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Human polymorphonuclear leukocytes (PMNLs, neutrophils) play a major role in the immune response to bacterial and fungal infections and eliminate pathogens through phagocytosis. During phagocytosis of microorganisms, the 5-lipoxygenase (5-LOX) pathway is activated resulting in generation of leukotrienes, which mediate host defense. In this study, a library of oligodeoxyribonucleotides (ODNs) with varying numbers of human telomeric repeats (d(TTAGGG)

The pentacyclic triterpenic acids isolated from the oleo gum resin of various Boswellia species are collectively called as Boswellic acids (BA). The oleo gum resin obtained from Indian variety i.e. Boswellia serrata (Family – Burseraceae) is commonly known as Salai guggal. The resin fraction of Salai guggal is rich in Boswellic acids and its essential oil is composed of a mixture of mono, di and sesquiterpenes while gum fraction chiefly contains pentose and hexose sugars. This oleo-gum resin is quite popular among traditional practitioners of traditional Chinese and Indian Systems of medicine owing to their wide range of useful biological properties such as anti-inflammatory, anti-arthritic, anti-rheumatic, anti-diarrheal, anti-hyperlipidemic, anti-asthmatic, anti-cancer, anti-microbial anti-fungal, anti-complementary and analgesic activity, etc. It has been used as a herbal medicine since the prehistoric time to cure acute and chronic ailments including inflammatory diseases. Phytochemical investigation of this herbal medicine lead to identification of Boswellic acids which are found to be novel, potent, specific anti-inflammatory agents due to non-redox inhibition of 5-lipoxygenase (5-LO) enzyme. However, the other important targets of Boswellic acids also include topoisomerases, angiogenesis, and cytochrome p450 enzymes. This review is a sincere attempt to discuss and present the current status of therapeutic potential, phytochemical as well as pharmacological profile of Boswellic acids primarily obtained from B. serrata .

Leukotrienes mediate several inflammatory events such as neutrophil chemoattraction, leukocyte adhesion, and central-release of cytokines and fever. However, there is no information available about their putative role in lipopolysaccharide (LPS) tolerance. The rational of the present study was to find out if central leukotrienes are involved in the development of LPS tolerance. Thus, we inhibited central leukotriene synthesis in tolerant rats using a pharmacological tool, i.e., a selective inhibitor of leukotriene synthesis MK-886 injected into the third ventricle (3V) of rats. Body core temperature (Tb) was measured using a datalogger placed inside the abdominal cavity. A low-dose of LPS (100 μg/kg ip) was given for 4 consecutive days to induce LPS tolerance. At day 4, rats received a microinjection of MK-886 into the 3V immediately before LPS, whereas control groups were treated with vehicle (saline). We observed that LPS failed to induce plasma cytokines surges, increased hypothalamic PGE2 levels and fever 3 days post LPS treatment, aptly characterizing the tolerance. When MK-886 was given to control rats treated with saline, no significant change in Tb was observed. However, a full LPS-induced fever was observed in tolerant rats pretreated with MK-886, which was associated with an enhancement in the hypothalamic PGE2 levels, that were not accompanied by plasma cytokines (IL-1β, and IL-6) and PGE2 surges. These data are consistent with the notion that central leukotrienes play a role in fever tolerance to LPS.

UNLABELLED: Sjogren-Larsson syndrome (SLS) is a neurocutaneous autosomal recessive disease caused by fatty aldehyde dehydrogenase (FADH) deficiency. This enzyme is involved in the biosynthesis pathways of some fatty acids, phytanic acid, and leukotrienes. The main features of the disease are its association with congenital ichthyosis, mental retardation, and spastic tetraplegia. METHODS: We report on the diagnostic and therapeutic management of 2 cases of SLS. RESULTS: The diagnosis of SLS was suspected in the first patient at 2 years of age before the clinical triad appeared and confirmed at 4 years of age by the culture of fibroblasts and the peak of lipids on 1.3 ppm spectroscopy. After 3 months of treatment with zileuton, an inhibitor of leukotriene synthesis, moderate clinical efficacy for pruritus and ichthyosis was observed. The second patient was diagnosed at 1 year of age with the association of psychomotor retardation and congenital ichthyosis, in accordance with acute Guillain-Barre syndrome. Diagnosis was confirmed with enzymology, and cerebral spectro-MRI featured an abnormal lipidic peak. Zileuton therapy was initiated at the time of diagnosis and was effective for pruritus after 6 months of treatment. CONCLUSION: We report 2 cases of SLS with delayed diagnosis, due to non neonatal symptoms. Treatment with zileuton shows partial efficacy especially in pruritus. The uncommon association of this rare dysmyelinating disease with Guillain-Barre syndrome in the second patient is discussed.

Leukotrienes have been shown to be involved in a variety of diseases such as cardiovascular diseases, cancer, asthma, ulcerative colitis, and rhinitis. 5-Lipoxygenase-Activating Protein (FLAP) was found to be a key enzyme of leukotriene synthesis. Comparative Molecular Field Analysis (CoMFA) and molecular docking studies were carried out on a series of substituted 2,2-bisaryl-bicycloheptanes FLAP inhibitors. The docking results provided a reliable conformational alignment scheme for 3-D QSAR model. Based on the docking conformations, highly predictive CoMFA model was performed with a leave-one-out cross-validated q2 of 0.651. The noncross-validated analysis with four optimum components revealed a conventional r2 value of 0.972, F=175.674, and an estimated standard error of 0.169. The predictive ability of this model was validated by the testing set with a conventional r2 value of 0.920. The analyses may be used to design more potent FLAP inhibitors and predict their activities prior to synthesis.

Recently, there has been great progress in elucidating the biochemistry of the arachidonic acid (AA) metabolism. The abnormal production of leukotrienes (LTs), due to the unbalanced-regulation of synthesizing and catabolizing enzymes, is probably induced by many bioactive substances, including Th2 cell-derived cytokines. Imbalances in these processes may play an important role in allergic reactions and other inflammatory diseases, thus making them potentially prime therapeutic targets for these diseases. Further studies on the regulation of LT-synthesis and catabolism are therefore required to clarify the importance of these imbalances on the initiation and progression of allergic and inflammatory diseases.

Human coactosin-like protein (CLP) is a small (MW approximately 17 kDa) evolutionarily conserved actin-binding protein. It can bind to actin filaments but not globular actin and belongs to the fourth class of ADF-H-domain-containing proteins. Human CLP can also bind to 5LO, which plays an important role in cellular leukotriene synthesis. Although the structure of hCLP has been determined by both NMR and X-ray experiments, how hCLP binds to the actin filament is still a controversial question. To obtain insights into the structure of the complex, we studied the three-dimensional structure and backbone dynamics of hCLP using multidimensional NMR spectroscopy. Guided by the solution structure of the protein, a series of site-directed mutants were generated and their F-actin-binding activities were measured by high-speed cosedimentation assays. Furthermore, the structure model of the hCLP-F-actin complex was proposed using computational docking with the docking results filtered by the mutation data. Several previously untested residues (including T66, L89, R91, K102, D116 and E119) in hCLP were found important for the F-actin-binding activity. The extended region of beta4-beta5 of hCLP (residue 66-75) was found very flexible and very important for F-actin binding. The C-terminal residues of hCLP were not involved in F-actin binding, which was different from UNC-60B. Based on our hCLP-F-actin-binding model, different affinities of the four classes of ADF-H domain containing proteins for F-actin were explained.

Urinary leukotriene E4 (LTE4) has been used as an index of total leukotriene synthesis. A wide variety of methods have been applied to measure LTE4 which has made direct comparison of urinary levels reported by different laboratories difficult. A new peptidoleukotriene immunoaffinity resin was utilized for urinary LTE4 purification in a method that is easy and inexpensive, utilizing commercially available reagents. This method is described and compared to other methods. LTE4 (50–250 pg/mL) added to a urine extract was quantitatively recovered using the immunoaffinity resin. Similarly, LTE4 (50–400 pg/mL) added to urine was recovered between 63 and 76%. The coefficient of variation of samples purified and quantified on the same or on different days ranged from 8–10%. There was a strong correlation (r2 = 0.95) between LTE4 concentrations determined after immunofiltration and immunoaffinity purification. Although there was a good correlation between urinary LTE4 levels measured without purification compared to after immunoaffinity purification, the high y-intercept of 179 indicates the presence of interfering substances in unpurified urine. Urinary LTE4 in normal healthy adults was 80 ± 7 pg/mg creatinine, similar to that previously reported following HPLC or immunofiltration purification. Urinary LTE4 was also measured in healthy children (age 3–12) and found to be 103 ± 9.

Atherosclerosis remains one of the main causes of cardiovascular disease, which is the leading cause of death worldwide. It is now accepted that atherosclerosis is an inflammatory, dynamic and complex disease involving multiple cell types, and many antiinflammatory strategies have recently emerged as potential therapeutic approaches for atherosclerotic disease. In this review, we discuss the most recent progress in the development of anti-inflammatory strategies. We highlight the beneficial effects of potent antiinflammatory drugs, including recently developed biologics, and we describe diverse emerging approaches that target inflammatory processes involved in atherosclerosis including tumor necrosis factor antagonists, anti-interleukins, viral-derived serpins, P-selectin inhibition and leukotriene synthesis inhibition.

The synthesis of leukotriene B4 by A23187-stimulated rat peritoneal leukocytes was studied in the presence of 0.1% normal human serum, serum from patients treated with NSAIDs for either an inflammatory (rheumatoid arthritis, RA) or a non-inflammatory condition (lumbar disc protrusion, LDP), and serum from RA patients drawn one week after withdrawal from NSAID treatment. The capacity for LTB4 synthesis was significantly lower in the presence of serum from NSAID treated patients: thirty per cent less than observed in presence of normal serum in the RA group, and fifty per cent in the LDP group. When NSAIDs were withdrawn from RA patients, the LTB4 production in presence of serum increased, but was not completely normalized after one week. These results indicate that NSAID treatment may down-regulate the capacity for leukotriene synthesis by an indirect effect.

(1995). Alterations of pulmonary capillary filtration and leukotriene synthesis due to infusion of a lipid emulsion enriched with Omega-3-fatty acids. Clinical Intensive Care: Vol. 6, No. 3, pp. 112-120.

A series of 5-hydroxyphenylpyrrolo-1,4-benzoxazine derivatives substituted by a pyridinylpiperazinyl alkyl chain were designed as multimediator compounds with potential antiasthmatic properties. These compounds were prepared and evaluated both in vitro against leukotriene synthesis and PAF activity and in vivo against histamine. Structure-activity relationships led to compound 11 which displayed the most potent activities in this series.

The interaction between ceruloplasmin (CP), the multicopper oxidase of human plasma, and 5-lipoxygenase (5-LO), the key enzyme of leukotriene synthesis, is shown for the first time. By Western-blotting and mass spectrometry of tryptic fragments, it is shown that 5-LO from protein extract of human leukocytes binds with immobilized CP. Dose-dependent influence of intact CP on leukotrienes synthesis is found: CP reduced leukotrienes synthesis in leukocytes in a dose above 50 μg/ml (normal CP concentration in plasma is about 300–400 μg/ml). Proteolyzed CP and apo-form of CP is unable to inhibit activity of 5-LO. CP increased activity of 5-LO at low doses (5–10 μg/ml). On the whole, the influence of CP on phagocytosis index of leukocytes coordinates with influence on activity of 5-LO: the index increased in the range of 2–10 μg/ml CP and decreased at doses of CP above 40 μg/ml. The dual role of CP in regulation of cellular response of leukocytes is discussed.

Evidence on aetiology in multiple sclerosis suggests that the prevalence depends on the interaction of two factors, diet and exposure to visible sunlight. The dietary features which may be beneficial include supplementation with fish oils, avoidance of saturated fats, and the associated intake of antioxidants with unsaturated fatty acids. Inhibition, by antioxidants, of the enzyme lipoxygenase inhibits leukotriene synthesis, and the presence of fish oils leads to the production of leukotrienes with less inflammatory properties. This is of particular importance in the retina where leukotrienes might be the underlying cause of retrobulbar neuritis. The antioxidant properties of vitamin A may also lead to inhibition of leukotriene synthesis. Visible solar radiation could be of benefit therefore by releasing vitamin A from visual pigment rhodopsin. The interaction of these two factors may explain the epidemiological observations on the prevalence of multiple sclerosis.

Administration of the leukotriene synthesis inhibitors nordihydroguaiaretic acid (NDHGA, 30 mg/kg), caffeic acid (20 mg/kg) or nafazatrom (100 mg/kg) and of the phosphodiesterase inhibitor and free radical trapper dipyridamole (10 mg/kg) prevented the alterations in enzyme activity displayed by acute CCl4 administration. The effect was less evident in preventing hepatic glycogen depletion or lipid peroxidation. A synergistic protective effect between dipyridamole and NDHGA or caffeic acid was observed. In conclusion, the present results show that acute hepatic damage induced by CCl4 can be partially prevented by leukotriene synthesis inhibitors and the protection is enhanced with the simultaneous use of phosphodiesterase inhibitors.

(1) In CD-1 mice and Sprague–Dawley rats, dark-induced elevation of body temperature ( T b ) was accompanied by an increase in hypothalamic prostaglandin E 2 (PGE 2 ) production. (2) Indomethacin, a cyclooxygenase inhibitor, at a dose (5 mg/kg) that did not affect the daytime values of T b , prevented the increase of T b after the onset of darkness. (3) Pretreatment of mice with the inhibitor of leukotriene synthesis, MK-886 (1 mg/kg), prevented the decrease of daytime T b . (4) The results suggest the involvement of PGE 2 and leukotrienes in the regulation of normal daily variations of T b .

Methyl 5S -(benzoyloxy)-6-oxohexanoate 2 , an intermediate in synthetic routes to the lipoxygenase-derived arachidonic acid metabolite leukotriene B 4 , is available in three steps from 2-cyclohexen-1-one, using Schreiber's unsymmetrical ozonolysis protocol.

Endothelial cells do not contain 5-lipoxygenase and thus are unable to generate LTA4 from arachidonate. Nonetheless, endothelial cells may play an important role in leukotriene synthesis by virtue of their ability to metabolize LTA4 derived from activated polymorphonuclear leukocytes (PMNL) and to modulate PMNL 5-lipoxygenase activity. Porcine aortic endothelial cells were found to metabolize exogenous LTA4 to LTC4, and under some conditions human umbilical vein endothelial cells have been found to generate LTB4. Production of LTB4 by these cells appears to be under poorly understood cellular control, and it remains a controversial area of research. Under physiologic conditions, endothelial cells are in constant contact with circulating PMNL, which are known to generate substantial amounts of LTA4. When these two cell types are coincubated in vitro, clear evidence of transcellular metabolism of PMNL-derived LTA4 to LTC4 by endothelial cells is found. Coincubations produce from two to greater than 10 times more LTC4 than either cell alone. In contrast to these findings, when these cells were activated by the receptor-mediated agonist fMLP, evidence for an endothelial cell inhibition of PMNL 5-lipoxygenase was obtained. Rather than augmentation of LTC4 production, as seen with A23187 activation, coincubation activated by fMLP generated significantly less LTC4 (0.23 +/- 0.08 versus 0.75 +/- 0.39 pmol/10(7) cells). The endothelial cell inhibition was removed when these cells were pretreated with aspirin, suggesting that their major cyclooxygenase product, prostacyclin, acts as a feedback regulator of LT synthesis. When cyclooxygenase was blocked, significant transcellular LTC4 synthesis was once again apparent (1.66 +/- 0.44 pmol/10(7) cells).

Signalling pathways that regulate the expression of plant genes are poorly understood. Recent evidence indicates that octadecanoid-derived signals may be parts of signalling pathways in plants in which C 18 fatty acids, liberated from membranes in response to environmental or developmental cues, are converted to intracellular signalling molecules such as jasmoric acid and traumatin. These events are analogous to prostaglandin and leukotriene synthesis in animals.

5-Lipoxygenase activating protein (FLAP) has been implicated in a number of different pathophysiological conditions owing to its involvement in leukotriene synthesis. Development of FLAP inhibitors has attracted considerable attention in recent years owing to genetic data supporting their potential as a valid pharmacological approach in prevention or treatment of atherosclerotic disease.Since 2005, among other companies, Merck applied for several FLAP inhibitor patents. Patent WO 2008/030369 is the most recent and discloses novel molecules that act as potent inhibitors of FLAP. These compounds are claimed to be useful in the treatment of atherosclerosis, asthma, symptoms of allergic rhinitis and chronic obstructive pulmonary disease either in monotherapy or in combination with established treatments for the above-mentioned disorders. Although data for the potency of representative molecules from the current patent are reported, it is difficult to compare these compounds with previously described compounds.Two FLAP inhibitors are already in clinical development for the treatment of respiratory and atherosclerotic disease by other pharmaceutical companies. Based on the in vitro activities of representative tested compounds from this patent, it is probable that these agents could be of therapeutic value but further preclinical studies are needed to evaluate their therapeutic potential and safety before clinical development.

Leukotrienes are bioactive lipid metabolites involved in respiratory and cardiovascular diseases. They are synthesized from arachidonic acid by the enzyme 5-lipoxygenase, and the integral membrane protein 5-lipoxygenase–activating protein (FLAP) plays an essential role in their biosynthesis. Ferguson et al . describe the crystal structure of human FLAP in complex with two different leukotriene biosynthesis inhibitors. The structures suggest how the inhibitors prevent arachidonic acid from binding to FLAP, from which it is likely transferred to 5-lipoxygenase. The structural data provide a basis for the development of drugs targeted against FLAP that would inhibit leukotriene biosynthesis. A. D. Ferguson, B. M. McKeever, S. Xu, D. Wisniewski, D. K. Miller, T.-T. Yamin, R. H. Spencer, L. Chu, F. Ujjainwalla, B. R. Cunningham, J. F. Evans, J. W. Becker, Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein. Science 317 , 510-512 (2007). [Abstract] [Full Text]

It has been recognized for many years that leukotrienes play an important role in mediating various effects of the allergic reaction. Recent evidence has shown that they play a role in other diseases. Leukotrienes can be separated into the fairly well-characterized cysteinyl leukotrienes and the less well-characterized leukotriene B(4). Effects of the leukotrienes are mediated through receptors that are expressed on a variety of cell types and can be modulated based on the inflammatory environment present. The pharmaceutical industry has long been interested in blocking leukotriene action. As such, two approaches have been developed that led to drugs approved for treating allergic disease. The most widely used class is the cysteinyl type 1 receptor antagonists, which block binding of the cysteinyl leukotrienes to the cell. The second class is an inhibitor of the 5-lipoxygenase enzyme that prevents synthesis of both the cysteinyl leukotrienes and leukotriene B(4). This review focuses on the role that leukotrienes play in various diseases, with the emphasis on allergic diseases, and considers the rationale for choosing either a leukotriene antagonist or synthesis inhibitor as a treatment option.

Extracts from Boswellia serrata have been reported to have anti-inflammatory activity, primarily via boswellic acid-mediated inhibition of leukotriene synthesis. In three small clinical trials, boswellia was shown to improve symptoms of ulcerative colitis and Crohn's disease, and because of its alleged safety, boswellia was considered superior over mesalazine in terms of a benefit-risk evaluation. The goal of this study was to evaluate the effectiveness of boswellia extracts in controlled settings of dextran sulfate- or trinitrobenzene sulfonic acid-induced colitis in mice. Our results suggest that boswellia is ineffective in ameliorating colitis in these models. Moreover, individual boswellic acids were demonstrated to increase the basal and IL-1β-stimulated NF-κB activity in intestinal epithelial cells in vitro as well as reverse proliferative effects of IL-1β. We also observed hepatotoxic effect of boswellia with pronounced hepatomegaly and steatosis. Hepatotoxity and increased lipid accumulation in response to boswellia were further confirmed in vitro in HepG2 cells with fluorescent Nile red binding/resazurin reduction assay and by confocal microscopy. Microarray analyses of hepatic gene expression demonstrated dysregulation of a number of genes, including a large group of lipid metabolism-related genes, and detoxifying enzymes, a response consistent with that to hepatotoxic xenobiotics. In summary, boswellia does not ameliorate symptoms of colitis in chemically induced murine models and, in higher doses, may become hepatotoxic. Potential implications of prolonged and uncontrolled intake of boswellia as an herbal supplement in inflammatory bowel disease and other inflammatory conditions should be considered in future clinical trials with this botanical.

Leukotrienes are lipid mediators with important roles in immunity. The enzyme 5-lipoxygenase initiates leukotriene synthesis; nuclear import of 5-lipoxygenase modulates leukotriene synthetic capacity. In this study, we used structural and functional criteria to identify potential nuclear import sequences. Specifically, we sought basic residues that 1) were common to different 5-lipoxygenases but not shared with other lipoxygenases, 2) were found on random coil/loop structures, and 3) could be replaced without eliminating catalytic activity. Application of these criteria to the putative bipartite nuclear import sequence of 5-lipoxygenase revealed that this region formed an alpha-helix rather than a random coil, that the critical residue arginine 651 serves a structural role, and that mutation of this residue eliminated catalytic activity. A previously unrecognized region corresponding to residues 518-530 on human 5-lipoxygenase was found to be unique to 5-lipoxygenase and on a random coil. This region alone was sufficient to drive import of green fluorescent protein to the same degree as complete 5-lipoxygenase. Replacement of basic residues in this region of the complete protein was capable of eliminating nuclear import without abolishing catalytic activity. Surprisingly, two subpopulations of cells expressing 5-lipoxygenase with this mutated region could be discerned: those with strongly impaired import and those with normal import. Taken together, these results show that the previously identified region with a bipartite motif is not a functional import sequence, whereas the newly identified basic region constitutes a true nuclear import sequence. Moreover, we suggest that another sequence that can mediate nuclear import of 5-lipoxygenase remains to be identified.

Leukotrienes (LTs) are potent lipid mediators which modulate a multitude of fundamental intracellular processes. While their pathophysiological role has been best established in asthma, they are probably important participants in many other disease processes characterized by inflammation, cellular proliferation, and fibrogenesis. They also subserve a homoeostatic role in antimicrobial host defence1. In view of the actions and importance of LTs, substantial effort over the last several years has been directed at increasing our understanding of their synthesis. The purpose of this brief chapter will be to review these recent advances in LT synthesis, with an emphasis on the biochemistry, molecular biology and cell biology of the key enzymes involved.

Leukotrienes have been recognized as mediators of inflammatory allergic diseases of the lung (22). Consequently, antileukotriene therapy appears to be nearly established as novel pharmacotherapy of allergic asthma (15, 31). Cysteinyl-leukotrienes (LTC4, LTD4, LTE4) appear to have considerable pathophysiological importance in allergie asthma, because functional lung parameters improve with antileukotriene therapy after LTD4 challenge, antigen provocation, cold air exposure, exercise-induced asthma, and even aspirin-induced asthma (22, 24, 46). Effective antileukotriene therapy comprises various LTD4 receptor antagonists (LTD4ra) and 5-lipoxygenase (5-LOX) inhibitors (15, 22). 5-LOX inhibitors can be differentiated into the direct 5-LOX inhibitors (LOI) and FLAP (Five Lipoxygenase Activating Protein) binding leukotriene synthesis inhibitors (LSI) (Figure 1).

The leukotriene (LT) synthesis inhibitors BAY x1005 and MK-886 were evaluated in human lung parenchyma challenged with an anti-IgE. The anti-IgE-induced LTE4 release was time- and dose-dependent. Treatment of the parenchyma with indomethacin (3 microM) prior to anti-IgE challenge inhibited the 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) release and enhanced (36%) the quantities of LTE4 detected during IgE-stimulations. BAY x1005 and MK-886 were assessed in the presence of indomethacin (3 microM) and the IC50 values for both inhibitors were similar (0.13 microM). BAY x1005 (1 microM) produced the same percent of inhibition of anti-IgE-induced LTE4 release in the presence or absence of indomethacin. BAY x1005 (1 microM) did not alter the 6-keto PGF1 alpha release during anti-IgE challenge. The results indicate that BAY x1005 and MK-886 are potent inhibitors of LT synthesis when human lung parenchyma were stimulated by an anti-IgE.

In coculture systems of human macrophage-like cells and human endothelial cells low concentrations of nicotine inhibit thromboxane as well as prostacyclin synthesis and induce a major increase of cell contact-dependent transcellular leukotriene synthesis.

Cell-substrate and cell-cell adhesion of neutrophils has been found to slow down the calcium ionophore A23187-induced synthesis of 5-lipoxygenase (5-LO) metabolites of arachidonic add. Addition of the exogenous substrate, arachidonic acid (AA), together with A23187, resulted in the enhanced production of leukotriene B4 (LTB4) and 5-hydroxyeicosatetraenoic acid (5-HETE) by adherent neutrophils in comparison with those by the cells in suspension. We observed also the enhanced production of 5-LO metabolites in attached cells when we stimulated the cells by the combined action of phorbol 12-myristate 13-acetate (PMA) and A23187. Thus, the adhesion to solid substrate and to other cells, an important regulatory factor for the activity of many cells, is a powerful regulator of leukotriene production by neutrophils.

There is good evidence from a number of cellular systems that the rate-limiting step of the arachidonic acid cascade consists in the release of arachidonate from phospholipids. At first sight, prostaglandin H synthase (PGHS) seems to be unrestricted under cellular conditions and the lipoxygenases although being partially dependent on Ca2+ are not limiting since phospholipase A2 requires Ca2+-levels that are higher than those for lipoxygenases as recently shown for leukotriene synthesis in leukocytes (1).

The importance of locally produced prostaglandins (PGs) in the inflammatory response has been well recognized since the observation by Vane and colleagues that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) inhibit PG synthesis1–3. More recently, it has been suggested that other products of arachidonic acid metabolism, such as leukotrienes, are also mediators of allergic and inflammatory reactions. Inhibitors of leukotriene synthesis and antagonists of their action have recently been developed and are presently undergoing clinical evaluation; the exact role and importance of these mediators in human disease will be clarified only when the outcome of these clinical studies is known. In this review we will describe the pharmacological effects of selective lipoxygenase inhibitors in tests conducted in animals, and will discuss the possible relevance to humans.

Rationale Mast cells and eosinophils synthesize various mediators, including transforming growth factor b (TGF-b) and cysteinyl leukotrienes (cysLTs), that may promote subepithelial fibrosis in asthma. We sought to determine the roles of TGF-b and cysLTs in myofibroblast differentiation stimulated by coculture of fibroblasts with mast cells or eosinophils. Methods IMR-90 human lung fibroblasts were serum starved and cocultured for 48 hours with either LAD-2 human mast cells or freshly isolated human blood eosinophils in the absence or presence of SB431542 (10 M) to block signaling through the TGF-b type I (ALK5) receptor; MK886 (1 M) to block leukotriene synthesis; MK571 (100 nM) to block the cysLT1 receptor; or Bay u9773 (3 M) to block the cysLT1 and cysLT2 receptors. a-Smooth muscle actin (a-SMA) expression was assessed as an index of myofibroblast differentiation. Results Mast cells and eosinophils stimulated 2.50.2 (n = 5, p Funded by NIH R01HL072891, Crane Asthma Center of Northwestern University.

Recent advances in research have led to the identification of an inflammatory component to asthma. Although many endogenous mediators are involved in inflammation, leukotrienes appear to play an especially important role in asthma. The leukotrienes produce tissue edema, mucus secretion, and smooth-muscle proliferation, along with a powerful bronchoconstriction. In addition, antileukotriene drugs have emerged as potential therapeutic agents for asthma. This study was designed to review the current information on these new agents. In this review, full-length articles of antileukotriene agents are examined. These articles were found through MEDLINE under the following medical headings: asthma, inflammation, leukotriene, leukotriene-receptor antagonist, and leukotriene-synthesis inhibitor. Most clinical studies cited are placebo-controlled trials involving healthy individuals and patients with asthma. These studies indicate that antileukotriene agents improve lung function and reduce the symptoms of asthma and the need for additional medication. Drugs that inhibit leukotriene-receptor binding and leukotriene synthesis hold promise as new additions to the armamentarium of clinicians who treat asthma. Furthermore, these drugs have already helped to elucidate some details of the pathophysiological features of asthma. Arch Intern Med. 1996;156:2181-2189