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COX-2 in Inflammation and Resolution

¹ Department of Experimental Medicine, Nephrology and Critical Care, William Harvey Research Institute, Charterhouse Square, London EC1M6BQ
² Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, 5 University Street, University College London, London WC1E 6JJ

	SUMMARY

TOP Summary Introduction: The Other Side... COX Metabolism and NSAIDs NSAIDs and COX-2 Inhibitors Pro-resolution Properties of COX... Aspirin and COX-2 in... Aspirin, COX-2, and Other... Conclusions and Implications for... References

 
Aspirin and the other NSAIDs have popularized the notion of inhibiting prostaglandins as a common anti-inflammatory strategy based on the erroneous premise that all eicosanoids are, within the context of inflammation, generally detrimental. However, our fascination with aspirin and the emergence of COX-2 has shown a more affable side to lipid mediators based on our increasing interest in the endogenous control of acute inflammation and in factors that mediate its resolution. Epilipoxins, for instance, are produced from aspirin’s acetylation of COX-2 and together with Resolvins and COX-2–derived prostaglandins of the D₂ and J₂ series represent an increasingly important family of immunoregulatory lipid mediators with strong implications for disease control and drug discovery.

	INTRODUCTION: THE OTHER SIDE OF INFLAMMATION

TOP Summary Introduction: The Other Side... COX Metabolism and NSAIDs NSAIDs and COX-2 Inhibitors Pro-resolution Properties of COX... Aspirin and COX-2 in... Aspirin, COX-2, and Other... Conclusions and Implications for... References

 
Inflammation, which occurs in response to an injurious stimulus, is a beneficial event that leads to removal of the offending factor and restoration of tissue structure and function. Thus, the hallmark of a successful inflammatory response is not only the clearance of injurious stimuli, but also the restoration of normal physiology. Stimulus clearance is mediated by a host of signals that drive the inflammatory response in a well-understood manner that involves the upregulation of cell adhesion molecules and chemokines, for instance, resulting in the accumulation of inflammatory leukocytes at the site of tissue injury. After the inflammatory stimulus has been neutralized, inflammation can abate. This abatement does not happen in a passive manner, as originally understood, through which the inflammatory response simply "fizzles out." On the contrary, "resolution" of the inflammatory response is now appreciated to be an active event managed by an increasing number of recognized soluble mediators. These mediators engage mechanisms that culminate in the switching off of inflammation and return the stromal tissue that hosted the response to its prior physiology (1, 2). It may be anticipated, therefore, that failure of acute inflammation to resolve may predispose to auto-immunity, chronic inflammation, and excessive tissue damage, as shown previously (3).

Intriguingly, of the factors and signals inherent to the successful resolution of inflammation, the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, through which arachidonic acid (AA) and other fatty acid precursors are metabolized, are essential (2, 4). This metabolic requirement is in stark contrast to the role of COX that has been established through the literature on nonsteroidal anti-inflammatory drugs (NSAIDs), according to which COX-derived AA metabolites are mostly pro-inflammatory. This article will examine the roles of diverse fatty acid metabolites and other signaling molecules in orchestrating the resolution of inflammation. New recognition of these roles will likely advocate for the development of drugs that are based on endogenous pro-resolution factors. At the very least, those in the business of developing anti-inflammatory drugs should be mindful of the existence of pro-resolution pathways and that unwittingly altering their normal functioning could come with unwanted side effects.

	COX METABOLISM AND NSAIDS

TOP Summary Introduction: The Other Side... COX Metabolism and NSAIDs NSAIDs and COX-2 Inhibitors Pro-resolution Properties of COX... Aspirin and COX-2 in... Aspirin, COX-2, and Other... Conclusions and Implications for... References

 
Although AA may also be metabolized by cytochrome p450 systems, the focus of this review will be on the activities of COX and, to a lesser extent, LOX. There are three isoforms of COX, also known as prostaglandin G/H synthase. The first, COX-1, is constitutively expressed in most tissues and synthesizes prostaglandins (PGs) at low levels, and has thus been presumed to function primarily in the maintenance of physiological functions (5). COX-2, on the other hand, is highly inducible in response to pro-inflammatory stimuli, cytokines, and mitogens, and it has thus been generally conceptualized to function in the inflammatory release of PGs (6–10). Since the initial discovery of COX-2, however, these generalizations have been challenged. Phorbol esters, for example, support the differentiation of the THP-1 human monocytic leukemia cell line, in part by inducing COX-1 (7, 11), and stem cell factor and dexamethasone induce COX-1 expression in mouse bone marrow–derived mast cells (12). Furthermore, COX-2 is expressed constitutively in discrete populations of neurons throughout the forebrain, as well as in the cortex and hippocampus; its expression is similarly constitutive in the macula densa of the juxta-glomerular apparatus and adjacent epithelial cells of the cortical thick ascending limb of the kidney (6, 7). In endothelial cells, however, its expression is somewhat controversial; some workers maintain that COX-2 is expressed in the endothelium under resting conditions in response to shear stress, for instance, or under circumstances of focal inflammation (e.g., atherosclerosis), whereas others detect no COX-2 expression in the endothelial cells from various vascular trees (9, 13, 14). Finally, COX-3, a splice variant of COX-1, is inhibited by acetaminophen and is thus thought to mediate the antipyretic and analgesic effects of this drug (15); however, the protein expression and functional relevance of acetaminophen-sensitive COX-3 in humans has been questioned (16).

COX converts AA, which is released from the plasma membrane via the action of phospholipase A2, into PGG₂ and then into PGH₂ (Figure 1). The latter, in turn, acts as a substrate for a series of downstream synthases responsible for the generation of PGs, thromboxane A₂, and prostacyclin (collectively called prostanoids) (Figure 1). Both COX-1 and -2 share similar structural properties, including a hydrophobic tunnel that allows AA access to the respective active sites. In COX-2, this hydrophobic tunnel has a side pocket, and the enzyme therefore manifests broader substrate recognition than does COX-1. This difference in substrate specificity will be important later when we discuss the ability of COX-2 to metabolize eicosapentaenoic acid and docosahexaenoic acid, either in the presence or absence of aspirin, to produce novel endogenous anti-inflammatory and pro-resolution lipid mediators. This structural distinction of the active site of COX-2 has lent itself to the discovery of compounds [i.e., the coxibs; e.g., rofecoxib (Vioxx, Merck)] that selectively inhibit COX-2 (17) and were thus developed and marketed as anti-inflammatory drugs. The coxibs, moreover, were reputed, by virtue of their limited gastric toxicity (18, 19), to have an advantage over traditional NSAIDs; it was initially believed that adverse gastric effects typically stem from the inhibition of COX-1. It is now generally believed that both COX-1 and COX-2 need to be inhibited simultaneously in order to elicit gastric ulceration, inasmuch as selective inhibition by coxibs only reduced ulceration by 50% compared to NSAIDs (18). In addition, the reported expression of COX-2 in the vascular endothelium, along with its roles in resolving acute inflammation and in healing gastric ulcers, has impugned the use of COX-2 inhibitors for treating chronic inflammation. Indeed, the association of adverse cardiovascular events associated with Vioxx consumption for chronic rheumatic pain has led to the voluntary withdrawal of Vioxx from the market. In the next few paragraphs, we will recount important evidence from the last ten years that shows COX-2 to be a versatile enzyme in the inflammatory response. This single enzyme possesses the ability, under certain conditions, to drive inflammation, and remarkably, the ability to resolve inflammation under other conditions.

View larger version (18K): [in this window] [in a new window]   Figure 1. The prostaglandin pathway. Synthesis of prostanoids by the COX enzymes following the catalytic release of arachidonic acid from membrane phospholipids by calcium-dependent phospholipase A2. PGH2 is metabolized as indicated by specific synthases. Alternatively, arachidonic acid can be metabolized by lipoxygenase or cytochrome P450 activities to leukotrienes, lipoxins, and hyroxyl/epoxyeicosatetraenoic fatty acids. Reproduced from (67).

	NSAIDS AND COX-2 INHIBITORS

TOP Summary Introduction: The Other Side... COX Metabolism and NSAIDs NSAIDs and COX-2 Inhibitors Pro-resolution Properties of COX... Aspirin and COX-2 in... Aspirin, COX-2, and Other... Conclusions and Implications for... References

COX inhibitors were then developed with up to 1000-fold selectivity for the inhibition of the "inducible" COX-2 isoform over the "constitutive" COX-1 isoform in various in vitro assay systems (22). Intriguingly, these COX-2 inhibitors showed little or no renal and gastric toxicity (23, 24). In terms of basic research, the development of selective COX-2 inhibitors resulted in the availability of various structurally diverse pharmacological tools, such as NS-398 (25), DUP-697 (26) and L-745,337 (23). The advent of effective COX-2 inhibitors, complemented by growing evidence that placed COX-2 at sites of inflammation and tissue injury, drove early studies that supported a pro-inflammatory role for this inducible enzyme (27, 28) and fueled speculation that its inhibition could me marshaled in the treatment of inflammatory diseases. In retrospect, however, the presumption that COX-2 was responsible solely for propagating the inflammatory response by synthesizing pro-inflammatory PGs appears specious.

A closer analysis reveals that the COX-2 inhibitors used in some of the early reports were administered at doses in excess of that required to inhibit COX-2. For instance, in one carrageenin air pouch study, the concentration of the highly selective COX-2 inhibitor, SC-58125, required to inhibit exudate formation was a 100-fold greater than that necessary to inhibit exudate PG levels (27). Significantly, this compound is 100-fold more potent as an inhibitor of COX-2 than of COX-1 in vitro; it is therefore possible that the SC-58125 doses used in this model inhibited COX-1 as well as COX-2. In addition to such pharmacological studies, the involvement of COX-1 in acute inflammatory models was similarly indicated in studies using knockout mice. AA induces edema in wild-type mice far more effectively than in COX-1–deficient mice (29), suggesting a role for COX-1 and not COX-2 in this model of inflammation. Additionally, COX-2–deficient and wild-type mice were found to have similar model responses in terms of ear swelling (induced by triphorbol myristate acetate) and paw swelling (in response to carrageenin) (30). Because mice devoid of COX-2 still express COX-1, it is conceivable that this constitutive isoform synthesizes sufficient bioactive PGs for inflammation to proceed. Collectively, these studies in COX-deficient mice indicate that both COX-1 and COX-2 can contribute to the inflammatory response.

Indeed, subsequent studies during the late 1990s began to suggest that in some tissues, most notably within the gastrointestinal system, COX-2 may be protective (31–33). In experimental models of colitis, for instance, the majority of PGs in the colonic mucosa are synthesized by COX-2 (34). Treatment with a selective COX-2 inhibitor (L-745,337) at doses that do not inhibit COX-1 depress mucosal PG synthesis and causes a marked exacerbation of colonic damage (35). Continuous treatment for up to one week results in perforation of the bowel wall and death. It was also shown that COX-2 mRNA and protein are strongly induced in murine models of gastrointestinal ulceration, concomitant with increased mucosal PG synthesis (36, 37). Treatment of the mice with the selective COX-2 inhibitor NS-398 reduces mucosal PG synthesis and significantly inhibits ulcer healing (38). These results have been confirmed by others who also show marked inhibition of gastric ulcer healing in rats by the COX-2 inhibitor L-745,337 at doses that selectively inhibit this inducible isoform (39). These studies thus question whether gastroprotective PGs are synthesized solely by COX-1 and suggest that COX-2 plays a significant role in protecting the gastrointestinal tract from injury. As mentioned earlier, it now seems that inhibition of both COX-1 and COX-2 in healthy gastrointestinal tissues is required to elicit ulcers.

	PRO-RESOLUTION PROPERTIES OF COX-2

TOP Summary Introduction: The Other Side... COX Metabolism and NSAIDs NSAIDs and COX-2 Inhibitors Pro-resolution Properties of COX... Aspirin and COX-2 in... Aspirin, COX-2, and Other... Conclusions and Implications for... References

 
The findings with NSAIDs and COX-deficient mice indicate that both COX-1 and COX-2 contribute to PG production at the site of inflammation and also that COX-2–derived PGs have roles in the resolution and healing phase as well as in the early stages of the inflammatory response. In the seminal paper on the phenotype of COX-2 knockouts, the mice developed suppurative peritonitis with multiple adhesions among the abdominal organs, consistent with chronic inflammation (40). In our laboratory, we have established that COX-2 is directly involved in regulating inflammatory resolution in a carrageenin-induced pleurisy model (41). Here we found two phases of COX-2 expression over the time course of this innate inflammatory response. The first peak (i.e., at about two hours) is associated with the onset of inflammation and is typified by polymorphonuclear leukocyte influx, PGE₂ production, and COX activity (41); both the dual and the COX-2 selective inhibitors inhibit this early phase of the inflammatory response. However, forty-eight hours after irritant injection, we observed a second peak in COX-2 protein expression coincident with both the resolution of inflammation and the late influx of mononuclear cells. This second peak, moreover, manifests negligible PGE₂ production but is associated with the clear presence of another PGH₂ metabolite, namely, PGD₂. Treatment with COX-2 selective inhibitors from between twenty-four and forty-eight hours post-injection of irritant appears to inhibit resolution and thus prolongs the inflammatory response; co-administration of PGD₂ and cyclopentenone PGs, however, results in a normal course of resolution. We have also demonstrated that distinct phospholipase isoforms are differentially involved, with respect to the early versus late phases, in supplying substrate to COX (42).

PGD₂ is derived from the metabolism of COX-derived PGH₂ by hematopoietic PGD₂ synthase (hPGD₂S). In a more recent study, we sought to further define the role of COX-associated downstream synthases in inflammation by examining the role of hPGD₂S in a model of lymphocyte-driven adaptive immunity elicited by methylated bovine serum albumin. Mice that are deficient in hPGD₂S were found to display a more aggressive inflammatory response that fails to resolve, whereas mice overexpressing the enzyme display few signs of inflammation (43). Although hPGD₂S-derived PGD₂ and its metabolites, the cyclopentenone PGs, possess potent but diverse biological roles in host defense, the suppressive effects of hPGD₂S on T-lymphocyte functioning in this model appears to be mediated by 15d-PGJ₂ and its inhibition of NF-B DNA binding (Figure 2). Contrary to the emerging literature, however, there was little apparent role for PGD₂, acting through either of its receptors [i.e., the D prostanoid (DP1) receptor and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2)], in controlling lymphocyte functioning. These findings suggest an important role for both COX-2 and hPGD₂S as checkpoint controllers in the progression from acute to resolving inflammation (Figure 2). In ongoing work, we have found an equally important role for hPGD₂S in the regulation of the onset phase of innate peritonitis as well as its resolution through the regulation of macrophage clearance to the draining lymphatics and regulatory lymphocyte functioning (R Rajakariar and DW Gilroy). This supports and complements the original findings with COX 2 in resolution of pleuritis as discussed above. Whether the absence of hPGD₂S predisposes to chronic inflammation or auto-immunity has yet to be determined. Nonetheless, the clear lack of inflammation in animals that overexpress hPGD₂S and the aggressive nature of the response in animals deficient in the enzyme further reinforce the critical role this downstream PGH₂-metabolizing enzyme plays in the etiology of T-lymphocyte driven immune responses. Balanced against its pro-resolution role, PGD₂ has been implicated in allergic inflammation as evidenced by its role in the pathogenesis of asthma (44). hPGD₂S is abundant in mast cells (45) and dendritic cells (46), and its levels rise in the broncho-alveolar lavage following allergen challenge of asthmatic subjects (47), suggesting that the role of PGs in disease is highly context-dependent.

View larger version (7K): [in this window] [in a new window]   Figure 2. Actions of PGD2 and 15-deoxy-12,14-PGJ2. PGD2 acts via the DP1 receptor, which acts via adenylyl cyclase, and chemoattractant receptor-homologous molecule expressed on T helper 2 cells (CRTH2). DP1 receptor is expressed in mast cells and eosinophils. CRTH2 is expressed on a small population of CD4 and CD8 T lymphocytes and in peripheral blood eosinophils and basophils. See text for details. AP-1, a family of transcription factors; PPAR, peroxisome proliferator-activated receptor ; IK, IB kinase; STAT-1, signal transducer and activator of transcription 1.

	ASPIRIN AND COX-2 IN INFLAMMATION

TOP Summary Introduction: The Other Side... COX Metabolism and NSAIDs NSAIDs and COX-2 Inhibitors Pro-resolution Properties of COX... Aspirin and COX-2 in... Aspirin, COX-2, and Other... Conclusions and Implications for... References

View larger version (27K): [in this window] [in a new window]   Figure 3. Pathways leading to the production of lipoxins and epilipoxins. I). 15-lipoxygenase produces 15(s)hydroperoxyeicosatetraenoic acid [15S-H(p)ETE], which serves as a substrate for polymorphonuclear leukocyte (PMN) 5-lipoxygenase [5-LOX] to generate 5,6-epoxytetraene. The latter is unstable and is converted to lipoxin A4 and B4 by lipoxin (Lx) hydrolases. II). 5-LOX in PMNs metabloizes arachidonic acid to leukotriene A4 which is taken up by platelets in a transcellular manner and converted by platelet 12-LOX to LxA4. III). Acetylation of the active site of COX-2 by aspirin results in the conversion of arachidonic acid to 15(R)-hydroxyeicosatetraenoic [15(R)-HETE] which when released by endothelial and epithelial cells may be transformed by leukocyte 5-LOX to generate 15-epi-LxA4 or 15-epi-LxB4.

The lipoxins act via intracellular Ah (aryl hydrocarbon) receptor (55) or a G protein–coupled receptor termed ALX-R, or N-formyl-peptide receptor 1 (fprl1), expressed by neutrophils, monocytes, epithelial cells, and activated T cells as well as by enterocytes, fibroblasts, and the intracellular aryl-hydrocarbon receptor in dendritic cells (56, 57). Lipoxins are anti-inflammatory in their ability to inhibit neutrophil chemotaxis and diapedesis through post-capillary venules and therefore entry into inflamed tissues in animal models (58). In contrast, LXA₄ also stimulates chemotaxis and adherence of monocytes to sites of inflammation (59), an essential mechanism in wound healing and clearance of leukocytes from inflamed sites. Attracted monocytes differentiate into macrophages capable of phagocytosing apoptotic neutrophils in a non-phlogistic manner (60), particularly during the resolution phase of inflammation, during which lipoxins promote monocyte chemotaxis and adherence without inducing neutrophil degranulation (61). 15-epilipoxins formed subsequent to aspirin administration [i.e., aspirin-triggered lipoxins (ATL)] share these properties in addition to other downstream beneficial effects that include increased vasorelaxation, prostacyclin synthesis, and induction of nitric oxide synthesis in endothelial cells (62). The benefits of lipoxins are potentially enormous and need to be exploited. The synthesis of stable analogs will be essential to elucidating the mechanisms of lipoxin action, and further understanding of the intrinsic mechanisms that underlie the ATL pathway is clearly needed.

	ASPIRIN, COX-2, AND OTHER PRO-RESOLVING PATHWAYS

TOP Summary Introduction: The Other Side... COX Metabolism and NSAIDs NSAIDs and COX-2 Inhibitors Pro-resolution Properties of COX... Aspirin and COX-2 in... Aspirin, COX-2, and Other... Conclusions and Implications for... References

 
Resolvins and docosatrienes are fatty acid metabolites of the COX/LOX pathways, in which the omega-3 fatty acids docosahexaenoic acid and eicosapentaneoic acid, rather than AA, are the substrates (2, 61, 63). Resolvins and docosatrienes were identified in inflammatory exudates during the resolving phase of acute inflammation and shown to be potent modulators, at nanogram doses, of inflammatory processes. Specifically, they potently inhibit PMN transen-dothelial migration and microglial cytokine expression and also ameliorate experimental models of dermal inflammation and leukocyte accumulation in peritonitis (63 ,64). The studies on resolvin metabolism are uncovering surprising new avenues in anti-inflammation research, putting fatty acid metabolites right at the forefront of potential drug therapy. These studies are also challenging existing dogma by indicating that not all eicosanoids are detrimental to inflammation. Many therapeutic contexts are likely to benefit from this more balanced appreciation of the various roles that eicosanoids play in homeostasis and pathophysiology. To add fuel to this notion, a recent and very surprising paper has shown that eicosanoids of the lipoxin family are orally active in models of acute inflammation (65).

	CONCLUSIONS AND IMPLICATIONS FOR DRUG DISCOVERY

TOP Summary Introduction: The Other Side... COX Metabolism and NSAIDs NSAIDs and COX-2 Inhibitors Pro-resolution Properties of COX... Aspirin and COX-2 in... Aspirin, COX-2, and Other... Conclusions and Implications for... References

 
It is becoming clear that inflammation has a number of tactically placed checkpoints that limit the magnitude and duration of the response. Defects in these endogenous anti-inflammatory pathways will arguably predispose the host to chronic inflammatory diseases. The COX and LOX pathways have both protective and pro-inflammatory roles in inflammation, with the precise function of each enzyme being dependant on the inflammatory stimulus, phase of the acute inflammatory response, and other molecules that are present to tip the balance in favor of resolving or non-resolving inflammation. Our new appreciation for inflammation-related checkpoints raises a number of important matters pertaining to anti-inflammatory drug development, and we need to be mindful that during inflammation there may be multiple endogenous pathways attempting to limit or switch off the ongoing response. These pathways must not be inadvertently altered by "anti-inflammatory" drugs. The alternative benefits from this protective biological system is the realization that factors expressed during resolution could be mimicked and used to push ongoing inflammation down a pro-resolution pathway. Such an approach would entail the development of therapeutics that would exert multiple effects at various phases of the inflammatory response—for example, to limit leukocyte trafficking, hasten cell clearance, and help restore homeostasis to inflamed stromal tissue. It is provocative to think that existing anti-inflammatory agents, such as steroids whose development was based on an entirely different strategy, may exert potent pro-resolution effects arising from their pro-apoptosis (e.g., in the activation of eosinophils) and pro-phagocytic properties (66). The potential side effects of developing "pro-resolvers" might arise from the premature resolution of inflammatory responses before they have the chance to deal adequately with the insulting (i.e., "pro-inflammatory") agent. In summary, all inflammatory responses are not the same, and pan-inflammatory inhibitors would not necessarily be the most effective approach to treating inflammation-driven diseases. We need to foster a greater understanding of the nature of the processes that drive each individual inflammatory response and tailor treatments accordingly. To achieve this goal, we must further elucidate the resolution of inflammation and identify possible approaches to promote this process in conjunction perhaps with anti-inflammatory therapies.

Derek Gilroy, PhD, obtained his degree from the William Harvey Research Institute, University of London. His doctoral research addressed the role of inducible cyclooxygenase in inflammation, in collaboration with the late Professors Derek Willoughby and Sir John Vane. He pursued postdoctoral training with Dr. Kenneth Wu, jointly at the University of Houston Texas and at Academia Sinica, Taipei, Tawian. Now at the William Harvey Research Institute, he also holds an appointment as New Blood Lecturer, funded as a Wellcome Trust Career Development Fellow at the department of Medicine, Rayne Institute, University College London. His research interests focus on the endogenous factors that control the resolution of acute innate and adaptive immunity, as well as aspirin-triggered nitric oxide and the regulation of cell trafficking. Address correspondence to DWG. E-mail d.gilroy{at}ucl.ac.uk; fax +020-7679-6351. Ravindra Rajakariar, PhD, (not shown) is a clinical research fellow in the department of experimental medicine, nephrology and critical care in the William Harvey Research Institute, London. His research has involved the role of PGD2 and cyclopentenone PGJ2 in the resolution of peritonitis in an experimental murine model and in end stage renal failure in patients on peritoneal dialysis.

Magdi Yaqoob, PhD, is Professor of Nephrology at the Royal London Hospital and the head of Experimental Medicine, Nephrology and Critical care in the William Harvey Research Institute, London. His research interests include mediators of ischemia reperfusion injury, mechanisms of high glucose–induced proximal tubular injury, and mediators in the resolution of peritonitis.

	References

TOP Summary Introduction: The Other Side... COX Metabolism and NSAIDs NSAIDs and COX-2 Inhibitors Pro-resolution Properties of COX... Aspirin and COX-2 in... Aspirin, COX-2, and Other... Conclusions and Implications for... References

 

1. Nathan, C. Points of control in inflammation. Nature 420, 846–852 (2002).[CrossRef][Medline]
2. Serhan, C.N. and Savill, J. Resolution of inflammation: The beginning programs the end. Nat. Immunol. 6, 1191–1197 (2005).[CrossRef][Medline]
3. Manderson, A.P., Botto, M., and Walport, M.J. The role of complement in the development of systemic lupus erythematosus. Annu. Rev. Immunol. 22, 431–456 (2004).[CrossRef][Medline]
4. Lawrence, T., Willoughby, D.A., and Gilroy, D.W. Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nat. Rev. Immunol. 2, 787–795 (2002).[CrossRef][Medline]
5. Smith, W.L., Garavito, R.M., and DeWitt, D.L. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. J. Biol. Chem. 271, 33157–33160 (1996).[Free Full Text]
6. Harris, R.C., McKanna, J.A., Akai, Y., Jacobson, H.R., Dubois, R.N., and Breyer, M.D. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J. Clin. Invest. 94, 2504–2510 (1994).[Medline]
7. Kaufmann, W.E., Worley, P.F., Pegg, J., Bremer, M., and Isakson, P. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc. Natl. Acad. Sci. USA 93, 2317–2321 (1996).[Abstract/Free Full Text]
8. Sirois, J. and Richards, J.S. Purification and characterization of a novel, distinct isoform of prostaglandin endoperoxide synthase induced by human chorionic gonadotropin in granulosa cells of rat preovulatory follicles. J. Biol. Chem. 267, 6382–6388 (1992).[Abstract/Free Full Text]
9. Hla, T. and Neilson, K. Human cyclooxygenase-2 cDNA. Proc. Natl. Acad. Sci. USA 89, 7384–7388 (1992).[Abstract/Free Full Text]
10. Kujubu, D.A., Fletcher, B.S., Varnum, B.C., Lim, R.W., and Herschman, H.R. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J. Biol. Chem. 266, 12866–12872 (1991).[Abstract/Free Full Text]
11. Smith, C.J., Morrow, J.D., Roberts, L.J., and Marnett, L.J. Differentiation of monocytoid THP-1 cells with phorbol ester induces expression of prostaglandin endoperoxide synthase-1 (COX-1). Biochem. Biophys. Res. Commun. 192, 787–793 (1993).[CrossRef][Medline]
12. Smith, C.J., Morrow, J.D., Roberts, L.J., and Marnett, L.J. Induction of prostaglandin endoperoxide synthase-1 (COX-1) in a human promonocytic cell line by treatment with the differentiating agent TPA. Adv. Exp. Med. Biol. 400A, 99–106 (1997).
13. Jones, D.A., Carlton, D.P., McIntyre, T.M., Zimmerman, G.A., and Prescott, S.M. Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J. Biol. Chem. 268, 9049–9054 (1993).[Abstract/Free Full Text]
14. Topper, J.N., Cai, J., Falb, D., and Gimbrone, M.A., Jr. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc. Natl. Acad. Sci. USA 93, 10417–10422 (1996).[Abstract/Free Full Text]
15. Ayoub, S.S., Botting, R.M., Goorha, S., Colville-Nash, P.R., Willoughby, D.A., and Ballou, L.R. Acetaminophen-induced hypothermia in mice is mediated by a prostaglandin endoperoxide synthase 1 gene-derived protein. Proc. Natl. Acad. Sci. USA 101, 11165–11169 (2004).[Abstract/Free Full Text]
16. Schwab, J.M., Schluesener, H.J., Meyermann, R., and Serhan, C.N. COX-3 the enzyme and the concept: Steps towards highly specialized pathways and precision therapeutics? Prostaglandins Leukot. Essent. Fatty Acids 69, 339–343 (2003).[CrossRef][Medline]
17. Kurumbail, R.G., Stevens, A.M., Gierse, J.K. et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature 384, 644–648 (1996).[CrossRef][Medline]
18. Bombardier, C., Laine, L., Reicin, A. et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N. Engl. J. Med. 343, 1520–1528 (2000).[Abstract/Free Full Text]
19. Silverstein, F.E., Faich, G., Goldstein, J.L. et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. J. Amer. Med. Assoc. 284, 1247–1255 (2000).[Abstract/Free Full Text]
20. Vane, J. Towards a better aspirin. Nature 367, 215–216 (1994).[CrossRef][Medline]
21. FitzGerald, G.A. and Patrono, C. The coxibs, selective inhibitors of cyclo-oxygenase-2. N. Engl. J. Med. 345, 433–442 (2001).[Free Full Text]
22. Gierse, J.K., Hauser, S.D., Creely, D.P., Koboldt, C., Rangwala, S.H., Isakson, P.C., and Seibert, K. Expression and selective inhibition of the constitutive and inducible forms of human cyclo-oxygenase. Biochem. J. 305 ( Pt 2), 479–484 (1995).[Medline]
23. Chan, C.C., Boyce, S., Brideau, C. et al. Pharmacology of a selective cyclooxygenase-2 inhibitor, L-745,337: A novel nonsteroidal anti-inflammatory agent with an ulcerogenic sparing effect in rat and nonhuman primate stomach. J. Pharmacol. Exp. Ther. 274, 1531–1537 (1995).[Abstract/Free Full Text]
24. Futaki, N., Yoshikawa, K., Hamasaka, Y., Arai, I., Higuchi, S., Iizuka, H., and Otomo, S. NS-398, a novel non-steroidal anti-inflammatory drug with potent analgesic and antipyretic effects, which causes minimal stomach lesions. Gen. Pharmacol. 24, 105–110 (1993).[Medline]
25. Futaki, N., Takahashi, S., Yokoyama, M., Arai, I., Higuchi, S., and Otomo, S. NS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro. Prostaglandins 47, 55–59 (1994).[CrossRef][Medline]
26. Gans, K.R., Galbraith, W., Roman, R.J., Haber, S.B., Kerr, J.S., Schmidt, W.K., Smith, C., Hewes, W.E., and Ackerman, N.R. Anti-inflammatory and safety profile of DuP 697, a novel orally effective prostaglandin synthesis inhibitor. J. Pharmacol. Exp. Ther. 254, 180–187 (1990).[Abstract/Free Full Text]
27. Seibert, K., Zhang, Y., Leahy, K., Hauser, S., Masferrer, J., Perkins, W., Lee, L., and Isakson, P. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc. Natl. Acad. Sci. USA 91, 12013–12017 (1994).[Abstract/Free Full Text]
28. Masferrer, J.L., Zweifel, B.S., Colburn, S.M., Ornberg, R.L., Salvemini, D., Isakson, P., and Seibert, K. The role of cyclooxygenase-2 in inflammation. Am. J. Ther. 2, 607–610 (1995).[Medline]
29. Langenbach, R., Morham, S.G., Tiano, H.F. et al. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Am. J. Ther. 83, 483–492 (1995).
30. Morham, S.G., Langenbach, R., Loftin, C.D. et al. Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Am. J. Ther. 83, 473–482 (1995).
31. Wallace, J.L. and Miller, M.J. Nitric oxide in mucosal defense: A little goes a long way. Gastroenterology 119, 512–520 (2000).[CrossRef][Medline]
32. Tanaka, A., Hase, S., Miyazawa, T., and Takeuchi, K. Up-regulation of cyclooxygenase-2 by inhibition of cyclooxygenase-1: A key to nonsteroidal anti-inflammatory drug-induced intestinal damage. J. Pharmacol. Exp. Ther. 300, 754–761 (2002).[Abstract/Free Full Text]
33. Morteau, O., Morham, S.G., Sellon, R., Dieleman, L.A., Langenbach, R., Smithies, O., and Sartor, R.B. Impaired mucosal defense to acute colonic injury in mice lacking cyclooxygenase-1 or cyclooxygenase-2. J. Clin. Invest. 105, 469–478 (2000).[Medline]
34. Ajuebor, M.N., Singh, A., and Wallace, J.L. Cyclooxygenase-2-derived prostaglandin D(2) is an early anti-inflammatory signal in experimental colitis. Am. J. Physiol Gastrointest. Liver Physiol. 279, G238–G244 (2000).[Abstract/Free Full Text]
35. Reuter, B.K., Asfaha, S., Buret, A., Sharkey, K.A., and Wallace, J.L. Exacerbation of inflammation-associated colonic injury in rat through inhibition of cyclooxygenase-2. J. Clin. Invest. 98, 2076–2085 (1996).[Medline]
36. Mizuno, H., Sakamoto, C., Matsuda, K., Wada, K., Uchida, T., Noguchi, H., Akamatsu, T., and Kasuga, M. Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology 112, 387–397 (1997).[CrossRef][Medline]
37. Schmassmann, A., Peskar, B.M., Stettler, C., Netzer, P., Stroff, T., Flogerzi, B., and Halter, F. Effects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastro-intestinal ulcer models in rats. Br. J. Pharmacol. 123, 795–804 (1998).[CrossRef][Medline]
38. Mizuno, H., Sakamoto, C., Matsuda, K., Wada, K., Uchida, T., Noguchi, H., Akamatsu, T., and Kasuga, M. Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology 112, 387–397 (1997).[CrossRef][Medline]
39. Schmassmann, A., Peskar, B.M., Stettler, C., Netzer, P., Stroff, T., Flogerzi, B., and Halter, F. Effects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastro-intestinal ulcer models in rats. Br. J. Pharmacol. 123, 795–804 (1998).[CrossRef][Medline]
40. Morham, S.G., Langenbach, R., Loftin, C.D. et al. Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell 83, 473–482 (1995).[CrossRef][Medline]
41. Gilroy, D.W., Colville-Nash, P.R., Willis, D., Chivers, J., Paul-Clark, M.J., and Willoughby, D.A. Inducible cyclooxygenase may have anti-inflammatory properties. Nat. Med. 5, 698–701 (1999).[CrossRef][Medline]
42. Gilroy, D.W., Newson, J., Sawmynaden, P., Willoughby, D.A., and Croxtall, J.D. A novel role for phospholipase A2 isoforms in the checkpoint control of acute inflammation. FASEB J. 18, 489–498 (2004).[Abstract/Free Full Text]
43. Trivedi, S.G., Newson, J., Rajakariar, R., Jacques, T.S., Hannon, R., Kanaoka, Y., Eguchi, N., Colville-Nash, P., and Gilroy, D.W. Essential role for hematopoietic prostaglandin D2 synthase in the control of delayed type hypersensitivity. Proc. Natl. Acad. Sci. USA 103, 5179–5184 (2006).[Abstract/Free Full Text]
44. Kay, A.B., Barata, L., Meng, Q., Durham, S.R., and Ying, S. Eosinophils and eosinophil-associated cytokines in allergic inflammation. Int. Arch. Allergy Immunol. 113, 196–199 (1997).[Medline]
45. Urade, Y., Ujihara, M., Horiguchi, Y., Igarashi, M., Nagata, A., Ikai, K., and Hayaishi, O. Mast cells contain spleen-type prostaglandin D synthetase. J. Biol. Chem. 265, 371–375 (1990).[Abstract/Free Full Text]
46. Urade, Y., Ujihara, M., Horiguchi, Y., Ikai, K., and Hayaishi, O. The major source of endogenous prostaglandin D2 production is likely antigen-presenting cells. Localization of glutathione-requiring prostaglandin D synthetase in histiocytes, dendritic, and Kupffer cells in various rat tissues. J. Immunol. 143, 2982–2989 (1989).[Abstract]
47. Murray, J.J., Tonnel, A.B., Brash, A.R., Roberts, L.J., Gosset, P., Workman, R., Capron, A., and Oates, J.A. Release of prostaglandin D2 into human airways during acute antigen challenge. N. Engl. J. Med. 315, 800–804 (1986).[Abstract]
48. Palmblad, J., Malmsten, C.L., Uden, A.M., Radmark, O., Engstedt, L., and Samuelsson, B. Leukotriene B4 is a potent and stereospecific stimulator of neutrophil chemotaxis and adherence. Blood 58, 658–661 (1981).[Abstract/Free Full Text]
49. Serhan, C.N., Hamberg, M., and Samuelsson, B. Lipoxins: Novel series of biologically active compounds formed from arachidonic acid in human leukocytes. Proc. Natl. Acad. Sci. USA 81, 5335–5339 (1984).[Abstract/Free Full Text]
50. Edenius, C., Haeggstrom, J., and Lindgren, J.A. Transcellular conversion of endogenous arachidonic acid to lipoxins in mixed human platelet-granulocyte suspensions. Biochem. Biophys. Res. Commun. 157, 801–807 (1988).[CrossRef][Medline]
51. Fiore, S. and Serhan, C.N. Formation of lipoxins and leukotrienes during receptor-mediated interactions of human platelets and recombinant human granulocyte/macrophage colony-stimulating factor-primed neutrophils. J. Exp. Med. 172, 1451–1457 (1990).[Abstract/Free Full Text]
52. Claria, J. and Serhan, C.N. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. Proc. Natl. Acad. Sci. USA 92, 9475–9479 (1995).[Abstract/Free Full Text]
53. Chiang, N., Arita, M., and Serhan, C.N. Anti-inflammatory circuitry: Lipoxin, aspirin-triggered lipoxins and their receptor ALX. Prostaglandins Leukot. Essent. Fatty Acids 73, 163–177 (2005).[CrossRef][Medline]
54. Claria, J. and Serhan, C.N. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. Proc. Natl. Acad. Sci. USA 92, 9475–9479 (1995).[Abstract/Free Full Text]
55. Schaldach, C.M., Riby, J., and Bjeldanes, L.F. Lipoxin A4: A new class of ligand for the Ah receptor. Biochemistry 38, 7594–7600 (1999).[CrossRef][Medline]
56. Fiore, S., Maddox, J.F., Perez, H.D., and Serhan, C.N. Identification of a human cDNA encoding a functional high affinity lipoxin A4 receptor. J. Exp. Med. 180, 253–260 (1994).[Abstract/Free Full Text]
57. Takano, T., Fiore, S., Maddox, J.F., Brady, H.R., Petasis, N.A., and Serhan, C.N. Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: Evidence for anti-inflammatory receptors. J. Exp. Med. 185, 1693–1704 (1997).[Abstract/Free Full Text]
58. Hachicha, M., Pouliot, M., Petasis, N.A., and Serhan, C.N. Lipoxin (LX)A4 and aspirin-triggered 15-epi-LXA4 inhibit tumor necrosis factor 1alpha-initiated neutrophil responses and trafficking: regulators of a cytokine-chemokine axis. J. Exp. Med. 189, 1923–1930 (1999).[Abstract/Free Full Text]
59. Maddox, J.F. and Serhan, C.N. Lipoxin A4 and B4 are potent stimuli for human monocyte migration and adhesion: selective inactivation by dehydrogenation and reduction. J. Exp. Med. 183, 137–146 (1996).[Abstract/Free Full Text]
60. Godson, C., Mitchell, S., Harvey, K., Petasis, N.A., Hogg, N., and Brady, H.R. Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. J. Immunol. 164, 1663–1667 (2000).[Abstract/Free Full Text]
61. Maddox, J.F. and Serhan, C.N. Lipoxin A4 and B4 are potent stimuli for human monocyte migration and adhesion: Selective inactivation by dehydrogenation and reduction. J. Exp. Med. 183, 137–146 (1996).[Abstract/Free Full Text]
62. Paul-Clark, M.J., Van Cao, T., Moradi-Bidhendi, N., Cooper, D., and Gilroy, D.W. 15-epi-lipoxin A4-mediated induction of nitric oxide explains how aspirin inhibits acute inflammation. J. Exp. Med. 200, 69–78 (2004).[Abstract/Free Full Text]
63. Bannenberg, G.L., Chiang, N., Ariel, A., Arita, M., Tjonahen, E., Gotlinger, K.H., Hong, S., and Serhan, C.N. Molecular circuits of resolution: Formation and actions of resolvins and protectins. J. Immunol. 174, 4345–4355 (2005).[Abstract/Free Full Text]
64. Serhan, C.N., Hong, S., Gronert, K., Colgan, S.P., Devchand, P.R., Mirick, G., and Moussignac, R.L. Resolvins: A family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J. Exp. Med. 196, 1025–1037 (2002).[Abstract/Free Full Text]
65. Bannenberg, G., Moussignac, R.L., Gronert, K. et al. Lipoxins and novel 15-epi-lipoxin analogs display potent anti-inflammatory actions after oral administration. Br. J. Pharmacol. 143, 43–52 (2004).[CrossRef][Medline]
66. Rhen, T. and Cidlowski, J.A. Antiinflammatory action of glucocorticoids—New mechanisms for old drugs. N. Engl. J. Med. 353, 1711–1723 (2005).[Free Full Text]
67. Mardini, I.A. and FitzGerald, G.A. Selective inhibitors of cyclooxygenase-2: A growing class of anti-inflammatory drugs. Mol. Interv. 1, 30–38 (2001).[Abstract/Free Full Text]

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