lungdisease. In this condition, neutrophils accumulate in
lungs subjected to chronic irritation, drawn there per-
haps by a chemotactic factor released by alveolar
macrophages that have been activated by the irri-
tant.’#{176}�The following sequence of events is then postu-
lated to take place. The neutrophils in the lungs
become activated to generate reactive oxidants and torelease the contents of their granules into the extracel-
lular environment. Among these contents is elastase, a
powerful protease that is able, among other things, to
For personal use only.on October 30, 2017. by guest www.bloodjournal.orgFrom
burger PE: Chronic granulomatous disease due to granulocytes with
abnormal NADPH oxidase activity and deficient cytochrome-b.
Blood6l:423, 1983
82. Segal AW, Cross AR, Garcia RC, Borregaard N, Valerius
NH, Soothill iF, iones OTG: Absence of cytochrome b245 in
chronic granulomatous disease. A multicenter European evaluation
of its incidence and relevance. N EngI i Med 308:245, 1983
83. Gabig TG: The NADPH-dependent Of-generating oxidasefrom human neutrophils. Identification of a flavoprotein componentthat is deficient in a patient with chronic granulomatous disease. iBiol Chem 258:6352, 1983
84. Gabig TG: Deficient flavoprotein component of the NADPH-
dependent 01-generating oxidase in the neutrophils from three malepatients with chronic granulomatous disease. i Clin Invest 73:701,
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85. Mills EL, Quie P0: Inheritance of chronic granulomatous
disease. Adv Host Defense Mech 3:55, 1983
86. Mills EL, Rholl KS, Quie P0: X-linked inheritance in
females with chronic granulomatous disease. i Clin Invest 66:332,
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87. Salin ML, McCord iM: Superoxide dismutase in polymor-
phonuclear leukocytes. i Clin Invest. 54:1005, 1974
Oxygen radicals mediate endothelial cell damage by complement-
stimulated granulocytes: An in vitro model of immune vascular
damage. i Clin Invest 61:1 161, 1978
106. Shasby DM, Vanbenthuysen KM. Tate RM, Shasby SS,
McMurtry I, Repine JE: Granulocytes mediate acute edematouslung injury in rabbits and in isolated rabbit lungs perfused withphorbol myristate acetate: Role of oxygen radicals. Am Rev Respir
Dis 125:443, 1982
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the edema ofacute hyperoxic lung injury by granulocyte depletion. iAppl Physiol 52:1237, 1982
108. Merritt TA, Cochrane CG, Holcomb K, Bohl B, Hallman
M, Stranger D, Edwards KD, Gluche L: Elastase and a,-proteinase
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BM Babior Oxidants from phagocytes: agents of defense and destruction
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