Leukotriene Synthesis Inhibitor Research Articles

Les antileucotriènes et asthme chez l'enfant d'âge préscolaire

Leukotrienes are potent inducers of bronchoconstriction and mediators of inflammation, and they increase vascular permeability and mucus production. These substances potentiate the influx of inflammatory cells in the airways of patients with asthma. Leukotriene synthesis inhibitors and receptor antagonists—antileukotrienes—are among the new class of antiasthmatic drugs. There are at present few published studies on the treatment of preschool children with antileukotrienes. While they seem to be effective in the management of chronic asthma and perhaps in the treatment of infants with virus-induced wheezing, it is still difficult to place them in the treatment of asthma in preschool children. Further evaluation and clinical experience should allow us to determine their place in the treatment of children with asthma.

Blockade of leukotriene B 4 prevents articular incapacitation in rat zymosan-induced arthritis

We investigated whether leukotrienes mediate cell influx and articular incapacitation in zymosan-induced arthritis. Rats received 1 mg zymosan intra-articularly (i.a.). The hyperalgesia was measured using the rat articular incapacitation test. Cell influx, leukotriene B 4 and prostaglandin E 2 levels were assessed in the joint exudate, at 6 h. Groups received either the leukotriene B 4 synthesis inhibitor MK 886 (3-[1-(4-chlorobenzyl)-3- t-butyl-thio-5-isopropylindol-2-yl)]-2,2-dimethylpropanoic acid 30 min before or 2 h after the zymosan; 0.3–3 mg kg −1 i.p.), the leukotrienes synthesis inhibitor BWA 4C ( N-(3-phenoxycinnamyl)-acetohydroxamic acid—2 h after the zymosan; 10 μg i.a.) or the peptido-leukotrienes antagonist sodium montelukast (30 min before and 2 h after the zymosan; 10 mg kg −1 per os). MK 886 inhibited the articular incapacitation and cell influx, while reducing leukotriene B 4, but not prostaglandin E 2 levels. BWA 4C inhibited the articular incapacitation. Sodium montelukast did not affect either of the parameters. The data suggest that leukotriene B 4 is involved in cell influx and articular incapacitation in zymosan arthritis.

Role of leukotrienes in killing of Mycobacterium bovis by neutrophils

The neutrophil (PMN) plays an important role in the phagocytosis and killing of microorganisms. Pro-inflammatory leukotrienes (LT) play an important role in various disease states. However LT elaborated by PMN have also been shown to be important in host defense, specifically phagocytosis and killing of microorganisms. Defective LT synthesis by phagocytes correlates with their reduced anti-microbial activity. Therefore, we determined if LT played an important role in the killing of Mycobacteria bovis ( M. bovis) by PMN. Endogenous LT play a role in the killing of mycobacteria since the LT synthesis inhibitor MK-886 reversed the killing of M. bovis by PMN. Increased synthesis of LT occurred following incubation of PMN with M. bovis. Treatment with granulocyte-colony stimulating factor, which augments PMN LT synthesis, also boosted anti-microbial activity. Furthermore, exogenous LTB 4 augmented dose-dependent killing of M. bovis by PMN. In conclusion, LT play a vital role in promoting mycobactericidal actions of PMN.

5-Lipoxygenase: Regulation and Pharmacology

5-Lipoxygenase (5-LO) plays an essential role in the biosynthesis of leukotrienes (LTs), proinflammatory mediators, which are mainly released from myeloid cells. Whereas LTB4 is a potent chemotactic and chemokinetic agent for leukocytes, the cysteinyl (cys) LTs C4, D4 and E4 cause vascular permeability and smooth muscle contraction. In view of these properties, LT synthesis inhibitors have been hypothesised to possess therapeutic potential for the treatment of asthma, allergic disorders and other inflammatory diseases. The expression of 5-LO in mammals is tightly regulated. Enzymatic activity in vitro can be modulated by calcium, ATP, phosphatidylcholine and lipid hydroperoxide; nevertheless activation of cellular 5-LO in response to external stimuli is rather incompletely understood. Intensive research revealed that on cell stimulation, 5-LO redistributes to the nuclear membrane where it colocalises with 5-lipoxygenase-activating protein and cytosolic phospholipase A2. Accumulating data suggest that phosphorylation of 5-LO by p38 MAPK-regulated MAPKAP-kinases and extracellular signal-regulated kinases 1 / 2 regulates cellular 5-LO activity and influences redistribution of the enzyme in the cell. In addition, the cellular redox tone regulates 5-LO product formation, and 5-LO reactions may be influenced by cellular proteins physically interacting with 5-LO. This review highlights the determinants of cellular 5-LO activity and summarises the molecular pharmacology of 5-LO.

Cysteinyl-leukotrienes receptor activation in brain inflammatory reactions and cerebral edema formation: a role for transcellular biosynthesis of cysteinyl-leukotrienes.

We studied the effect of intravascular activation of human neutrophils on the synthesis of cysteinyl leukotrienes (cysLT) and the formation of cerebral edema in guinea-pig brains. Challenge with the chemotactic formylated tripeptide fMLP (0.1 microM) of neutrophil-perfused brain in vitro resulted in blood-brain barrier disruption associated with a significant increase of cysLT. Both events were completely prevented by neutrophil pretreatment with a specific 5-lipoxygenase (5-LO) inhibitor. Perfusion with the 5-LO metabolite leukotriene B4 (10 nM), together with neutrophils treated with the 5-LO inhibitor, did not restore the alteration in permeability observed upon perfusion with untreated and activated neutrophils. The dual cysLT1-cysLT2 receptor antagonist BAYu9773 was more potent and more effective than a selective cysLT1 antagonist in preventing the brain permeability alteration induced by neutrophil activation. RT-PCR showed significant expression of cysLT2 receptor mRNA in human umbilical vein endothelial cells. Intravital microscopy in mice showed that inhibition of leukotriene synthesis significantly reduced firm adhesion of neutrophils to cerebral vessels without affecting rolling. These data support the hypothesis that neutrophil and endothelial cells cooperate toward the local synthesis of cysLT within the brain vasculature and, acting via the cysLT2 receptor on endothelial cells, may represent a contributing pathogenic mechanism in the development of cerebral inflammation and edema.

Blockade of endogenous leukotrienes exacerbates pulmonary histoplasmosis.

Leukotrienes are classical mediators of inflammatory response. New aspects of leukotriene function have recently been described. We examine here the previously unreported role that leukotrienes play in the regulation of cytokines in a murine model of histoplasmosis. We demonstrate that administration of MK 886, a leukotriene synthesis inhibitor, caused Histoplasma capsulatum-infected mice to die by the day 15 of infection, whereas the correlating death rate in untreated infected mice was 0%. Treating infected animals with MK 886 inhibited leukotriene synthesis but increased leukocyte recruitment to the lungs. Subsequent to this phenomenon, levels of tumor necrosis factor alpha, interleukin-1 (IL-1), IL-6, and KC chemoattractant cytokines and fungi in the lung parenchyma increased, as did inflammatory response. In contrast, IL-2, IL-5, IL-12, and gamma interferon cytokine levels actually decreased. Thus, murine response to pulmonary histoplasmosis may be leukotriene modulated. This finding may enable us to alter the course of the immune response and inflammation caused by histoplasmosis. The data from the present study suggest an important new strategy for immunologic or drug intervention in human patients.

INDUCTION OF INDUCIBLE NITRIC OXIDE SYNTHASE BY LIPOPOLYSACCHARIDE/INTERFERON GAMMA AND SEPSIS DOWN-REGULATES 5-LIPOXYGENASE METABOLISM IN MURINE ALVEOLAR MACROPHAGES

□ Pretreatment with lipopolysaccharide (LPS) suppresses rat alveolar macrophage leukotriene synthesis in a nitric oxide (NO)-dependent mechanism. The authors examined the effect of NO on alveolar macrophage leukotriene synthesis following in vitro and in vivo models of sepsis. Treatment of alveolar macrophages from inducible NO synthase (iNOS) wild-type but not knock-out mice with LPS inhibited leukotriene synthesis. iNOS was induced early in alveolar macrophages from cecal ligation and puncture rats and mice compared to sham animals with associated reduced leukotriene synthesis. iNOS knock-out mice were protected from the decrease in alveolar macrophage 5-lipoxygenase metabolism. iNOS regulates alveolar macrophage 5-lipoxygenase metabolism following endotoxin exposure.

Evaluating the prophylactic potential of zafirlukast against the toxic effects of acetic acid on the rat colon

The present work was conducted to assess the possible protective effects of zafirlukast against the toxic damage induced by acetic acid in rat colon. Zafirlukast is a potent and selective cysteinyl leukotriene receptor antagonist which is used mainly in the prophylaxis of bronchial asthma. Two doses of zafirlukast were used (40 and 80 mg/kg) dissolved in gum acacia and given either orally or rectally (0.5 ml/kg). Several parameters including, macroscopic score, histopathological and biochemical such as malondialdehyde (MDA), myeloperoxidase (MPO), catalase and reduced glutathione (GSH) levels were measured using standard assay procedures. The study showed that pretreatment with zafirlukast in a dose of 80 mg/kg orally produced a significant decrease in tissue malondialdehyde, myeloperoxidase, and an increase in both reduced glutathione and catalase levels, while there was no significant changes with the rectal route. The 40 mg/kg dose had no significant protective effects when given either orally or rectally. The available data indicate that the inhibition of leukotriene synthesis or action may have a role in inflammatory bowel disease (IBD) as they are considered as important mediators in this condition.

Prolonged lipopolysaccharide inhibits leukotriene synthesis in peritoneal macrophages: mediation by nitric oxide and prostaglandins

Resident rat peritoneal macrophages synthesize a variety of prostanoids and leukotrienes from arachidonic acid. Overnight treatment with lipopolysaccharide (LPS) induces the synthesis of cyclooxygenase-2 (COX-2) and an altered prostanoid profile that emphasizes the preferential conversion of arachidonic acid to prostacyclin and prostaglandin E 2. In these studies, we report that exposure to LPS also caused a strong suppression of 5-lipoxygenase but not 12-lipoxygenase activity, indicated by the inhibition of synthesis of both leukotriene B 4 and 5-hydroxyeicosatetraenoic acid (5-HETE), but not of 12-HETE. Inhibition of 5-lipoxygenase activity by LPS was both time- and dose-dependent. Treatment of macrophages with prostaglandin E 2 partially inhibited leukotriene synthesis, and cyclooxygenase inhibitors partially blocked the inhibition of leukotriene generation in LPS-treated cells. In addition to COX-2, nitric oxide synthase (NOS) was also induced by LPS. Treatment of macrophages with an NO donor mimicked the ability of LPS to significantly reduce leukotriene B 4 synthesis. Inhibition of NOS activity in LPS-treated cells blunted the suppression of leukotriene synthesis. Inhibition of both inducible NOS and COX completely eliminated leukotriene suppression. Finally, macrophages exposed to prolonged LPS demonstrated impaired killing of Klebsiella pneumoniae and the combination of NOS and COX inhibitors restored killing to the control level. These results indicate that prolonged exposure to LPS severely inhibits leukotriene production via the combined action of COX and NOS products. The shift in mediator profile, to one that minimizes leukotrienes and emphasizes prostacyclin, prostaglandin E 2 and NO, provides a signal that reduces leukocyte function, as indicated by impaired killing of Gram-negative bacteria.

Evidence-based veterinary dermatology: a systematic review of the pharmacotherapy of canine atopic dermatitis.

The efficacy of pharmacological interventions used to treat canine atopic dermatitis, excluding fatty acid supplementation and allergen-specific immunotherapy, was evaluated based on the systematic review of prospective clinical trials published between 1980 and 2002. Studies were compared with regard to design characteristics (randomization generation and concealment, masking, intention-to-treat analyses and quality of enrolment of study subjects), benefit (improvement in skin lesions or pruritus scores) and harm (type, severity and frequency of adverse drug events) of the various interventions. Meta-analysis of pooled results was not possible because of heterogeneity of the drugs evaluated. Forty trials enrolling 1607 dogs were identified. There is good evidence for recommending the use of oral glucocorticoids and cyclosporin for the treatment of canine atopic dermatitis, and fair evidence for using topical triamcinolone spray, topical tacrolimus lotion, oral pentoxifylline or oral misoprostol. Insufficient evidence is available for or against recommending the prescription of oral first- and second-generation type-1 histamine receptor antagonists, tricyclic antidepressants, cyproheptadine, aspirin, Chinese herbal therapy, an homeopathic complex remedy, ascorbic acid, AHR-13268, papaverine, immune-modulating antibiotics or tranilast and topical pramoxine or capsaicin. Finally, there is fair evidence against recommending the use of oral arofylline, leukotriene synthesis inhibitors and cysteinyl leukotriene receptor antagonists.

Cysteinyl leukotrienes as common mediators of asthma and allergic disease

SummaryThe cysteinyl leukotrienes (CysLTs) induce a number of pro‐inflammatory effects including smooth muscle contraction, an increase in blood flow, plasma exudation, mucous secretion, and activation of inflammatory cells. They play a key role in asthma and allergy, and can be recovered from different body fluids (e.g. bronchoaleveolar or nasal lavage and urine) during allergen‐induced hypersensitivity reactions. The advent of antileukotriene agents (i.e. leukotriene receptor antagonists or leukotriene synthesis inhibitors) has helped clarify how the different mechanisms contribute to inflammation, as well as offer new treatment options for both asthma and allergy. It is now clear that the release of leukotrienes is the final common path for the many different factors causing airway obstruction and inflammation. In asthma, clinical studies have shown that treatment with antileukotrienes can improve pulmonary function, alleviate symptoms, reduce asthma exacerbations, and decrease the need for bronchodilator therapy. Similarly, in patients with allergic rhinitis, improvements have been seen in nasal symptoms, eye symptoms and quality of life. Antileukotrienes provide a new opportunity for simultaneous management of allergic diseases of the upper and lower respiratory tract, and are a rational treatment approach to the concept of ‘one airway’ disease. In future, their utility may also extend to inflammatory disorders of other organ systems (e.g. skin).

Inhibition of leukotriene synthesis, pharmacokinetics, and tolerability of a novel dietary fatty acid formulation in healthy adult subjects

Background: Numerous studies have explored dietary-management strategies for decreasing leukotriene synthesis by inflammatory cells through supplementation with polyunsaturated fatty acids such as gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA). Objectives: This study sought to determine the optimal daily intake, ratios, and formulation of dietary GLA and EPA required to safely reduce leukotriene biosynthesis in healthy individuals, and to evaluate the pharmacokinetics and safety profile of such a formulation. Methods: Two preliminary trials were conducted to determine the minimum effective levels of GLA and EPA intake needed to reduce leukotriene biosynthesis and prevent increases in plasma arachidonic acid (AA) concentrations. These preliminary trials were followed by a single-center, randomized, double-blind, placebo-controlled, parallel-group, escalating-intake inpatient trial of a dietary GLA/EPA emulsion (PLT 3514) in healthy adult subjects. Subjects consumed either 10, 20, or 100 g of the PLT 3514 emulsion (respectively containing 0.75 g GLA + 0.5 g EPA, 1.5 g GLA + 1 g EPA, and 7.5 g GLA + 5 g EPA), or a placebo emulsion containing olive oil daily for 14 days. Plasma fatty acids were measured by gas chromatography. Stimulated whole blood leukotrienes were measured by high-performance liquid chromatography with ultraviolet detection. Results: Thirty subjects were included in the preliminary trials; 47 subjects were enrolled in the escalating-intake trial, of whom 42 completed the study. In the preliminary trials, intake of GLA 1.5 g/d in gelatin capsules decreased the capacity to synthesize leukotrienes but increased plasma levels of AA (both, P < 0.05). Inclusion of 0.25 or 1 g of dietary EPA prevented the increase in plasma AA concentrations. Dietary GLA and EPA showed significantly enhanced bioavailability when consumed in 20 g PLT 3514 emulsion compared with consumption in gelatin capsules ( P < 0.05), resulting in a reduction in the amount of intake required to block leukotriene biosynthesis. Pharmacokinetic analyses indicated that fasting plasma GLA and EPA levels plateaued within 7 days' daily consumption at all levels of intake, whereas the time to maximum plasma concentration (T max) was shorter for GLA than for EPA. The T max was similar on days 1 and 14 for both GLA and EPA. There were no clinically significant between-group differences in changes in vital signs, mean clinical laboratory values, or abbreviated hematology laboratory tests, or significant differences in the occurrence of treatment-emergent adverse events between the group consuming up to 20 g/d of the GLA/EPA emulsion and the group consuming placebo. Conclusion: Consumption of specific proportions and intake levels of dietary GLA and EPA in a novel emulsion formulation inhibited leukotriene biosynthesis and appeared to be well tolerated in this population of healthy adult subjects.

Targeting cysteinyl leukotrienes in patients with rhinitis, sinusitis and paranasal polyps.

Leukotrienes have been known in the field of immunology since the 1930s. At that time they were referred to as the slow reacting substance of anaphylaxis. They were not, however, characterized until the 1980s, when they were noted to be formed during the breakdown of arachidonic acid by the enzyme 5-lipoxygenase. The leukotrienes consist of leukotriene (LT) A4, LTB4, LTC4, LTD4 and LTE4, so named because the molecule was originally isolated from leukocytes and therefore its carbon backbone contains three double bonds in series, which constitutes a trion. This structural information provided the key to the oxidative pathway of lipometabolism, known as the 5-lipoxygenase. Leukotrienes are classified as inflammatory mediators, and therefore they are produced by a number of cell types, particularly mast cells, eosinophils, basophils, macrophages and monocytes. With the identification of asthma, allergic rhinitis and paranasal sinusitis associated with inflammatory pathways, the leukotrienes have been implicated in the pathogenesis of these conditions and have become targets for therapeutic modulation. Leukotriene synthesis inhibitors have been used successfully in the treatment of patients with asthma where they have demonstrated the ability to induce bronchial dilatation, provide protection against broncho-provocation tests and significantly diminish symptoms. When it was serendipitously noted that patients who had concomitant nasal pathology also showed improvement, leukotriene synthesis inhibitors were used as adjuvant therapy in the management of patients with rhinitis, sinusitis and nasal polyposis. Preliminary studies have demonstrated improvements in nasal airflow and reduced recurrence of nasal polyps as noted by endoscopy and imaging studies. Leukotriene synthesis inhibitors therefore appear to be a novel treatment modality for patients with rhinitis, sinusitis and nasal polyps when used as adjunctive therapy.

The role of L-carnitine in treatment of a murine model of asthma.

Leukotrienes, one of the mediators of inflammation in asthma, have a strong bronchoconstrictive effect. L-carnitine has been reported to influence respiratory functions. It has also been reported that L-carnitine inhibits leukotriene synthesis. To evaluate the effects of L-carnitine on oxygen saturation, urine leukotriene E4 levels and lung histopathology in a murine model of asthma, high IgE responder BALB/c mice (n = 24) were systemically sensitized to ovalbumin and chronically challenged with low particle mass concentrations of aerosolized ovalbumin, and then they were divided into 3 groups (study groups A, B, and C) each including eight mice. After methacholine-induced bronchoconstriction, the mice in groups A and B were given intraperitoneal L-carnitine (250 and 125 mg/kg, respectively), while the mice in group C were given placebo. Oxygen saturation of the mice was measured by pulse oxymeter before and after methacholine and after L-carnitine/ placebo application. In addition, urine leukotriene E4 levels were measured before asthma development, and 24-h after L-carnitine injection in asthmatic mice. Inflammation in the lung tissues of the sacrificed animals was scored histopathologically to determine the effect of L-carnitine on tissue level. A control group of non-sensitized mice (n = 8) treated with placebo only was used for comparison of urine leukotriene E4 levels and of histopathological parameters. Oxygen saturation of the mice in the study groups tended to decrease after methacholine and to improve after L-carnitine injection, although these changes were not significant at all time points. Urine leukotriene E4 levels of all 3 study groups increased significantly after asthma development. The rate of increment was smallest in the group given the highest L-carnitine dose (group A). Inflammation at the tissue level was also mildest in group A, and severest in the group that was not given carnitine (group C). All of the study groups and the control group differed significantly with respect to inflammation scores. In conclusion, L-carnitine improved oxygen saturation, and decreased urine leukotriene E4 levels and inflammation in lung tissues in the present murine model of asthma.

Leukotriene Modifiers: Novel Therapeutic Opportunities in Asthma

AbstractFor Abstract see ChemInform Abstract in Full Text.

Regulation of leukotriene synthesis by arachidonic acid in human polymorphonuclear leukocyte adhesive interactions is dependent on the presence of albumin.

We have previously demonstrated that the pretreatment of polymorphonuclear leukocytes (PMNs) with the chemotherapeutic drug, Suramin, increases both cell attachment and inhibits calcium ionophore A23187-stimulated leukotriene (LT) synthesis. Here, we examined the effects of extracellular arachidonic acid (AA) and albumin on attachment and LT synthesis in the interaction of PMNs with both collagen-coated surfaces and human umbilical vein endothelial cell (HUVEC) monolayers. Suramin decreased the release of radiolabelled AA and 5-lipoxygenase metabolites by [(14)C-AA]-prelabelled PMNs stimulated with A23187, with and without human serum albumin (HSA) in the culture medium. Addition of 1 microM AA together with calcium ionophore stimulated the release of endogenous AA to the same level as control and Suramin-pretreated cells, but attachment was unaffected and LT synthesis was still inhibited with Suramin treatment. Using 24 microM AA, regulation of LT synthesis was dependent on the presence of HSA in the medium. Without HSA, 24 microM AA induced detachment of PMNs and increased LT synthesis in Suramin-treated cells above the control level. In the presence of HSA, 24 microM AA did not influence PMN attachment or abolish Suramin-induced inhibition of LT synthesis. These results suggest that tight attachment of PMNs to a solid surface leads to decreased LT synthesis during subsequent stimulation of the cells by A23187 in the presence or absence of exogenous substrate.

A Randomized, Placebo-Controlled Trial of a Leukotriene Synthesis Inhibitor in Patients With COPD

Patients with COPD classically have neutrophilic bronchial inflammation and raised airway concentrations of the neutrophil chemoattractant leukotriene B(4) (LTB(4)). A small phase II trial was conducted to assess the effects of a leukotriene synthesis inhibitor on bronchial inflammation in patients with stable COPD. A randomized, double-blind, placebo-controlled, parallel-group study. Respiratory medicine department of a university hospital. Seventeen patients with chronic bronchitis and COPD (mean FEV(1), 35.5% predicted; SD, 14.8% predicted) were randomized to receive 14 days of the oral leukotriene synthesis inhibitor BAYx1005 (500 mg bid) or placebo. Spontaneous sputum samples obtained at baseline and at the end of treatment were assayed for LTB(4), myeloperoxidase (an indirect marker of neutrophil numbers and/or activation), and chemotactic activity (Boyden chamber). After 14 days, there were no significant differences (p > 0.05) in absolute LTB(4) concentrations between the two treatment groups. However, BAYx1005 treatment produced a significantly greater median reduction in LTB(4) of - 3.1 nM (interquartile range [IQR], - 9.6 to - 0.2 nM) vs 3.0 nM (IQR, - 0.3 to 8.5 nM) [p = 0.001], with concentrations decreasing from 8.0 nM (IQR, 4.3 to 24.4 nM) at baseline to 4.2 nM (IQR, 1.9 to 11.9 nM) at the end of treatment (p = 0.03). There were no changes in the placebo group and no differences in sputum myeloperoxidase concentration or chemotaxis between the two treatment arms (p > 0.05). This small study suggests that a leukotriene synthesis inhibitor can produce modest reductions in some measures of neutrophilic bronchial inflammation in patients with COPD. This class of anti-inflammatory agent requires further study in larger numbers of patients to determine clinical benefit.

5-Lipoxygenase Inhibitors for the Treatment of COPD

The potential for leukotrienes as mediators to target in the development of novel therapies for diseases such as COPD is underscored by their inflammatory behavior and the capacity of leukotriene receptor antagonists and synthesis inhibitors to reduce inflammatory responses when administered in vivo. Airway neutrophilia in COPD patients is believed to be a contributing source of inflammation and is associated with airway remodeling. The presence of neutrophils is mediated in part by leukotriene B(4) (LTB(4)), and the capacity for LTB(4) alone to replicate many aspects of neutrophilic inflammation has provided the focus of drug development toward its specific antagonism. More recently, the potential involvement of the monocyte-macrophage lineage in the etiology of COPD has received growing attention as a target for leukotriene inhibition. The future avenues for exploration of leukotriene inhibition could have been expanded by the realization that 5-lipoxygenase activity is primarily located at the nuclear membrane and the existence of differing cell surface and nuclear receptors to LTB(4). The success of compounds under development in this and other anti-inflammatory classes, however, depends as much on the evolution of clinical studies designed to test the "proof of concept" in efficacy through the examination of surrogate markers or physiologic readouts of changes in lung function.

5-lipoxygenase: cellular biology and molecular pharmacology.

5-lipoxygenase (5-LO) plays an essential role in the biosynthesis of leukotrienes, proinflammatory mediators which are mainly released from myeloid cells. Whereas LTB(4) is a potent chemotactic and chemokinetic agent for a variety of leukocytes, the cysteinyl-leukotrienes C, D(4) and E(4) cause vascular permeability and smooth muscle contraction. In view of these properties, leukotriene synthesis inhibitors have been hypothesized to possess therapeutic potential for the treatment of asthma, allergic disorders and other inflammatory diseases. Whereas cysteinyl-leukotriene receptor antagonists possess potential for antileukotriene therapy in asthma, results from clinical trials with leukotriene synthesis inhibitors were less encouraging. The expression of 5-LO in mammals is tightly regulated. Enzymatic activity in vitro can be modulated by calcium, ATP, phosphatidylcholine and lipid hydroperoxides; nevertheless activation of cellular 5-LO in response to external stimuli is rather incompletely understood. Intensive research revealed that on cell stimulation, 5-LO redistributes to the nuclear membrane where it colocalizes with 5-lipoxygenase-activating protein and cytosolic phospholipase A(2). In addition, various cellular proteins interacting with 5-LO have been identified. It was suggested that enzyme phosphorylation could influence redistribution and cellular activity of 5-LO and that the cellular redox tone regulates 5-LO product formation. This review highlights the determinants of cellular 5-LO activity and summarizes the molecular pharmacology of 5-LO.

Postnatal Dexamethasone for Bronchopulmonary Dysplasia

Inflammation leading to alveolar and airway damage is a significant contributing factor to the development of bronchopulmonary dysplasia (BPD). Preterm infants, who may have developmental immaturity of their hypothalamic-pituitary-adrenal axis and decreased cortisol response to stress, could be particularly vulnerable to the effects of inflammatory injury. For these reasons, using anti-inflammatory agents such as dexamethasone to prevent BPD has appeared to be reasonable. Clinical studies have demonstrated decreased inflammatory markers and suppression of cytokine-mediated inflammatory reactions in the bronchoalveolar lavage fluid of preterm infants treated with dexamethasone. (1) In addition, corticosteroids have been associated with numerous potential physiologic benefits on the lung, including increased surfactant synthesis, enhanced beta-adrenergic activity, increased antioxidant production, stabilization of cell and lysosomal membranes, and inhibition of prostaglandin and leukotriene synthesis. (1) Acute improvement in lung function, with increased dynamic compliance and decreased pulmonary resistance, has also been demonstrated within 12 hours of treatment with dexamethasone. (2) Likely because of this acute improvement in lung function, which facilitates weaning from mechanical ventilation, postnatal steroids have been widely used. In the recent multicenter North American Thyrotropin-releasing Hormone Trial for the prevention of lung disease in preterm infants, 72% of infants weighing less than 1,500 g who were ventilated at 14 days received postnatal steroids in an effort to prevent BPD (personal communication, Dr Roberta Ballard, June, 2001). However, the long-term effects of dexamethasone on pulmonary outcome, survival, and neurodevelopmental outcome in preterm infants has raised some questions about its use. The following criteria for assessing the benefit of postnatal steroids have been proposed: 1. Decreased mortality. 2. Decreased outcome of BPD or death at 36 weeks’ postmenstrual age (PMA). 3. No significant acute adverse effects. 4. No long-term effects on growth or neurodevelopmental outcome. 5. No increased occurrence of disease, such as cardiac disease or diabetes, throughout life. In this review and …