A highly selective mPGES-1 inhibitor to block abdominal aortic aneurysm progression in the angiotensin mouse model.

Abdominal aortic aneurysm (AAA) is a deadly, permanent ballooning of the aortic artery. Pharmacological and genetic studies have pointed to multiple proteins, including microsomal prostaglandin E2 synthase-1 (mPGES-1), as potentially promising targets. However, it remains unknown whether administration of an mPGES-1 inhibitor can effectively attenuate AAA progression in animal models. There are still no FDA-approved pharmacological treatments for AAA. Current research stresses the importance of both anti-inflammatory drug targets and rigor of translatability. Notably, mPGES-1 is an inducible enzyme responsible for overproduction of prostaglandin E2 (PGE2)-a well-known principal pro-inflammatory prostanoid. Here we demonstrate for the first time that a highly selective mPGES-1 inhibitor (UK4b) can completely block further growth of AAA in the ApoE-/- angiotensin (Ang)II mouse model. Our findings show promise for the use of a mPGES-1 inhibitor like UK4b as interventional treatment of AAA and its potential translation into the clinical setting.

Analgesic effects of a highly selective mPGES-1 inhibitor.

The growing opioid use and overdose crisis in the US is closely related to the abuse of pain medications. Particularly for postoperative pain (POP), ~ 310 million major surgeries are performed globally per year. Most patients undergoing surgical procedures experience acute POP, and ~ 75% of those with POP report the severity as moderate, severe, or extreme. Opioid analgesics are the mainstay for POP management. It is highly desirable to develop a truly effective and safe non-opioid analgesic to treat POP and other forms of pain. Notably, microsomal prostaglandin E2 (PGE2) synthase-1 (mPGES-1) was once proposed as a potentially promising target for a next generation of anti-inflammatory drugs based on studies in mPGES-1 knockouts. However, to the best of our knowledge, no studies have ever been reported to explore whether mPGES-1 is also a potential target for POP treatment. In this study, we demonstrate for the first time that a highly selective mPGES-1 inhibitor can effectively relieve POP as well as other forms of pain through blocking the PGE2 overproduction. All the data have consistently demonstrated that mPGES-1 is a truly promising target for treatment of POP as well as other forms of pain.

Development of pharmacotherapies for abdominal aortic aneurysms.

The cardiovascular field is still searching for a treatment for abdominal aortic aneurysms (AAA). This inflammatory disease often goes undiagnosed until a late stage and associated rupture has a high mortality rate. No pharmacological treatment options are available. Three hallmark factors of AAA pathology include inflammation, extracellular matrix remodeling, and vascular smooth muscle dysfunction. Here we discuss drugs for AAA treatment that have been studied in clinical trials by examining the drug targets and data present for each drug's ability to regulate the aforementioned three hallmark pathways in AAA progression. Historically, drugs that were examined in interventional clinical trials for treatment of AAA were repurposed therapeutics. Novel treatments (biologics, small-molecule compounds etc.) have not been able to reach the clinic, stalling out in pre-clinical studies. Here we discuss the backgrounds of previous investigational drugs in hopes of better informing future development of potential therapeutics. Overall, the highlighted themes discussed here stress the importance of both centralized anti-inflammatory drug targets and rigor of translatability. Exceedingly few murine studies have examined an intervention-based drug treatment in halting further growth of an established AAA despite interventional treatment being the therapeutic approach taken to treat AAA in a clinical setting. Additionally, data suggest that a potentially successful drug target may be a central inflammatory biomarker. Specifically, one that can effectively modulate all three hallmark factors of AAA formation, not just inflammation. It is suggested that inhibiting PGE2 formation with an mPGES-1 inhibitor is a leading drug target for AAA treatment to this end.

Microsomal Prostaglandin E Synthase-1 Expression by Aortic Smooth Muscle Cells Attenuates the Differentiated Phenotype.

The development of numerous types of cardiovascular disease is associated with alteration of the vascular smooth muscle cell (SMC) phenotype. We have previously shown that abdominal aortic aneurysm progression in a mouse model of the disease is associated with reduced differentiation of SMCs within the lesion and that cyclooxygenase-2 (COX-2) is critical to initiation and progression of the aneurysms. The current studies used human aortic SMC (hASMC) cultures to better characterize mechanisms responsible for COX-2-dependent modulation of the SMC phenotype. Depending on the culture conditions, hASMCs expressed multiple characteristics of a differentiated and contractile phenotype, or a dedifferentiated and secretory phenotype. The pharmacological inhibition of COX-2 promoted the differentiated phenotype, whereas treatment with the COX-2-derived metabolite prostaglandin E2 (PGE2) increased characteristics of the dedifferentiated phenotype. Furthermore, pharmacological inhibition or siRNA-mediated knockdown of microsomal prostaglandin E synthase-1 (mPGES-1), the enzyme that functions downstream of COX-2 during the synthesis of PGE2, significantly increased expression of characteristics of the differentiated SMC phenotype. Therefore, our findings suggest that COX-2 and mPGES-1-dependent synthesis of PGE2 contributes to a dedifferentiated hASMC phenotype and that mPGES-1 may provide a novel pharmacological target for treatment of cardiovascular diseases where altered SMC differentiation has a causative role.

Effect of genetic variation in P2Y12 on TRAP-stimulated platelet response in healthy subjects.

In platelets, thrombin receptor signaling depends upon the release of adenosine diphosphate and subsequent activation at purinergic subtype Y (P2Y) receptors. The purpose of this study is to evaluate the influence of specific P2Y12 polymorphisms on platelet reactivity in healthy subjects mediated by thrombin receptor activating peptide (TRAP). We recruited a total of 29 healthy volunteers who had been previously genotyped for two polymorphisms of the P2Y12 receptor: the H2 haplotype (rs2046934) and 34C>T (rs6785930). Flow cytometry and the VerifyNow assay were used to assess platelet activation and aggregation stimulated by TRAP in the presence and absence of specific receptor antagonists for the P2Y1, P2Y12, and thromboxane A2 receptors. We identified a significant recessive effect of the P2Y12-receptor H2 haplotype on TRAP-induced flow cytometry. Specifically, H2/H2 carriers (n = 5) demonstrated a significant reduction in both glycoprotein IIb/IIIa receptor activation (p < 0.001) and CD62P expression (p = 0.035). While the VerifyNow assay did not reveal any effect of haplotype on TRAP-mediated platelet aggregation (p = 0.72), the H2/H2 subjects demonstrated greater platelet inhibition in the presence of cangrelor, a specific receptor antagonist for the P2Y12 receptor (p = 0.023). No consistent effects of the separate 34C>T genotype (rs6785930) were demonstrated under the conditions evaluated. The findings of this study suggest a potential association between P2Y12-receptor H2/H2 carriers and reduced platelet function mediated by TRAP in healthy volunteers.

ß-Arrestin-2 deficiency attenuates abdominal aortic aneurysm formation in mice.

RATIONALE: Abdominal aortic aneurysms (AAAs) are a chronic inflammatory vascular disease for which pharmacological treatments are not available. A mouse model of AAA formation involves chronic infusion of angiotensin II (AngII), and previous studies indicated a primary role for the AngII type 1a receptor in AAA formation. ß-arrestin (ßarr)-2 is a multifunctional scaffolding protein that binds G-protein-coupled receptors such as AngII type 1a and regulates numerous signaling pathways and pathophysiological processes. However, a role for ßarr2 in AngII-induced AAA formation is currently unknown. OBJECTIVE: To determine whether ßarr2 played a role in AngII-induced AAA formation in mice. METHODS AND RESULTS: Treatment of ßarr2(+/+) and ßarr2(-/-) mice on the hyperlipidemic apolipoprotein E-deficient (apoE(-/-)) background or on normolipidemic C57BL/6 background with AngII for 28 days indicated that ßarr2 deficiency significantly attenuated AAA formation. ßarr2 deficiency attenuated AngII-induced expression of cyclooxygenase-2, monocyte chemoattractant protein-1, macrophage inflammatory protein 1α, and macrophage infiltration. AngII also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 in apoE(-/-)/ßarr2(+/+) aortas, whereas ßarr2 deficiency diminished this increase. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 activation with CI1040 (100 mg/kg per day) reduced the level of AngII-induced cyclooxygenase-2 expression in apoE(-/-)/ßarr2(+/+) mice to the level observed in apoE(-/-)/ßarr2(-/-) mice. AngII treatment also increased matrix metalloproteinase expression and disruption of the elastic layer in apoE(-/-)/ßarr2(+/+) aortas, and ßarr2 deficiency reduced these effects. CONCLUSIONS: ßarr2 contributes to AngII-induced AAA formation in mice by phosphorylated extracellular signal-regulated kinase 1/2-mediated cyclooxygenase-2 induction and increased inflammation. These studies suggest that for the AngII type 1a receptor, G-protein-independent, ßarr2-dependent signaling plays a major role in AngII-induced AAA formation.

Cyclooxygenase-2 inhibition attenuates abdominal aortic aneurysm progression in hyperlipidemic mice.

Abdominal aortic aneurysms (AAAs) are a chronic inflammatory disease that increase the risk of life-threatening aortic rupture. In humans, AAAs have been characterized by increased expression of cyclooxygenase-2 and the inactivation of COX-2 prior to disease initiation reduces AAA incidence in a mouse model of the disease. The current study examined the effectiveness of selective cyclooxygenase-2 (COX-2) inhibition on reducing AAA progression when administered after the initiation of AAA formation. AAAs were induced in hyperlipidemic apolipoprotein E-deficient mice by chronic angiotensin II (AngII) infusion and the effect of treatment with the COX-2 inhibitor celecoxib was examined when initiated at different stages of the disease. Celecoxib treatment that was started 1 week after initiating AngII infusion reduced AAA incidence by 61% and significantly decreased AAA severity. Mice treated with celecoxib also showed significantly reduced aortic rupture and mortality. Treatment with celecoxib that was started at a late stage of AAA development also significantly reduced AAA incidence and severity. Celecoxib treatment significantly increased smooth muscle alpha-actin expression in the abdominal aorta and did not reduce expression of markers of macrophage-dependent inflammation. These findings indicate that COX-2 inhibitor treatment initiated after formation of AngII-induced AAAs effectively reduces progression of the disease in hyperlipidemic mice.

Effectiveness of cyclooxygenase-2 inhibition in limiting abdominal aortic aneurysm progression in mice correlates with a differentiated smooth muscle cell phenotype.

Abdominal aortic aneurysms (AAAs) are a chronic condition that often progress over years to produce a weakened aorta with increased susceptibility for rupture, and currently, there are no pharmacological treatments available to slow disease progression. AAA development has been characterized by increased expression of cyclooxygenase-2 (COX-2), and inactivation of COX-2 before disease initiation reduces AAA incidence in a mouse model of the disease. The current study determined the effectiveness of COX-2 inhibition on AAA progression when treatment was begun after initiation of the disease. COX-2 inhibitor treatment with celecoxib was initiated after angiotensin II-induced AAA formation in a strain of nonhyperlipidemic mice that we have previously identified as highly susceptible to AAA development. When analyzed at different time points during progression of the disease, celecoxib treatment significantly reduced the incidence and severity of AAAs. The celecoxib treatment also protected the mice from aortic rupture and death. The aneurysmal lesion displayed an altered smooth muscle cell (SMC) phenotype, whereas celecoxib treatment was associated with increased expression of differentiated SMC markers and reduced dedifferentiation marker expression during AAA progression. Maintenance of a differentiated SMC phenotype is associated with the effectiveness of COX-2 inhibition for limiting AAA progression in nonhyperlipidemic mice.

Diclofenac enables prolonged delivery of naltrexone through microneedle-treated skin.

PURPOSE: The purpose of this study was to determine if non-specific COX inhibition could extend pore lifetime in hairless guinea pigs following microneedle treatment. METHODS: Hairless guinea pigs were treated with microneedle arrays ± daily application of Solaraze® gel (3% diclofenac sodium (non-specific COX inhibitor) and 2.5% hyaluronic acid); transepidermal water loss was utilized to evaluate pore lifetime. To examine the permeation of naltrexone, additional guinea pigs were treated with microneedles ± daily Solaraze® gel followed by application of a 16% transdermal naltrexone patch; pharmacokinetic analysis of plasma naltrexone levels was performed. Histological analysis was employed to visualize morphological changes following microneedle and Solaraze® treatment. RESULTS: Animals treated with microneedles + Solaraze® displayed extended pore lifetime (determined by transepidermal water loss measurements) for up to 7 days. Enhanced naltrexone permeation was also observed for an extended amount of time in animals treated with microneedles + Solaraze®. No morphological changes resulting from microneedle treatment or COX inhibition were noted. CONCLUSIONS: Non-specific COX inhibition is an effective means of extending pore lifetime following microneedle treatment in hairless guinea pigs. This may have clinical implications for extending transdermal patch wear time and therefore increasing patient compliance with therapy.

Cyclooxygenase-2 deficiency attenuates adipose tissue differentiation and inflammation in mice.

Obesity is associated with a variety of disorders and is a significant health problem in developed countries. One factor controlling the level of adiposity is the differentiation of cells into adipocytes. Adipocyte differentiation requires expression of peroxisome proliferator-activated receptor γ (PPARγ), which is activated by ligands to regulate expression of genes involved in adipocyte differentiation. Although 15-deoxy-Δ(12,14)-prostaglandin (PG) J(2) (15d-PGJ(2)) has long been known to be a potent activator of PPARγ, the importance of its synthesis in adipose tissue in vivo is not clear. The current study utilized mice deficient in cyclooxygenase-2 (COX-2) to examine the role of COX-2-derived PGs as in vivo modulators of adiposity. As compared with strain- and age-matched wild-type controls, the genetic deficiency of COX-2 resulted in a significant reduction in total body weight and percent body fat. Although there were no significant differences in food consumption between groups, COX-2-deficient mice showed increased metabolic activity. Epididymal adipose tissue from wild-type mice produced a significantly greater level of 15d-PGJ(2), as compared with adipose tissue isolated from mice deficient in COX-2. Furthermore, production of the precursor required for 15d-PGJ(2) formation, PGD(2), was also significantly reduced in COX-2-deficient adipose tissue. The expression of markers for differentiated adipocytes was significantly reduced in adipose tissue from COX-2-deficient mice, whereas preadipocyte marker expression was increased. Macrophage-dependent inflammation was also significantly reduced in adipose tissue of COX-2-deficient mice. These findings suggest that reduced adiposity in COX-2-deficient mice results from attenuated PPARγ ligand production and adipocyte differentiation.

Effects of genetic deficiency of cyclooxygenase-1 or cyclooxygenase-2 on functional and histological outcomes following traumatic brain injury in mice.

BACKGROUND: Neuroinflammation contributes to the pathophysiology of acute CNS injury, including traumatic brain injury (TBI). Although prostaglandin lipid mediators of inflammation contribute to a variety of inflammatory responses, their importance in neuroinflammation is not clear. There are conflicting reports as to the efficacy of inhibiting the enzymes required for prostaglandin formation, cyclooxygenase (COX) -1 and COX-2, for improving outcomes following TBI. The purpose of the current study was to determine the role of the COX isoforms in contributing to pathological processes resulting from TBI by utilizing mice deficient in COX-1 or COX-2. RESULTS: Following a mild controlled cortical impact injury, the amount of cortical tissue loss, the level of microglial activation, and the capacity for functional recovery was compared between COX-1-deficient mice or COX-2-deficient mice, and their matching wild-type controls. The deficiency of COX-2 resulted in a minor (6%), although statistically significant, increase in the sparing of cortical tissue following TBI. The deficiency of COX-1 resulted in no detectable effect on cortical tissue loss following TBI. As determined by 3[H]-PK11195 autoradiography, TBI produced a similar increase in microglial activation in multiple brain regions of both COX-1 wild-type and COX-1-deficient mice. In COX-2 wild-type and COX-2-deficient mice, TBI increased 3[H]-PK11195 binding in all brain regions that were analyzed. Following injury, 3[H]-PK11195 binding in the dentate gyrus and CA1 region of the hippocampus was greater in COX-2-deficient mice, as compared to COX-2 wild-type mice. Cognitive assessment was performed in the wild-type, COX-1-deficient and COX-2-deficient mice following 4 days of recovery from TBI. There was no significant cognitive effect that resulted from the deficiency of either COX-1 or COX-2, as determined by acquisition and spatial memory retention testing in a Morris water maze. CONCLUSION: These findings suggest that the deficiency of neither COX-1 nor COX-2 is sufficient to alter cognitive outcomes following TBI in mice.

Cyclooxygenase-2 inhibition increases lipopolysaccharide-induced atherosclerosis in mice.

AIMS: The risk of adverse cardiovascular events in humans is increased with chronic use of cyclooxygenase-2 (COX-2) inhibitors. However, the role of COX-2 in animal models of cardiovascular disease has been controversial. In humans and animal models, cardiovascular disease is increased by bacterial infection of the supporting tissue of the teeth, a condition known as periodontal disease. Periodontal disease may result in chronic exposure to pro-inflammatory mediators, such as bacterial lipopolysaccharide (LPS), thereby producing a systemic inflammatory response. The current study examined the role of COX-2 in atherosclerosis induced by LPS derived from the periodontal disease pathogen Porphyromonas gingivalis (P. gingivalis). METHODS AND RESULTS: Porphyromonas gingivalis LPS was administered by chronic infusion for 28 days and atherosclerosis development was examined in the aortic root of ApoE (apolipoprotein E)-deficient mice. The extent of atherosclerosis was compared between mice receiving control diet or diet containing the COX-2 inhibitor celecoxib. The role of COX-2 in P. gingivalis LPS-induced inflammatory cell activation was examined in peritoneal macrophages. Porphyromonas gingivalis LPS infusion significantly increased atherosclerosis development. In mice infused with P. gingivalis LPS, administration of the COX-2 inhibitor celecoxib further increased the extent of atherosclerotic lesion area. In peritoneal macrophages, P. gingivalis LPS increased the expression of COX-2 mRNA (messenger ribonucleic acid) and the production of prostaglandin (PG) E(2) (PGE(2)), the latter of which was inhibited by celecoxib. Porphyromonas gingivalis LPS-induced expression of tumour necrosis factor alpha (TNFalpha) was enhanced by inactivation of COX-2 and was attenuated by treatment with PGE(2). CONCLUSION: The inhibition of COX-2-derived PGE(2) may enhance P. gingivalis LPS-induced atherosclerosis by increasing macrophage production of TNFalpha.

Cyclo-oxygenase-1-selective inhibitor SC-560.

In the title compound, 5-(4-chloro-phen-yl)-1-(4-methoxy-phen-yl)-3-(trifluoro-meth-yl)-1H-pyrazole (SC-560), C(17)H(12)ClF(3)N(2)O, a COX-1-selective inhibitor, the dihedral angles between the heterocycle and the chlorobenzene and methoxybenzene rings are 41.66 (6) and 43.08 (7)°, respectively. The dihedral angle between the two phenyl rings is 59.94 (6)°. No classic hydrogen bonds are possible in the crystal, and intermolecular interactions must be mainly of the dispersion type. This information may aid the identification of dosage formulations with improved oral bioavailability.

Genetic deficiency of cyclooxygenase-2 attenuates abdominal aortic aneurysm formation in mice.

OBJECTIVE: Abdominal aortic aneurysms (AAAs) are characterized by chronic inflammation which contributes to the remodeling and eventual weakening of the vessel wall. Increased cyclooxygenase-2 (COX-2) expression is detected in human aneurysmal tissue and is suggested to contribute to the disease. The aim of the current study was to define the role of COX-2 expression in the development of AAAs, using a model of the disease. METHODS: AAAs were induced in mice by chronic angiotensin II infusion, and were analyzed following 3, 7, 21 or 28 days of the infusion. AAA incidence and severity, together with the expression of inflammatory markers, were compared between abdominal aortas from COX-2-deficient mice and their wild-type littermate controls. RESULTS: The AAA incidence in COX-2 wild-type mice was 54% (13/24), whereas AAAs were not detected in COX-2-deficient mice (0/23) following 28 days of angiotensin II infusion. The genetic deficiency of COX-2 also resulted in a 73% and 90% reduction in AAA incidence following 7 and 21 days of angiotensin II infusion, respectively. In COX-2 wild-type mice, COX-2 mRNA expression in the abdominal aorta was induced by angiotensin II beginning 3 days following initiation of the infusion, which continued throughout progression of the disease. Abundant COX-2 protein expression was detected in medial smooth muscle cells adjacent to the AAAs. The deficiency of COX-2 significantly attenuated mRNA expression in the abdominal aorta of the macrophage marker CD68, and the inflammatory cell recruitment chemokines, monocyte chemotactic protein-1 and macrophage inflammatory protein-1alpha. CONCLUSIONS: Our findings suggest that increased COX-2 expression in smooth muscle cells of the abdominal aorta contributes to AAA formation in mice by enhancing inflammatory cell infiltration.

Attenuated cyclooxygenase-2 expression contributes to patent ductus arteriosus in preterm mice.

Patent ductus arteriosus (DA) is the second most common congenital heart defect, the incidence of which is increased in premature infants, although mechanisms responsible are not clear. Our previous studies with genetic or pharmacological inactivation of cyclooxygenase-2 (COX-2) in mice, emphasized the importance of this enzyme in normal DA closure. The current study was designed to determine whether reduced COX-2 expression contributes to patent DA in preterm mice. Real-time PCR analysis indicated that COX-2 expression in the fetal mouse DA significantly increased with advancing gestational age. Furthermore, we observed a significant induction in COX-2 expression in the DA at 3 h after birth at full-term gestation. In contrast, COX-2 expression was significantly attenuated in the DA of preterm neonatal mice. DA closure was incomplete in preterm mice at 3 h postpartum, a time-point when the DA of full-term neonates was completely remodeled. Additionally, COX-2 expression was significantly attenuated in the DA of mice deficient in the prostanoid receptor EP4, which also show a patent DA phenotype, suggesting the importance of this receptor for the induction of COX-2 required for DA closure. Overall, these studies suggest that attenuated expression of COX-2 may contribute to increased patent DA at preterm gestation.

Selective cyclooxygenase-2 inhibition with celecoxib decreases angiotensin II-induced abdominal aortic aneurysm formation in mice.

OBJECTIVE: Inflammation plays an integral role in the development of abdominal aortic aneurysms (AAAs), and the expression of cyclooxygenase (COX)-2 is increased in aneurysmal tissue compared with normal aorta. Nonsteroidal anti-inflammatory drugs, which inhibit the activity of COX-1 and COX-2, decrease AAA expansion in humans and animal models of the disease. In the current study, we investigated the effectiveness of selective inhibition of COX-1 or COX-2 in attenuating AAA formation. METHODS AND RESULTS: Eight-week-old male apolipoprotein E-deficient mice were treated with selective inhibitors of COX-1 or COX-2, SC-560 (approximately 25 mg.kg(-1).day(-1)), or celecoxib (approximately 125 mg.kg(-1).day(-1)), respectively. COX inhibitors were administered 1 week before angiotensin II (Ang II; 1000 ng.kg(-1).min(-1)) or saline infusion and throughout the time course of the experiment. COX-1 inhibition had no effect on incidence (control: 90% [9:10] versus SC-560: 89% [8:9]) or severity of Ang II-induced AAA formation. In contrast, celecoxib decreased the incidence (control: 74% [22:30] versus celecoxib: 11% [2:19]; P<0.001) and severity (P=0.001) of AAA formation. Celecoxib also decreased the incidence and severity of AAAs in nonhyperlipidemic mice. CONCLUSIONS: COX-2-derived prostanoids play a fundamental role in the development of Ang II-induced AAAs in both hyperlipidemic and nonhyperlipidemic mice.

Generation of a conditional allele of the mouse prostaglandin EP4 receptor.

Genetic disruption of the mouse EP4 receptor results in perinatal lethality associated with persistent patent ductus areteriosus (PDA). To circumvent this, an EP4 allele amenable to conditional deletion using the Cre/loxP system was generated. The targeting construct was comprised of a floxed exon2 in tandem with the neomycin-resistance gene in intron 2, flanked by third 3' LoxP site. Mice homozygous for the targeted allele (EP4(lox+neo/lox+neo)), or following its Cre-mediated deletion (EP4(del/del)), also die within hours of birth with PDA. In contrast, mice homozygous for a partially recombined allele, retaining exon2 but lacking neo (EP4(flox/flox)), are viable and show no overt phenotype. Postnatal deletion of the floxed EP4 gene is efficiently achieved in the liver and kidney in a transgenic mouse expressing the inducible Mx1Cre recombinase. The EP4(flox) mouse should provide a useful reagent with which to examine the physiologic roles of the EP4 receptor.

Phenotypes of the COX-deficient mice indicate physiological and pathophysiological roles for COX-1 and COX-2.

The development of mice deficient in either cyclooxygenase-1 (COX-1) or COX-2, as well as mice deficient in both COX isoforms, has provided models to elucidate the physiological and pathophysiological roles of these enzymes. The findings obtained with the COX-deficient mice suggest that COX-2 may be more important than COX-1 for supplying prostaglandins (PGs) to maintain tissue homeostasis. Furthermore, both isoforms may be involved in the development of diseases, such as inflammation and cancer. Therefore, the contribution of each isoform to the prevention or development of disease is more complex than originally described. Studies with the COX-deficient mice suggest that in addition to COX-2-selective inhibition, therapeutic advances may also be achieved with COX-1-selective inhibitors which lack gastrointestinal side effects.

Cyclooxygenase-1-selective inhibition prolongs gestation in mice without adverse effects on the ductus arteriosus.

Preterm delivery is the leading cause of neonatal mortality and contributes significantly to infant morbidity. Classical cyclooxygenase (COX) inhibitors, such as indomethacin, which inhibit both COX-1 and COX-2, are effective for delaying premature labor, but their use is limited by serious complications to the fetus and neonate, including adverse effects on the ductus arteriosus (DA). Using isoform-selective inhibitors, we characterized the roles of the COX isoforms in the initiation of labor and the regulation of fetal and neonatal DA closure in mice. Chronic inhibition of COX-2 during pregnancy (gestation days 15-18) significantly increased neonatal mortality by preventing closure of the DA after birth, whereas acute COX-2 inhibition near the end of term (gestation day 18) constricted the fetal DA. In contrast, the inhibition of COX-1 during pregnancy lacked these prenatal and postnatal adverse effects on the DA and effectively delayed the initiation of full-term labor and LPS-induced preterm labor. These findings suggest that premature fetal DA closure or neonatal patent DA observed following indomethacin tocolysis in women may result from the inhibition of COX-2. Therefore, COX-1-selective inhibitors may provide effective treatment to delay preterm labor with fewer adverse effects on fetal or neonatal health than nonselective or COX-2-selective inhibitors.