Asthma Research Group, Father Sean O'Sullivan Research Center, St. Joseph's Hospital, and Department of Medicine, McMaster University, Hamilton, Ontario L8N 4A6, Canada
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ABSTRACT |
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Isoprostanes are produced during peroxidation of membrane lipids by free radicals and reactive oxygen species. Initially, they were recognized as being valuable markers of oxidative stress, and in the past 10 years, dozens of disease states and experimental conditions with diverse etiologies have been shown to be associated with marked increases in urinary, plasma, and tissue levels of isoprostanes. However, they are not just mere markers; they evoke important biological responses on virtually every cell type found within the lung, and these responses exhibit compound-, tissue-, and species-related variations. In fact, the isoprostanes may mediate many of the features of the disease states for which they are used as indicators. In this review, I describe the chemistry, metabolism, and pharmacology of isoprostanes, with a particular emphasis on pulmonary cell types, and the possible roles of isoprostanes in pulmonary pathophysiology.
oxidative stress; arachidonic acid; lipid peroxidation; inflammation; smooth muscle; endothelium; platelet
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INTRODUCTION |
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JUST OVER A DECADE AGO, Morrow et al.
(106) first described the nonenzymatic production of a
series of prostaglandin-like compounds during peroxidation of membrane
phospholipids by free radicals and reactive oxygen species. Since that
seminal discovery, many studies have pointed out the usefulness of
these compounds, particularly 8-iso-PGF2, as
markers of oxidative stress under many different clinical and
experimental conditions (reviewed in Refs. 59,
112, 144). Concurrently, others began
to show that they also evoke important biological responses, first in vascular smooth muscle and platelets and then in many other cell types
(see CELLULAR ACTIONS). From these two avenues of
investigation, a large and rapidly growing literature has developed,
beginning in 1992 with the first three papers by Morrow and colleagues
(102, 103, 106) to use the term "isoprostane" in
referring to these compounds and growing exponentially ever since (see
Fig. 1). In response to this outpouring
of data, there have been a number of reviews of the existing literature
(112, 144); however, these have emphasized particularly
the chemistry of the isoprostanes (e.g., their structure, genesis,
nomenclature, and detection), with relatively less discussion about
their biological actions. I (59) have previously
reviewed some of the biological effects of isoprostanes on smooth
muscle. However, since the writing of that review, the literature has
doubled again (Fig. 1), and it is now known that isoprostanes have
effects on virtually every cell type found in the lungs; moreover,
there have been some important new advances in our understanding of the
signaling pathways by which isoprostanes act. In this review, I collate
these data and bring them to bear particularly on pulmonary physiology
and pathophysiology.
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PRODUCTS OF LIPID PEROXIDATION |
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For detailed descriptions of isoprostane chemistry (e.g., their
generation and nomenclature), the reader is directed to those earlier
reviews written by Morrow and Roberts (112) and Rokach et
al. (144). Briefly, though, oxygen-centered
radicals such as peroxide and superoxide can react with the unsaturated
bonds of arachidonic acid, leading to the formation of as many as four different bicycloendoperoxide intermediates differing in whether the
peroxide group has been added to C-6/C-8, to C-9/C-11, or to C-12/C-14
(Fig. 2). Reduction of the
intermediates leads to four different classes of isoprostane
regioisomers, all composed of a cyclopentane ring with two alkyl chains
cis to one another (Fig. 2). The prostanoids, on the other
hand, have the two side chains trans to one another (Fig.
3).
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In addition to its well-described role in the production of
prostanoids, cyclooxygenase (COX) can also contribute to
isoprostane production in vascular smooth muscle (68,
69), endothelium (167), platelets (74, 127,
132-134), monocytes (125, 129, 131), macrophages (149, 160), and mesangial cells
(74). However, it is not entirely clear whether the
isoprostanes are direct products of COX or arise secondarily to an
"overflow" of COX-derived reactive oxygen species. Some recent data
(167) suggest the latter may be the case;
8-iso-PGF2 production in endothelial cells
was shown to be COX dependent (in that it could be inhibited by
indomethacin or aspirin) and also sensitive to catalase but not to
superoxide dismutase, suggesting that hydrogen peroxide
(H2O2) originating from COX was responsible.
Reactive nitrogen species may also participate in the production of
isoprostanes. For example, nitric oxide (NO; on its own a weak
oxidizing agent) reacts with superoxide to produce peroxynitrite (ONOO), a highly reactive and cytotoxic molecule
(136). Exposure of myelin suspensions (162),
low-density lipoproteins (101), or human plasma
(101) to peroxynitrite leads to lipid peroxidation and
generation of isoprostanes; this effect is not mimicked by NO or
superoxide alone (162). BN-80933 (a new neuroprotective compound combining potent antioxidant and selective neuronal NO synthase inhibitory actions) significantly reduced
8-iso-PGF2
levels in a rat model of cerebral
ischemia-reperfusion injury (87); however, a
follow-up study indicated that this effect of BN-80933 might be due
more to its antioxidant properties than to its ability to inhibit NO
synthesis (30). N-nitro-L-arginine methyl ester (a NO synthase inhibitor) greatly inhibited
cytokine-induced production of 8-iso-PGF2
from pulmonary artery smooth muscle (69); this effect did
not involve modulation of COX activity by NO because cytokine-induced
release of PGE2 from these cells was unaffected.
Polyunsaturated fatty acids other than arachidonic acid are also
vulnerable to reactive oxygen species and produce isoprostanes. For
example, in addition to the four classes of F2-isoprostanes that can arise from arachidonic acid (eicosatetraenoic acid), peroxidation of eicosapentaenoic acid is predicted to lead to the
generation of six classes of F3-isoprostanes (117,
144), -linolenic and
-linolenic acids to two classes of
E1- and F1-isoprostanes, respectively
(13, 123), and docosahexaenoic acid to eight classes of
D4-isoprostanes and eight classes of
E4-isoprostanes (140) (Fig. 2). Each of these
classes comprise up to eight racemic isomers, leading to an astounding
number of isoprostane molecules!
Although dozens (hundreds?) of different isoprostane molecules can be
produced by such free radical-mediated peroxidation, the group of
isoprostane molecules most commonly referred to in the literature are
those in which peroxidation occurs at C-9/C-11 of arachidonic acid,
producing the family of 8-isoprostanes. Moreover, the particular member
of this family that is by far the most prominent in the literature is
8-iso-PGF2 (Fig. 3). However, there is now
evidence that D- and E-ring isoprostane species can also be produced in
vivo and can accumulate to levels only slightly less than those of
8-iso-PGF2
(i.e., 1-2 orders of
magnitude higher than circulating levels of prostaglandins) (82,
105, 107, 108, 112, 113, 140). Also, like their PGD2
and PGE2 cousins, dehydration of D- and E-ring isoprostanes
in vitro and in vivo has produced A2- or
J2-isoprostanes (17, 18). The widely differing
pharmacological actions of some of these isoprostanes are only just
beginning to be understood (see CELLULAR ACTIONS).
The bicyclic endoperoxide intermediates that give rise to the isoprostanes can also rearrange to form other highly reactive molecules such as the isolevuglandins (12, 145) and isothromboxanes (104, 144), and isoleukotrienes have also been identified (48), but these are not discussed in this review.
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MARKERS OF OXIDATIVE STRESS |
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For many reasons, isoprostanes are very well suited as biochemical
markers of oxidative stress. First, they can be measured accurately
down to picomolar levels (9, 152, 166) with analytic techniques such as HPLC (8), gas chromatography-mass
spectrometry (1, 45, 108, 111, 133, 143, 144, 152), or
radioimmunoassay (15, 166). The former two techniques are
supremely able to discriminate between the different types of
isoprostanes but require extensive preparation of the material (e.g.,
phospholipid extraction, alkaline hydrolysis) and expensive
instrumentation (111). Radioimmunoassays are somewhat
easier to perform and are widely commercially available; however, many
of these are not able (or have not yet been shown to be able) to
distinguish between the prostanoids and the isoprostanes, let alone
between the different types of isoprostanes. One group (15) has described a radioimmunoassay that uses a
monoclonal antibody directed against
8-iso-PGF2 conjugated to BSA; this assay
exhibits a detection limit of 23 pmol/l, with very low cross-reactivity ratios of ~10:1 for 8-iso-PGF2
, 100:1 for
PGF2
, 8-iso-PGF3
, and
8-iso-15-keto-13,14-dihydro-PGF2
, and
10,000:1 for 8-iso-15-keto-PGF2
and
15-keto-13,14-dihydro-PGF2
. It is even possible to use isoprostanes to assess oxidative stress or damage in specific target
organs of interest (e.g., via biopsy); for example, in carbon
tetrachloride-induced hepatoxicity, isoprostanes were markedly elevated
in the liver, lung, and kidney but not in the brain or heart
(103).
Second, they are stable in isolated samples of body fluids; their presence was first detected in fresh and stored samples of plasma and urine (3, 106) and then more recently in cerebrospinal (46), pericardial (86), and bronchoalveolar (43, 98) fluids. A particularly exciting recent development has been the demonstration that they can be detected in breath condensates (15, 100), providing an exceedingly noninvasive route for their measurement.
Third, and most importantly, their measured values do not exhibit diurnal variations (53, 166) but do vary markedly in clinical and experimental conditions characterized by oxidative stress, and these values closely parallel disease severity.
In this way, a long list of respiratory-related pathologies has come to
be associated with isoprostanes. 8-iso-PGF2
is generated in substantial amounts in otherwise "normal"
individuals exposed to cigarette smoke (19, 28, 105, 127,
141), allergen (32, 99), ozone (50),
or hyperoxia (160, 161) and during ventilated
ischemia (11) and is markedly elevated in patients with a wide variety of lung diseases such as asthma (32, 35, 97), chronic obstructive pulmonary disease (128),
interstitial lung disease (98), cystic fibrosis (23,
100), acute lung injury including acute respiratory distress
syndrome (15), and severe respiratory failure in
infants (43).
Similarly, a number of cardiovascular conditions feature marked elevations in isoprostane levels, including renal (158), cerebral (87), and myocardial (29, 94, 142) ischemia-reperfusion injury; unstable angina (21); heart failure (86); coronary heart disease (90); acute ischemic stroke (163); hypercholesterolemia (26); atherosclerosis (131, 135); and preeclampsia (5, 156). Isoprostane levels are increased in pulmonary hypertension (20) and during exposure to agents that are associated with hypertension, such as subpressor doses of angiotensin II (47, 116, 139), inflammatory mediators (68, 69), and growth factors (116).
Finally, 8-iso-PGF2 has been found to be a
useful marker of oxidative damage and lipid peroxidation in disease
states as diverse as Alzheimer's disease (96), multiple
sclerosis (46), diabetes mellitus (27, 45),
systemic lupus erythematosus (58), and several hepatic
pathologies (10, 103, 110, 130) as well as in experimental
settings ranging from humans in space flight (157) to sled
dogs during endurance exercise training (55)!
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STORAGE, RELEASE, AND METABOLISM |
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Although the synthesis of prostanoids by COX first requires that arachidonic acid be liberated from the plasma membrane by phospholipases (22, 115), this is not necessarily true for the production of isoprostanes by free radicals; there is now good reason to believe that the latter can act on free fatty acids as well as on those still esterified to membrane phospholipids (102).
For example, isoprostanes have been identified within phospholipids extracted from surgical specimens of lung (11), atherosclerotic vasculature (119, 131, 135), lymphatics (118), brain (140), and preeclamptic decidua basalis (156). Levels of free and esterified isoprostanes in plasma from smokers remain significantly elevated above baseline for weeks after cessation of smoking, even though other markers of smoking such as urinary nicotine and cotinine become undetectable (105, 141). In carbon tetrachloride-induced hepatotoxicity (103), isoprostanes begin to accumulate almost immediately in phospholipids extracted from the liver (and to some extent in the lungs and kidney) and shortly thereafter in the circulation; the latter reach a peak at 4 h (77-fold) and remain markedly elevated above baseline at 24 (21-fold) and 48 (10-fold) h, indicating prolonged oxidative stress and/or on-going release of esterified isoprostanes. The presence of the isoprostanes within the membrane is expected to have profound effects on membrane fluidity as discussed in MEDIATORS OF PULMONARY PATHOPHYSIOLOGY? Membrane properties.
Isoprostanes esterified in the membrane may then be released at some later time by phospholipases (144) because they are suitable substrates for bee venom phospholipase A2 (102, 108), and phospholipase A2 inhibitors (mepacrine) partially reduce growth factor-induced isoprostane release in cultured cells (116).
Once isoprostanes are generated and released into the circulation, they
appear to be quickly metabolized and eliminated. In one study done in
the rabbit (8), it was shown that a bolus injection of
8-iso-PGF2 was rapidly distributed in the
circulation, with a half-life of distribution of ~1 min, and then was
rapidly eliminated, with a half-life of ~4 min. Using HPLC, they went on to show that 8-iso-PGF2
was degraded to
several
-oxidized metabolites, culminating in formation of
-tetranor-15-keto-13,14-dihydro-8-iso-PGF2
. It was hypothesized that the metabolism of this isoprostane followed a
sequential pathway similar to that ascertained for prostaglandins, involving 1) oxidation of C-15 by 15-hydroxyprostaglandin
dehydrogenase and 2) reduction of the C-13,14 double bond by
13-reductase followed by 3)
-oxidation to
-tetranor-15-keto-13,14-dihydro-8-iso-PGF2
. The parent 8-iso-PGF2
and its metabolites
began to accumulate in the urine within 20 min; 80% of the original
radioactive label was present in the urine by 4 h. These findings
parallel closely those made in an earlier study (143)
using a single human volunteer and a rhesus monkey; 75% of the
original radioactivity was found in the urine 4.5 h after infusion
of the parent compound, with the primary metabolite being
2,3-dinor-5,6-dihydro-PGF2
. A more recent study done by
another group (19) showed that the metabolites also
include 2,3-dinor-PGF2
in humans and
2,3,4,5-tetranor-5,6-dihydro-PGF2
in rats.
Other more chemically reactive isoeicosanoids such as the A2-isoprostanes (18) and isolevuglandins (12) covalently adduct to proteins and are therefore protected from rapid clearance via the kidney.
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CELLULAR ACTIONS |
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Although there is an abundant literature pertaining to isoprostanes as markers of oxidative stress, we are only just now beginning to appreciate the wide variety of actions that the isoprostanes exert on the function of many different cell types. Thus isoprostanes should be considered not just "markers" but perhaps also as "mediators" of disease (see MEDIATORS OF PULMONARY PATHOPHYSIOLOGY?). However, the current literature describing the effects of isoprostanes is woefully inadequate at this time.
First, almost all the studies to date have focused on
8-iso-PGF2 despite the growing awareness that
hundreds of isoprostane species can potentially exist, and evidence for
the in vivo generation of some of these is now in hand (see
PRODUCTS OF LIPID PEROXIDATION). Thus this fixation on
8-iso-PGF2
is distracting and detrimental; consider the results if the bulk of our understanding of
prostanoid pharmacology came from studies of prostacyclin alone [or
thromboxane (Tx) A2 alone or some other single eicosanoid]
and the effects of the other prostanoids were extrapolated from them.
Comparisons of the effects of 8-iso-PGF2
and
8-iso-PGE2 in a given tissue often reveal
important differences; 8-iso-PGE2 evokes an
electrophysiological response in epithelial cells (33),
relaxation in canine airway smooth muscle (62),
biochemical responses in calcifying vascular cells (124),
and altered sensory neuronal function (34), whereas 8-iso-PGF2
is ineffective in all these
respects. Only a handful of studies (62, 63, 79, 121, 146)
have been done with isoprostanes other than
8-iso-PGF2
and
8-iso-PGE2; these, too, describe important
differences between the isoprostanes. For example, in platelets
pretreated with SQ-29548 to eliminate confounding effects via
TxA2 (TP) receptors, eight different isoprostanes were
tested and only 8-iso-PGE2 markedly increased
cAMP accumulation (83). These marked differences in
pharmacology between nearly identical chemical species attest to a
highly discriminative mechanism, such as the involvement of specific
membrane receptors, rather than to nonspecific effects, such as altered
membrane fluidity (see Classic prostanoid receptors or unique
isoprostane receptors? and Membrane properties).
Second, most of the existing pharmacological data were obtained in
rodents, primarily the rat. Relatively few studies have been done with
human tissues (25, 62, 71, 118, 121, 154), and there is
strong evidence for species-related differences in the responses to
isoprostanes: 1) in contrast to the airways in other
species, those in the rabbit (54) and dog
(62) do not constrict in response to
8-iso-PGE2 or
8-iso-PGF2; 2) rat pulmonary
arteries exhibit a relaxant response to
8-iso-PGF2
(67), in contrast to
the vasoconstriction seen in other species; and 3)
8-iso-PGE2 constricts porcine and bovine but not
ovine coronary arteries (76).
Third, the majority of the literature pertains to the effects of isoprostane on vascular smooth muscle and platelets; their effects on other cell types are only just now beginning to be understood.
Clearly, then, there is currently a very limited understanding of the physiological effects of these autacoids!
Classic prostanoid receptors or unique isoprostane receptors?
PGs were the first group of arachidonic acid metabolites to be
identified and characterized in detail. There is now an extensive literature for these compounds that is not reviewed here; for this, the
reader is referred elsewhere (22, 115). Briefly, however,
there are five major prostanoid receptor types, termed D-prostanoid
(DP), E-prostanoid (EP), F-prostanoid (FP), I-prostanoid (IP), and TP
receptors that are each approximately an order of magnitude more
selective for either PGD2, PGE2,
PGF2, PGI2, or TxA2,
respectively (22, 115). The EP receptors can be further subclassified into four subtypes and the TP receptors into two subtypes
(22, 115).
Vascular smooth muscle.
The biological actions of 8-iso-PGF2 were
first investigated in the renal vasculature in which they elicit
profound vasoconstriction (106). Since then,
8-iso-PGF2
and
8-iso-PGE2 have been found to have excitatory
effects on virtually every vascular smooth muscle in which they have
been tested, as might be predicted by the widespread distribution of TP
receptors on the vasculature including the aorta (77, 164,
174) and carotid (95), coronary (76, 78, 94,
153), cerebral (56), pial (56),
pulmonary (4, 66, 70, 164), renal (38, 106,
158), portal (88), umbilical (121),
and retinal (81, 91) arteries.
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Airway smooth muscle.
Several groups have described TP antagonist-sensitive excitatory
responses to 8-iso-PGE2 and
8-iso-PGF2 in airway smooth muscle of the rat
(70), guinea pig (71), human (62,
71), and pig (Janssen, unpublished observations). Interestingly,
rabbit (54) and canine (62) trachealis do not
exhibit a contractile response, whereas canine bronchi show only
moderate contractions (62), consistent with the
distribution of TP receptors in the airways of different species
(22, 115). Once again, Janssen et al. (62)
found that 8-iso-PGE2 was generally 10-100
times more potent than 8-iso-PGF2
, the
isoprostane most commonly studied elsewhere. Furthermore, they were
amazed at the specificity of these responses. For example, two
isoprostanes that are nearly identical in structure to
8-iso-PGF2
,
8-iso-PGF2
(differs solely in the orientation
of a single hydroxyl group on the cyclopentane ring) and
8-iso-PGF3
(differs only in possessing one
extra double bond; Fig. 3), lacked any spasmogenic activity; in fact, 8-iso-PGF3
evoked dose-dependent relaxations
(Fig. 5). In ongoing studies of the
mechanisms underlying these bronchoconstrictor responses in human
airway smooth muscle, my laboratory has identified many aspects in
common with the signaling pathway underlying vasoconstriction; that is,
the responses are sensitive to the TP receptor antagonist ICI-192605,
the tyrosine kinase inhibitor genistein, and the Rho kinase inhibitor
Y-27632 (Janssen, unpublished observations).
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Platelets.
8-iso-PGE2 and
8-iso-PGF2 stimulate shape change and
aggregation in platelets (75, 83, 85, 109, 134) and reduce the antiadhesive effects of NO (93). In fact, several
groups hypothesized that elevated levels of isoprostanes contribute to the increased activation of platelets (as indicated by plasma levels of
TxA2 metabolites) seen in hypercholesterolemia
(26), acute ischemic stroke (163),
diabetes mellitus (27), and preeclampsia (156). Interestingly, 8-iso-PGF3
interferes with ADP-induced platelet aggregation (83).
Epithelium.
There have been no studies yet on the effect of isoprostanes on airway
epithelium. However, in gastrointestinal epithelium (33),
8-iso-PGE2 and/or
8-iso-PGF2 alter membrane ion channel activity (as indicated by increased short-circuit current), apparently via EP receptors (because their effects are not blocked by TP receptor
antagonists but are reduced by desensitization of EP receptors).
Endothelium.
Diverse responses to isoprostanes have been described in cultured
endothelial cells. In the endothelium of microvessels,
8-iso-PGF2 stimulates DNA synthesis and
proliferation, ET-1 mRNA and protein expression, TxA2
synthesis, Ins(1,4,5)P3 formation, and elevation of [Ca2+]i (39, 57, 81), the
latter effect being, in part, sensitive to a blocker of
receptor-operated Ca2+ influx (SKF-96365) but not to one of
voltage-dependent Ca2+ influx (nifedipine). Another study
(172) with human umbilical vein endothelial cells showed
that 8-iso-PGE2 and/or
8-iso-PGF2
did not increase expression of
intercellular adhesion molecule-1 or E-selectin but did induce some
change in the endothelial cells, which, in turn, was sufficient to
enhance neutrophil adhesion (see Inflammatory cells). At the
whole animal level, isoprostanes increase plasma exudation in guinea
pig airways (assessed via Evans blue dye extravasation)
(108) and edema formation in rabbit lung (4).
Inflammatory cells.
8-iso-PGE2 and
8-iso-PGF2 were both found to enhance human
polymorphonuclear granulocyte activity and adhesion to endothelial cells but did so via some indirect mechanism because neither
isoprostane increased expression of CD11b or P-selectin nor were the
levels of interleukin (IL)-6 or IL-8 altered, but CD11b expression was increased when naive neutrophils were exposed to isoprostane-pretreated endothelial cells or to supernatants from pretreated endothelial cells
(172). Interestingly, this indirect activation was not inhibited by antagonists of TP or ET receptors (SQ-29548 and bosentan, respectively).
Neuronal cells.
8-iso-PGF2 augments sensory neuronal function
in that it increases the release of transmitters from isolated sensory neurons, enhances the firing of C-nociceptors in situ and of cultured sensory neurons in vitro, and significantly reduces the threshold levels of mechanical and thermal stimuli required to trigger hind paw
withdrawal (34). E-ring isoprostanes inhibit
norepinephrine release in rat hypothalamus (31). Finally,
8-iso-PGF2
triggers Ca2+ influx
in astrocytes via N-type (i.e.,
-conotoxin-sensitive) Ca2+ channels (57).
Nonpulmonary cell types. Isoprostanes also constrict myometrium (25), muscularis mucosa of the canine proximal colon (33), gastric fundus, (147), ileum (147), and lymphatic vessels (118, 154), stimulate alkaline phosphatase activity and differentiation in calcifying vascular cells but inhibit these in preosteoblasts (124), and induce hypertrophy in cardiac ventricular myocytes. The latter effect is accompanied by inositol phosphate formation and is dependent on activation of c-Jun amino-terminal kinase (JNK1), c-Jun, phosphatidylinositol 3-kinase, and p70 S6 kinase (80).
Summary and physiological relevance.
It is clear, then, that isoprostanes are not just markers but
that they can exert a wide range of biological effects, particularly on
pulmonary cell types, depending on the species, tissue, and isomer
being tested. Collectively, these findings emphasize the need for
further investigations in this area and the danger in generalizing from
studies done with 8-iso-PGF2 in rodent tissues.
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MEDIATORS OF PULMONARY PATHOPHYSIOLOGY? |
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The recent awareness that isoprostanes are produced in abundance during oxidative stress and that they possess a diverse repertoire of biological actions may provide a whole new perspective on our understanding of pulmonary pathophysiology.
Membrane properties. Much attention has been focused recently on the effects of free radicals in the lungs (7, 61, 89, 137); it may be that these are, in part, the result of actions exerted by isoprostanes on the membrane. For example, arachidonic acid is a long hydrocarbon chain that contributes to some extent to the fluidity and hydrophobic nature of the membrane; conversion of this molecule into a hairpinlike structure by forming a cyclopentane ring at its center as well as by introducing several hydroxyl groups on that cyclopentane ring while it is still esterified within the membrane would markedly alter membrane fluidity, integrity, and hydrophobicity (102, 112), all of which are common features of lipid peroxidation.
Mechanical responses to free radicals.
Similarly, the mechanical responses evoked by reactive oxygen species
may, in fact, be mediated by isoprostanes produced by those free
radicals. Canine airway smooth muscle exhibits a relaxant response to
H2O2 (41, 61), whereas human
airways show a bronchoconstrictor response (Fig.
6) (137). The substantial
body of literature summarized above predicts that such
exposure to H2O2 would lead to generation of a
variety of isoprostanes, although the precise composition of this
mixture of isoprostanes (the relative proportions of different isoprostane species) might vary from tissue to tissue. Although it
might therefore seem hard to predict the response of the tissues to
such complex mixtures, it is worth pointing out that in the dog, most
isoprostanes evoke substantial relaxations, but none exhibit any
appreciable excitatory activity (62), so the net effect
that one might predict from a mixture of isoprostanes is bronchodilation, which is, in fact, the observed response to
H2O2 (Fig. 6) (41, 61). In human
airway smooth muscle, on the other hand, several isoprostanes are
powerful constricting agents, and only one
(8-iso-PGF3) is moderately inhibitory at very
high concentrations (62), which would account for the
observed bronchoconstrictor response to H2O2
(Fig. 6) (137). Likewise in pulmonary vascular smooth
muscle, both H2O2 and isoprostanes evoke
contractions with similar pharmacological sensitivities (14, 60,
62, 65).
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Airway hyperresponsiveness.
Isoprostanes may contribute to nonspecific airway hyperresponsiveness
because subthreshold concentrations of
8-iso-PGE2 and 8-iso-PGF2 have been shown in vascular smooth
muscle (146) and platelets (134) to amplify
the responses to norepinephrine, angiotensin II, and the Tx mimetic
U-46619. Recently, it has been shown that lipopolysaccharide-induced
murine airway hyperresponsiveness is COX independent and yet sensitive
to a blocker of TP receptors or to the free radical scavenger
N-acetylcysteine (51, 52); these observations
are all consistent with the generation and pharmacological actions of isoprostanes.
Lung transplantation. Cerebral, myocardial, and renal ischemia-reperfusion injury are all associated with generation of isoprostanes (see MARKERS OF OXIDATIVE STRESS), a substantial proportion of which may remain esterified within membrane phospholipids and be released over a prolonged period of time (see STORAGE, RELEASE, AND METABOLISM). These facts may be highly pertinent to lung transplantation; the donor lungs may, in fact, represent a major source of isoprostanes for days or weeks after the operation, affecting many parameters of lung function. Related to this, restoration of bronchial blood flow is recognized to be vital to the success of lung transplantation (126), and this may be adversely affected by the ongoing release of isoprostanes from the oxidatively stressed lungs.
Acute lung injury and pulmonary hypertension.
Acute lung injury and pulmonary hypertension are associated with
increased metabolism of arachidonic acid (6, 44, 64, 92, 122,
138, 165, 173) and are sensitive to inhibitors of TP receptors
(16, 42, 114, 122, 151, 159, 165, 173), Tx synthase
(16, 64, 114), COX (16, 64, 122, 151), and
phospholipase A2 (84). Thus some speculate
that TxA2 plays a central role in mediating these
pathological changes, although others conclude differently
(44). However, recent data (2, 44, 150, 168,
169) link superoxide and peroxide to these changes, which raises
another possibility: isoprostanes generated by COX or nonenzymatically
by free radicals and acting through TP receptors may mediate these
changes. 8-iso-PGF2 is released from several
sources under conditions associated with acute lung injury and
hypertension: from deendothelialized pulmonary artery smooth muscle on
stimulation with growth factors (platelet-derived growth factor,
transforming growth factor-
), proinflammatory cytokines (tumor
necrosis factor-
, interferon-
, and IL-1
), or superoxide
(68, 69, 116); from pulmonary arterial endothelium stimulated with H2O2 (49); and
from renal mesangial cells stimulated with IL-1 (74).
8-iso-PGF2
generated in this way would potentially disrupt endothelial barrier function (49) and
trigger pulmonary and systemic vasoconstriction (see Vascular
smooth muscle).
Summary. There is growing interest in isoprostanes as putatively important mediators in lung pathophysiology. First, they are produced in abundance by reactive oxygen species released from inflammatory cells in the airways or in a COX-dependent fashion by virtually every cell type present in the lungs (smooth muscle, epithelium, endothelium, platelets, and inflammatory cells; see PRODUCTS OF LIPID PEROXIDATION). Second, they exert important biological actions on airway and pulmonary vascular smooth muscles, epithelium or endothelium, sensory nerves, and lymphatics (see CELLULAR ACTIONS); these actions can account, in part, for the nonspecific smooth muscle hyperresponsiveness, bronchoconstriction, hypertension, edema, and hypertrophy that characterize many lung-related diseases. Third, the unique nature of the generation and pharmacology of isoprostanes can account for the sometimes paradoxical effects of steroids, free radical scavengers, COX inhibitors, and TP receptor blockers in experimental and clinical settings.
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FUTURE DIRECTIONS? |
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The isoprostane field is still in its infancy, and many important questions remain unanswered. Clearly, one important avenue of investigation pertains to the therapeutics designed to prevent the actions of isoprostanes in the lung.
On one hand, it should be possible to interfere with their production
by using free radical scavengers. Numerous studies have documented an
inverse relationship between the levels of isoprostanes and free
radical scavengers such as vitamins A (23), C (130, 141), and E (21, 23, 26, 27, 130, 135, 148);
-carotene (23, 130); selenium (35);
superoxide dismutase and catalase (11), or a superoxide
dismutase mimetic (4-hydroxy-2,2,6,6-tetramethyl piperidynoxyl) (149).
In some cases, oral supplementation with these scavengers was
accompanied by amelioration, proportional to the reduction in
isoprostane levels, of the pathophysiology being studied (11, 26,
130, 149). COX inhibitors and steroids, both used with success
in the treatment of many pulmonary disorders, have also been shown to
suppress isoprostane production by inflammatory cells stimulated with
proinflammatory cytokines and growth factors (125, 129, 131, 149,
160).
Rather than interfering with isoprostane production, an alternative
approach would be to interfere with isoprostane signaling at the
receptor level; TP receptor blockers have already been shown to be
useful in this respect (see Classic prostanoid receptors or
unique isoprostane receptors?). Further work is needed to clarify whether a novel isoprostane-specific receptor is, in fact, involved, and if so, what agents can be used to block those selectively. It is
worth noting that although isoprostanes mediate such a variety of
effects within the lungs, many of the currently available therapies for
pulmonary diseases, including leukotriene antagonists, antihistamines, anticholinergics, -adrenergic blockers, and
-agonists, are
ineffective against the isoprostanes. Alternatively, a better
understanding of the second messenger signaling pathways underlying
isoprostane responses might also allow for the development of novel
treatments for pulmonary diseases characterized, in part, by oxidative stress.
More investigation is needed to further elucidate the cellular actions of isoprostanes in the lungs. There have been no studies of their effects on airway epithelium or innervation and virtually none pertaining to their effects on different inflammatory cell types and the endothelium. Although some of their effects on smooth muscle have been described, little or nothing is known about their effects on gene expression, cytoskeletal rearrangement, hypertrophy, or apoptosis in smooth muscle. Also, their interactions with other spasmogens (resulting in nonspecific hyperresponsiveness) needs to be studied in more detail. The biological effects of many isoprostanes and their metabolites have not yet been examined, even though there is now evidence that isoprostanes with nearly identical structures can have very different pharmacological effects (see CELLULAR ACTIONS). The signaling pathways involved are still poorly understood, and almost nothing has been published about their effects on kinases, ion channels, and Ca2+ handling.
Assuming that the exponential growth in the number of publications pertaining to isoprostanes continues (Fig. 1), the next few years are certain to hold answers to many of these questions.
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ACKNOWLEDGEMENTS |
---|
Funding support for the studies of isoprostane effects on smooth muscle have been provided by the Canadian Institutes of Health Research and the Ontario Thoracic Society.
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FOOTNOTES |
---|
Address for reprint requests and other correspondence: L. J. Janssen, Dept. of Medicine, McMaster Univ., 50 Charlton Ave. East, Hamilton, ON L8N 4A6, Canada (E-mail: janssenl{at}mcmaster.ca).
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