The prostaglandin endoperoxide H synthase isoform 2, cyclooxygenase 2 (COX-2), is induced at high levels in migratory and other responding cells by pro-inflammatory stimuli. COX-2 is generally considered to be a mediator of inflammation. Its isoform, COX-1, is constitutively expressed in most tissues and is thought to mediate "housekeeping" functions. These two enzymes are therapeutic targets of the widely used nonsteroidal anti-inflammatory drugs (NSAIDs). To investigate further the different physiologic roles of these isoforms, we have used homologous recombination to disrupt the mouse gene encoding COX-2 (Ptgs2). Mice lacking COX-2 have normal inflammatory responses to treatments with tetradecanoyl phorbol acetate or with arachidonic acid. However, they develop severe nephropathy and are susceptible to peritonitis.

Cyclooxygenases 1 and 2 (COX-1 and COX-2) are key enzymes in prostaglandin biosynthesis and the target enzymes for the widely used nonsteroidal anti-inflammatory drugs. To study the physiological roles of the individual isoforms, we have disrupted the mouse Ptgs1 gene encoding COX-1. Homozygous Ptgs1 mutant mice survive well, have no gastric pathology, and show less indomethacin-induced gastric ulceration than wild-type mice, even though their gastric prostaglandin E2 levels are about 1% of wild type. The homozygous mutant mice have reduced platelet aggregation and a decreased inflammatory response to arachidonic acid, but not to tetradecanoyl phorbol acetate. Ptgs1 homozygous mutant females mated to homozygous mutant males produce few live offspring. COX-1-deficient mice provide a useful model to distinguish the physiological roles of COX-1 and COX-2.

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 (Ϸ25 mg ⅐ kg Ϫ1 ⅐ day Ϫ1), or celecoxib (Ϸ125 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), respectively. COX inhibitors were administered 1 week before angiotensin II (Ang II; 1000 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) or saline infusion and throughout the time course of the experiment. COX-1 inhibition had no effect on incidence (control: 90% [9:10] versus ) or severity of Ang II-induced AAA formation. In contrast, celecoxib decreased the incidence (control: 74% Key Words: cyclooxygenase-1 Ⅲ cyclooxygenase-2 Ⅲ abdominal aortic aneurysms Ⅲ celecoxib Ⅲ prostaglandin E 2 A bdominal aortic aneurysms (AAAs) are an increasing health concern, particularly in the male population Ͼ65 years of age. AAAs are a permanent dilation of the artery leading to extensive remodeling of the vessel wall with a potential for rupture and resulting mortality. Hallmarks of AAAs are proteolytic degradation and the presence of an inflammatory infiltrate within the vascular wall. 1 Inflammatory cells within the vascular wall are a significant source of proteolytic enzymes that contribute to the disease. 1,2 Thus, a putative cause of human AAAs may be cellular remodeling within the vascular wall resulting from chronic inflammation and matrix degradation. See page 956Prostanoids are a class of inflammatory mediators that are dramatically increased in aneurysmal tissue. [3][4][5] Prostanoids, which include prostaglandins and thromboxane A 2 , are synthesized by the 2 known isoforms of prostaglandin G/H synthase, also known as cyclooxygenase (COX)-1 and COX-2. 6 -8 COX-1 is constitutively expressed in most tissues, whereas COX-2 expression is inducible and is primarily responsible for the synthesis of prostanoids that contribute to inflammation. 6 -8 COX-2 expression is induced during the development of aneurysms, whereas, COX-1 expression is not altered, suggesting a primary role for COX-2 in the development of this disease. [3][4][5] Although a variety of inflammatory cells are present in aneurysmal tissue, macrophages are believed to have a pronounced role in the pathogenesis of AAAs. 2,9,10 Activated macrophages within the inflammatory infiltrate of human AAAs are a significant source of COX-2 expression, which may be responsible for the synthesis of prostanoids contributing to the vascular inflammation. 4,5 The prostanoid most often observed in human aneurysmal tissue is prostaglandin E 2 (PGE 2 ). 4,5 PGE 2 synthesized by macrophages and smooth muscle cells (S...

The transition to pulmonary respiration following birth requires rapid alterations in the structure of the mammalian cardiovascular system. One dramatic change that occurs is the closure and remodeling of the ductus arteriosus (DA), an arterial connection in the fetus that directs blood flow away from the pulmonary circulation. A role for prostaglandins in regulating the closure of this vessel has been supported by pharmacological and genetic studies. The production of prostaglandins is dependent on two cyclooxygenases (COX-1 and COX-2), which are encoded by separate genes. We report here that the absence of either or both COX isoforms in mice does not result in premature closure of the DA in utero. However, 35% of COX-2(؊͞؊) mice die with a patent DA within 48 h of birth. In contrast, the absence of only the COX-1 isoform does not affect closure of the DA. The mortality (35%) and patent DA incidence due to absence of COX-2 is, however, significantly increased (79%) when one copy of the gene encoding COX-1 is also inactivated. Furthermore, 100% of the mice deficient in both isoforms die with a patent DA within 12 h of birth, indicating that in COX-2-deficient mice, the contribution of COX-1 to DA closure is gene dosage-dependent. Together, these data establish roles for COX-1, and especially for COX-2, in the transition of the cardiopulmonary circulation at birth. T he ductus arteriosus (DA) is an arterial connection in the fetus between the pulmonary artery and the aorta. The DA directs deoxygenated blood away from the pulmonary circulation toward the descending aorta and to the umbilicoplacental circulation where oxygenation occurs. The DA plays a critical role in the cardiovascular physiology of the fetus and newborn (for review see ref. 1). In utero patency of the DA is essential for proper fetal health, and premature DA closure causes pulmonary hypertension, congestive heart failure, and edema. In contrast, failure of the DA to close after birth, designated patent DA, compromises postnatal health by contributing to respiratory complications, including pulmonary hypertension and edema (2).A family of lipid mediators known as prostaglandins (PGs) are among the factors that have been shown to influence the tone of the DA. The initial reaction in the synthesis of all PGs is catalyzed by prostaglandin G͞H synthase, also known as cyclooxygenase (COX), two isoforms of which have been identified. Both COX-1 and COX-2 catalyze the synthesis of PGH 2 , a product required for the formation of the various biologically active PGs (3). Individual PGs act through specific receptors to mediate their biological effects. The role for PGs in regulation of DA tone was initially determined from the observation that nonsteroidal anti-inflammatory drugs (NSAIDs), which act by inhibiting COX (4), modulate DA tone in utero and following birth (1).The dilation of the DA in utero is an active process maintained primarily by PGE 2 . The PG receptors that may have a role in dilation of the DA include the PGE 2 receptors, EP2 (5) and EP...

Cyclooxygenase (COX)-1- and COX-2-deficient mice have unique physiological differences that have allowed investigation into the individual biological roles of the COX isoforms. In the following, the phenotypes of the two COX knockout mice are summarized, and recent studies to investigate the effects of COX deficiency on inflammatory responses and cancer susceptibility are discussed. The data suggest that both isoforms have important roles in the maintenance of physiological homeostasis and that such designations as house-keeping and/or response gene may not be entirely accurate. Furthermore, data from COX-deficient mice indicate that both isoforms can contribute to the inflammatory response and that both isoforms have significant roles in carcinogenesis.