Keeping the Balance Implications for Health and Disease

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Figure 3 Products of lipoxygenase metabolism. (see color insert)

promote angiogenesis. The 15-LOX isoenzymes (15-LOX-1, 15-LOX-2) convert arachidonic acid to 15-S-HETE and linoleic acid to 13-^-hydroxy-9,11-octadecadienoic acid (13-S-HODE). These substances may have effects opposite to those of the 5-, 8-, and 12-LOX, as they induce epithelial cell differentiation and promote both growth inhibition and cell apoptosis.

Leukotrienes are a family of paracrine mediators derived from oxidative metabolism of arachidonic acid by 5-LOX. Leukotriene B4 (LTB4) is a powerful chemoattractant, responsible for the recruitment of leukocytes to sites of inflammation. 5-LOX is found primarily in inflammatory cells, such as granulocytes, monocytes, and mast cells. Leukotriene receptors include B-LTj, a high-affinity receptor present on leukocytes, and B-LT2, a moderate-affinity receptor that has widespread tissue distribution. A cysteinyl leukotriene receptor, CysLTj, is found on smooth muscle cells of the bronchioles and on vascular endothelial cells.

Vascular Effects

Regulation of Blood Flow

Because of their ability to modulate the balance between vasoconstriction and vasodilatation, eicosanoids provide a highly responsive mechanism for regulating organ and tissue blood flow. An excellent example of this is the effect of PGE2 on the ductus arteriosus. Fetuses have high circulating levels of PGE2, and in the 1970s, experiments on fetal lambs showed that the vasodilatatory effects of PGE2 are responsible for the maintenance of ductus arteriosus patency in utero. After birth, PGE2 levels decrease dramatically, a response associated with closure of the ductus arteriosus and establishment of postnatal patterns of pulmonary artery blood flow. Because they inhibit PGE2 production, NSAIDs such as indomethacin are used to induce ductus closure in low-birth-weight infants who have persistent patency of the ductus arteriosus. Conversely, the synthetic agent, PGEj, is administered to infants when maintenance of a patent ductus arteriosus is beneficial. This situation occurs in newborns with cardiopulmonary anomalies whose systemic or pulmonary blood flow depends upon shunting between the aorta and the pulmonary artery.

Products of P450 Monooxygenases

Cytochrome (CYP) P450s are a large family of enzymes present in virtually all mammalian tissues. These enzymes have a variety of roles and have been most extensively studied for their ability to metabolize various exogenous substances such as xenobiotics, as well as a vast variety of drugs. A number of CYP P450s employ arachidonic acid and other fatty acids as substrates, resulting in the generation of eicosanoids. The only fatty acid—utilizing CYP to be

Angiogenesis

Angiogenesis is a process whereby new blood vessels are created in response to inducible stimuli. This feature of the microvasculature occurs in a variety of settings, both physiologic and pathologic, including chronic inflammation, embryogenesis, parturition, and tumorigenesis. Products of cyclooxygenase activity, including TxA2, PGE2, and PGI2, directly stimulate endothelial cell migration and angiogene-sis in vivo and may result in increased endothelial cell survival. In addition, the product of 12-LOX, 12-S-HETE, possesses activities contributing to angiogenesis, as it modulates both endothelial cell adhesion and motility. In in vivo studies, selective Cox-2 inhibitors effectively suppressed formation of new blood vessels in response to basic fibroblast growth factor. In in vitro model systems employing coculture of endothelial cells with epithelial tumors, cyclooxygenase inhibition reduced production of pro-staglandins and proangiogenic factors and inhibited both endothelial cell migration and in vitro angiogenesis. Related data also suggested that NSAIDs have antiangiogenic properties that are independent of cyclooxygenase inhibition. As a result, NSAIDs are currently under study as both chemo-preventive and cancer therapeutic agents.

Renal Function

In the kidney, eicosanoids are important regulators of blood flow and glomerular filtration rate. Consistent with this, the predominant eicosanoids produced in the kidney are PGE2, PGI2, and TxA2. As a component of the body's response to stress, the synthesis of eicosanoids by renal parenchyma and endothelial cells is increased in response to vasoconstrictive stimuli such as angiotensin, vasopressin, or catecholamines. PGE2 causes vasodilatation of the renal vasculature, and production of PGE2 in the kidney is an important compensatory response in patients with shock, congestive heart failure, or ureteral obstruction. Administration of NSAIDs to patients with these conditions reduces prostaglandin production and is frequently associated with impairment of renal function. This failure is not associated with structural damage to the renal parenchyma and is reversible when the drugs are discontinued. In normal individuals, NSAIDs only rarely cause changes in renal blood flow or glomerular filtration rate.

Inflammation

The tissue response to inflammation is characterized by vasodilatation, increased vascular permeability, and early neutrophil accumulation. This response is largely produced by the local activity of eicosanoids that are produced by both damaged tissues and inflammatory cells. Cellular release of PGI2 and PGE2 causes vasodilatation, and TxA2, leukotrienes, and histamine all increase vascular permeability. PGE2, together with histamine and bradykinin, produces pain at the site of inflammation. Neutrophil chemoattraction and activation are caused by TxA2 and LTB4, as well as by complement activation. LTB4 stimulates the synthesis and release of inflammatory cytokines, such as tumor necrosis factor and IL-1, thereby potentiating the inflammatory response.

By virtue of their ability to inhibit prostaglandin, throm-boxane, and leukotriene synthesis, NSAIDs markedly attenuate the inflammatory process. As a result, naturally occurring salicylates have been used for centuries to treat pain and fever. The term "nonsteroidal anti-inflammatory drug" was coined by rheumatologists in 1949 to distinguish the activity of phenylbutazone from that of glucocorticoids, whose anti-inflammatory properties in the treatment of arthritis had recently been identified. This term came to apply to all "aspirin-like drugs" that were used clinically as antipyretics, analgesics, and anti-inflammatory agents. Recently, Cox-2 has been identified as the inducible isoenzyme responsible for inflammation. Because the beneficial effects of NSAIDs on the gastric mucosa and kidney are mediated by Cox-1, selective Cox-2 inhibitors were developed to minimize the side effects of NSAIDs while preserving their anti-inflammatory efficacy.

Hemostasis and Coagulation

When the endothelium is injured, the resulting exposure of collagen and thrombin lead to platelet activation and adhesion to the site of injury. Following adhesion, a number of active substances are released by platelets, including TxA2. TxA2 contributes to hemostasis by causing local vasoconstriction, enhancing platelet aggregation, and mediating further release of TxA2 from platelets. Although beneficial following trauma, the vasoconstrictive and platelet-aggregating effects of TxA2 are highly detrimental in the setting of atheromatous narrowing of coronary and cerebral arteries. NSAIDs, because of their ability to inhibit Cox-1, decrease TxA2 synthesis and reduce platelet function. As a result, NSAIDs, particularly aspirin, are beneficial preventive agents for patients at high risk of coronary artery and cerebral vascular disease. An overview of randomized trials of aspirin for the prevention of occlusive vascular disease concluded that 81 to 325 mg of aspirin daily provided protection against myocardial infarction, stroke, and death due to cardiovascular disease. This benefit was achieved at a small risk of increased hemorrhage and gastrointestinal tract ulceration due to long-term aspirin use.

Protection of the Gastroduodenal Mucosa

Prostaglandins produced by constitutive activity of Cox-1 in the upper gastrointestinal tract exert important protective effects in gastroduodenal tissue. In the harsh chemical environment of the stomach and duodenum, prostaglandins are responsible for protection of the mucosa through promotion of mucus production, bicarbonate secretion, and mucosal blood flow. PGE2 also inhibits both basal and stimulated gastric acid release. This effect may be particularly important in individuals with duodenal ulcer disease.

The use of nonselective NSAIDs (i.e., NSAIDs able to inhibit both Cox-1 and Cox-2) can produce damage to the mucosa of the stomach and duodenum and increase the complication rate of preexisting peptic ulcers. Some degree of gastrointestinal upset is present in approximately 30 percent of patients using nonselective NSAIDs on a regular basis. In addition, endoscopic surveillance of patients using NSAIDs regularly demonstrates a 20 percent prevalence of gastric ulceration, often not associated with dyspepsia. Patients with a prior history of gastroduodenal ulcers are at particular risk for serious complications, including upper gastrointestinal hemorrhage and perforation. Because of their specificity for the inducible isoenzyme, selective Cox-2 inhibitors have a significantly reduced incidence of both minor and severe gastrointestinal side effects.

Regulation of Reproductive Function

The eicosanoids, particularly prostaglandin family members, are regulators of many aspects of the reproductive process. PGE2 stimulates LHRH secretion and may also directly stimulate ovarian follicle maturation. PGE2 also promotes both ejaculation and implantation of the embryo in the uterine wall. PGE2 and PGF2a from seminal fluid promote fertility by enhancing transport of sperm into the fallopian tube. Eicosanoids also regulate gestational length and parturition. Levels of PGE2, PGF2a and LTB4 are elevated in the maternal circulation prior to the onset of spontaneous labor, and exogenous administration of PGE2 or PGF2a induces softening of the cervix and uterine contractions in both full-term and preterm labor. Although their use in pregnancy is somewhat controversial, both pGE2 and the synthetic prostaglandin misoprostol (PGE1) have been used successfully for induction of labor.

Role in Ischemia—Reperfusion Injury

Eicosanoids are important mediators of the harmful consequences of tissue ischemia and reperfusion. Although decreased tissue perfusion causes compensatory increases in PGI2 levels, ischemia also stimulates thromboxane synthesis and release. Upon reestablishment of blood flow to an ischemic organ, the ratio of TxA2 to PGI2 is increased, producing a net vasoconstrictive effect. Together with lipoxygenase metabolites produced during ischemia, TxA2 activates neutrophils, which become sequestered in the ischemic organ and the lung. The products of neutrophil activation include locally destructive proteases and reactive oxygen species, as well as inflammatory cytokines that contribute to increased capillary permeability and edema. As a result, tissue injury and decreased capacity for oxygenation occur both in the ischemic organ and at the diffusional surfaces of the lung. Leukotrienes produced as a result of myocardial ischemia can be particularly damaging upon restoration of coronary blood flow, as these agents may have negative inotropic and arrhythmogenic effects. There is no one pharmacologic agent able to counteract the harmful effects of ischemia—reperfusion injury. Once tissue perfusion has been reestablished, pharmacological therapy focuses upon limiting leukocyte activation and the resulting tissue damage. For example, vasodilatation can be promoted by nitrates, calcium channel blockers will limit neutrophil superoxide formation and release, and angiotensin-converting enzyme inhibitors can prevent leukocyte adhesion.

Eicosanoids and Tumorigenesis

In 1968, Williams recognized that tumors contained increased levels of prostaglandins compared to adjacent normal tissue. Since that time, data from a wide array of studies suggest that prostaglandins stimulate tumorigenesis. By-products of eicosanoid production include a number of potentially genotoxic substances, including organic free radicals, peroxides, and activated oxygen species. These substances are suspected to play a role in every stage of carcinogenesis, including activation of environmental carcinogens, direct DNA damage, stimulation of proliferation, inhibition of apoptosis, suppression of antitumor immunity, and stimulation of metastasis.

The cellular processes responsible for eicosanoid-mediated tumorigenesis are incompletely understood. There are numerous clinical associations and experimental links between inflammation and epithelial cancers. Inflammatory bowel disease, burn injuries, chronic ulcers, and longstanding cirrhosis examples of conditions that carry a cancer risk proportional to their duration in an individual. Initiation of the inflammatory response activates intracellular signaling cascades that govern cell proliferation and motility. When this condition becomes chronic, it provides a setting for selection of cells with other defects in growth control, eventually producing a clone of cells with a malignant phenotype. Recently, it was recognized that abnormal cell proliferation in a terminally differentiated epithelial cell population leads to progressive telomere shortening, resulting eventually in anaphase bridging, chromosomal instability, "telomere crisis," and the emergence of cells with unlimited proliferative potential due to reactivation of telomerase.

An interesting new observation in the field of eicosanoid biology comes from study of the peroxisome proliferated-activated receptor (PPAR) transcription factors. These receptors were initially cloned as a family of orphan receptors, but are now known to interact with a wide variety of ligands, including hypolipidemic drugs and the eicosanoids 8-S-HETE, LTB4, and prostaglandins of the J series. In this capacity, certain eicosanoids resemble steroid and thyroid hormones. Cell culture data also suggests that PPARs may be a target of NSAID activity, although in vivo data confirming this have yet to be reported.

The antitumor effects of NSAIDs have been examined in both animal models and human clinical trials. Many antitumor effects have been ascribed to NSAID-mediated inhibition of cyclooxygenase activity. In particular, upregulation of Cox-2 may be a key component of epithelial tumorigen-esis, and its suppression the main factor associated with the antitumor activity of NSAIDs. Tissue-selective overexpression of Cox-2 by promoter-specific targeting of murine epithelial cells induced tumorigenesis. In an animal model of FAP, intestinal tumor formation was dramatically decreased by either genetic deletion of Cox-2 or its inhibition by a Cox-2 specific NSAID. Recent studies in human tumor xenografts that constitutively expressed both Cox-1 and Cox-2 showed that selective inhibition of Cox-2 decreased intratumoral PGE2 and reduced tumor growth. This result was also achieved by specifically inhibiting PGE2 with a neutralizing antibody, but not by selective inhibition of Cox-1 with a new NSAID, SC-560.

In addition to enhanced expression in tumors, Cox-2 and PGE2 are also increased in fibroblasts and endothelial cells associated with intestinal tumors. Disruption of the PGE2 receptor, EP2, in ^pc-mutant mice produces tumor suppression, an effect primarily due to a positive feedback mechanism for Cox-2 expression by PGE2 in adenoma stromal cells. Cox-2 is highly expressed in tumor-associated endothelial cells, and PGE2 supports angiogenesis in human tumors. These observations led to the hypothesis that Cox-2 upregulation supports tumor angiogenesis, and that NSAIDs are antiangiogenic because of their ability to suppress cyclooxygenase activity. This concept is supported by data showing that selective Cox-2 inhibitors suppress angiogen-esis in the FGF-rat corneal micropocket assay.

Lipoxygenase metabolites may also play a role in tumor formation. Because they promote cell proliferation and angiogenesis and suppress tumor cell apoptosis, the 5-, 8-, and 12-LOX isoforms are characterized as "tumorigenic," whereas the opposite effects of 15-LOX suggest that this enzyme may inhibit tumor formation. In support of this characterization, human epithelial tumors exhibit decreased levels of 15-LOX compared to normal tissues, and in vitro treatment of colorectal cancer cells with NSAIDs increased levels of 15-LOX, augmented tumor apoptosis, and decreased cell growth. This effect appeared to be a direct effect of NSAIDs on 15-LOX expression rather than a shift of substrate from cyclooxygenase to lipoxygenase metabolic pathways.

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