Isoprostanes and Lung Vascular Pathology - ATS Journals

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Firestone Institute for Respiratory Health, St. Joseph's Hospital, and Department of ...... Siore AM, Parker RE, Stecenko AA, Cuppels C, McKean M, Christ-.
Translational Review Isoprostanes and Lung Vascular Pathology Luke J. Janssen Firestone Institute for Respiratory Health, St. Joseph’s Hospital, and Department of Medicine, McMaster University, Hamilton, Ontario, Canada

Isoprostanes are products of peroxidative attack of membrane lipids. As such, they accumulate to substantial levels in conditions of oxidative stress, including many pulmonary vascular diseases such as acute lung injury and pulmonary hypertension, and are increasingly being used as indicators of disease state and severity. However, our group and others have hypothesized that they are more than inert markers, but may also act as signal transduction molecules. As isomers of prostaglandins, they can exert powerful biological effects on many lung cell types through actions on prostanoid receptors. In this review, we collect many lines of evidence that point to causal roles for the isoprostanes in those disease states. Keywords: isoprostanes; acute lung injury; pulmonary hypertension; thromboxane receptors

OXIDATIVE STRESS AND ISOPROSTANES Many disease states are characterized by oxidative stress and accumulation of reactive oxygen species such as peroxide (H2O2), superoxide (O2-), and peroxynitrite (ONOO-). These highly reactive nucleophilic molecules react avidly with electrophilic functional groups in proteins and lipids, producing a variety of oxidative breakdown products. In particular, they can attack the unsaturated bonds of membrane lipids, including arachidonic acid, leading to the formation of a class of molecules that are isomers of the prostanoids, and are therefore referred to as ‘‘isoprostanes’’ (Figure 1). Potentially, there are hundreds of different isoprostane compounds, all comprising a cyclopentane ring with two alkyl side chains oriented cis to one another, in contrast to the trans configuration of those side chains in the prostanoids. Isoprostanes are present at nanomolar concentrations in the blood of normal individuals (1–5) and their concentrations are further increased several orders of magnitude in many disease states, particularly pulmonary diseases. For example, measured levels of isoprostanes and their metabolites are elevated in patients with acute lung injury (ALI) (6), pulmonary arterial hypertension (PAH) (7–11), asthma (12–14), chronic obstructive pulmonary disease (14, 15), interstitial lung disease (16), or cystic fibrosis (17). They are also elevated in otherwise normal individuals exposed to ozone (18), cigarette smoke (15, 19–23), or allergen (24). This direct relationship between isoprostane formation/ accumulation and oxidative stress, together with several other

CLINICAL RELEVANCE We first summarize the powerful biological actions of isoprostanes (‘‘markers’’ of oxidative stress) on every lung cell type, then relate these findings to lung pathophysiology (pulmonary arterial hypertension and acute lung injury).

of their characteristics, have made the isoprostanes a marker of choice for lung disease state. Those characteristics include the facts that they are relatively stable, that they are easily collected either in samples of blood and urine (11, 23, 25–30), lavage fluids (31, 32) (and therefore probably also sputum samples) or even breath condensates (33–35), and that relatively inexpensive and straightforward assays are available to quantify them. However, our group and others have hypothesized that isoprostanes are not merely markers of disease state, but may in fact be causal agents in lung diseases, or at least agents that exacerbate those clinical conditions. The rationale for making this claim is the already long and growing list of the biological actions that isoprostanes exert on various cell types, as summarized in the next section.

ISOPROSTANES EXERT A VARIETY OF EFFECTS ON LUNG-DERIVED CELLS Isoprostane Pharmacology: Overview

Isoprostanes have been found to be powerfully excitatory in every vascular tissue in which this question has been investigated, including the aorta (36, 37), pulmonary (38–40), renal (3, 41–43), carotid (44), coronary (45, 46), cerebral (47), pial (47), portal (48), umbilical (49), and retinal (50, 51) arteries. Many groups have shown isoprostanes to mediate these effects through prostanoid receptors that are selective for thromboxane A2 (referred to as TP receptors) (52) (Figure 2). More recently, our group and others have described responses in other tissues that appear to involve other prostanoid receptors, including those that are selective for prostaglandin E2 (53–55) and prostaglandin F2a (55) (EP and FP receptors, respectively). This crossreactivity should not be surprising given the many structural similarities between prostanoids and isoprostanes. Interestingly, there is some evidence to suggest the possible existence of a novel group of isoprostane-selective receptors (52). Recently, we set out to characterize in detail the effects of isoprostanes upon various lung-derived cell types:

(Received in original form March 19, 2008 and in final form April 9, 2008) These studies were supported by operating funds provided by the Canadian Institutes of Health Research (MOP 42,541). Correspondence and requests for reprints should be addressed to L. J. Janssen, L-314, St. Joseph’s Hospital, 50 Charlton Ave. East, Hamilton, ON, L8N 4A6 Canada. E-mail: [email protected] Am J Respir Cell Mol Biol Vol 39. pp 383–389, 2008 Originally Published in Press as DOI: 10.1165/rcmb.2008-0109TR on April 25, 2008 Internet address: www.atsjournals.org

Airway Smooth Muscle

Several isoprostanes, particularly those of the E-ring conformation, evoke bronchoconstriction in human airways but bronchodilation in canine, porcine, and bovine airways (56, 57). The former effect involves TP receptors acting through the monomeric G-protein RhoA and its downstream effector RhoA-associated kinase (ROCK), while the bronchodilation involves EP2 recep-

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Figure 1. Structures of four different isoprostane families produced from arachidonic acid, after cyclization at the carbon groups indicated: the fatty acid side chains are cis to each other, in contrast to the prostaglandin molecule PGF2a shown below, in which the side chains are trans. Each isoprostane structure represents several subtypes, which differ according to the orientation of the hydroxyl groups or whether the functional group on C9 (X) is an alcohol (F-ring) or a ketone (E-ring).

tors and is cAMP/PKA mediated. We also found that isoprostanes at subthreshold concentrations (insufficient to directly evoke substantial constriction) cause marked nonspecific airway hyperresponsiveness (58, 59): that is, they greatly augment the magnitudes of bronchoconstrictor responses to cholinergic and histaminergic stimulation, as well as to potassium chloride. Both

the direct bronchoconstrictor effect and the indirect airway hyperresponsiveness are cardinal features of asthma. Another group described differential regulation by isoprostanes of cytokine secretion from cultured human airway smooth muscle cells stimulated by interleukin-1b (IL-1b) (60). In particular, secretion of granulocyte/macrophage colony-stimulating factor was

Figure 2. At submicromolar concentrations, prostaglandins act selectively at various prostanoid receptors, which in turn activate a variety of signaling pathways. Pharmacologic studies using various receptor blockers show that isoprostanes may also activate certain of these prostanoid receptors. There are also provocative data that suggest the possibility of a novel isoprostanespecific receptor.

Translational Review

inhibited by E-ring isoprostanes acting upon EP2-receptors, while that of granulocyte colony-stimulating factor was augmented by the same E-ring isoprostanes acting on both EP2and EP4-receptors; F-ring isoprostanes had no effect on either cytokine. Pulmonary Vasculature

We also found that the isoprostanes evoke both powerful vasoconstriction or vasodilation in the pulmonary artery (PA) or vein of the human, dog, pig, and cow, depending on the particular isoprostane molecule and tissue bed being studied (54, 61, 62). Once again, the E-ring compounds were as potent or more so than the F-ring compounds on which most previous studies have focused exclusively. While the mechanisms underlying vasodilation are yet unclear, the excitatory responses involve TP-receptors coupled to RhoA/ROCK, with a possible additional contribution made by EP3 receptors and changes in Ca21-signaling (via the classical phosphoinositide signaling cascade) (54). The ability of the isoprostanes to directly modulate pulmonary vasoreactivity is highly relevant to PAH and ALI. Bronchial Vasculature

In this systemic vascular bed, which nourishes the airways and pulmonary vasculature, we also found vasoconstrictor effects via TP-receptors coupled to tyrosine kinase and ROCK (63), accompanied by suppression of K1 currents. Airway Epithelium

Only the E-ring isoprostanes (not the F-ring compounds) evoked a substantial increase in short-circuit current through an action upon EP4-receptors coupled to adenylate cyclase and soluble guanylate cyclase, which in turn activate a transepithelial Cl2 conductance (64). This may account in part for the mucous formation seen in asthma, COPD, and cystic fibrosis, as well as to the edema formation seen in ALI. Cholinergic Innervation

Only one isoprostane (15-E2t-IsoP) out of several subtypes tested augmented cholinergic neurotransmission in bovine airway tissues through an action upon FP-receptors (65). This is also relevant to asthma, given the possible role of the excitatory innervation in that condition (66). Interestingly, others have shown this same isoprostane to inhibit ACh release from parasympathetic nerves in the guinea-pig trachea, through an action upon EP3-receptors (67). Pulmonary Lymphatics

Most recently, we have found in bovine pulmonary lymphatic vessels that isoprostanes elicit powerful contractions that are sensitive to TP receptor blockers (unpublished observations). Others have documented the effects of isoprostanes on endothelium and inflammatory cells, albeit in nonpulmonary preparations. Altogether, then, it seems that every cell type present in the lung is sensitive in one way or another to the isoprostanes. These accumulating data point toward a possible causal role for the isoprostanes in lung disease.

ACUTE LUNG INJURY AND PULMONARY HYPERTENSION In addition to their potential role in asthma (in producing direct bronchoconstriction as well as nonspecific airway hyperresponsiveness), there is now abundant evidence that isoprostanes may also be important in pulmonary vascular pathophysiology.

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For example, isoprostane levels in general are elevated in patients with PAH (7–11, 68) and in animal models of PAH induced by exposure for several weeks to hypoxia (69, 70) or hyperoxia (9, 71–75), although none of these studies correlated the time-course of isoprostane accumulation with that of the hypertensive changes, nor assessed the relative levels of specific isoprostane subtypes. 15-F2t-IsoP is released from several sources under conditions associated with PAH (and ALI), including PA upon stimulation with growth factors (platelet-derived growth factor, transforming growth factor b), pro-inflammatory cytokines (TNF-a, interferon-g, and IL-1b), H2O2 or O2- (76–78), or from PA-endothelium stimulated with H2O2 (79). Isoprostanes can exert their pulmonary hypertensive actions in many different ways (see Figure 3). First, we have shown their ability to directly constrict the pulmonary arteries and veins (54, 56, 58, 59, 61, 63, 64); it remains to be seen whether or not they can also increase the responsiveness of those smooth muscles to other vasoconstrictors (as we found them to do in airway smooth muscle). In addition, given their constrictor actions on the airways, the isoprostanes can disaffect ventilation, leading to lung hypoxia accompanied by hypoxic pulmonary vasoconstriction. Furthermore, they can induce the pulmonary endothelium to release a vasoconstrictor substance (80) such as endothelin, which is also elevated in PAH (10): exposure of vascular smooth muscle cells to H2O2 causes increased activity of cytosolic phospholipase A2 (which can liberate isoprostanes from the membrane), accumulation of isoprostanes, expression of pre–pro-endothelin mRNA, and production of endothelin-1 (81). Jankov and coworkers (71, 74, 75) and Yi and colleagues (82) showed that stimulation of TP receptors in PA by 15-F2t-IsoP results in marked production of endothelin-1 in a RhoA/ROCK-dependent fashion, and that PAH (as indicated by hypertrophy and increased levels of endothelin-1 and 15-F2t-IsoP) could be prevented by TP receptor blockers but not a cyclooxygenase-2 inhibitor, suggesting strongly that isoprostanes (rather than thromboxanes, which require cyclo-oxygenase activity) play a key role in these pathologic changes. Isoprostanes could also contribute to lung inflammation via increased production of proinflammatory cytokines by smooth muscle and endothelial cells, and via direct actions on the inflammatory cells themselves. Over a longer time course, the isoprostanes could contribute to smooth muscle hypertrophy and hyperresponsiveness (both characteristic of PAH and of asthma). In addition to showing that isoprostanes can reproduce the features of PAH, the postulate that isoprostanes play a causal role in PAH would also require evidence that blocking isoprostane production and/or action prevents the manifestations of PAH: in fact, there are many reports that free radical scavengers (72, 75, 83–86) and TP receptor blockers (71, 87–90) reverse the hypertensive changes. In a particularly illuminating study (68), levels of thromboxanes and isoprostanes were both elevated in primary PAH, but only the isoprostanes were reduced by epoprostanol, with a time course that correlated strongly with anti-hypertensive changes (the thromboxanes were unchanged). Similar points can be made for ALI. That is, isoprostanes in general are elevated in patients with ALI (6) as well as in several animal models of ALI, including those induced by sepsis (91–93), endotoxin (94–96), lipopolysaccharide (97), meconium aspiration (98, 99), rhabdomyolysis (32), ischemiareperfusion injury (100, 101), acrolein (102), and hyperoxia (103) (once again, none of those studies assessed which specific isoprostane subtype[s] was produced). ALI can also be produced by overinflation (104–107), but the involvement of isoprostanes has not yet been examined in this model. ALI is characterized in part by profound edema formation, which in turn is a product of three key ingredients: (1) increased

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Figure 3. Central theme of this treatise: isoprostanes not only accumulate in many respiratory disease states, but exert a wide variety of biological effects which may account for many of the features of those disease states.

intravascular pressures; (2) increased tissue permeability; and (3) decreased drainage of fluid from the interstitial space. We have shown that isoprostanes can act at all three levels. First, we have already documented above their powerful vasoconstrictor effect upon the pulmonary artery, pulmonary vein, and bronchial artery. The increased hydrostatic pressures alone could result in movement of fluids into the interstitial space. However, this leak would be exacerbated by the ability of the isoprostanes to activate the endothelium (above) and thereby increase its permeability. Our studies also show that isoprostanes increase airway epithelial permeability by stimulating chloride secretion, which would be followed by movement of water into the airway lumen. Third, and most importantly, we have begun to explore their powerful constrictor actions on the pulmonary lymphatics (others have already published this effect in nonpulmonary lymphatics). Further support for a causal role for isoprostanes in ALI is found in multiple reports that experimentally induced ALI is sensitive to free radical scavengers (93, 94, 97, 99, 103, 105, 108) and TP-receptor blockers (95, 96, 109–111): both findings are consistent with isoprostane signaling. One study showed sepsisinduced ALI to be completely dependent upon inducible nitric oxide synthase (NOS) in inflammatory cells (91): iNOS is a potent source of reactive oxygen/nitrogen species including peroxyni-

trite, a highly potent catalyst for isoprostane formation (112, 113), and human PA produces isoprostanes in an NOS-dependent fashion after inflammatory stimulation (76).

CONCLUSION AND FUTURE DIRECTIONS Many disease states are accompanied by accumulation of isoprostanes in proportion to the degree of oxidative stress, including ALI and PAH (summarized above). Given their potent and diverse biological activity, it is entirely plausible that the isoprostanes could account for many of the symptoms found in those disease states (summarized in Figure 3). For these reasons, we feel it is imperative to gain a better understanding of the effects of isoprostanes on the various cell types in the lungs. One important and specific question that must be answered is the nature of the mix of isoprostanes that are produced in those diseases, given the unique potencies and efficacies of the different isoprostane species. This may vary between the different disease conditions. Also, it may turn out that the specific subtype(s) of isoprostane that is produced in that condition has not yet been evaluated pharmacologically. Finally, a better understanding of the signaling mechanisms underlying isoprostane-evoked responses will also be useful in this endeavor.

Translational Review Conflict of Interest Statement: L.J does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

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