Role Of Leukotrienes Research Articles

Characterization of the Cysteinyl Leukotriene 2 Receptor in Novel Expression Sites of the Gastrointestinal Tract

Cysteinyl leukotrienes (cysLTs: LTC₄, LTD₄, and LTE₄) are pro-inflammatory lipid molecules synthesized from arachidonic acid. They exert their actions on at least two cysLT receptors (CysLT₁R and CysLT₂R). Endothelial expression and activation of these receptors is linked to vasoactive responses and to the promotion of vascular permeability. Here we track the expression pattern of CysLT₂R in a loss-of-function murine model (CysLT₂R-LacZ) to neurons of the myenteric and submucosal plexus in the small intestine, colonic myenteric plexus, dorsal root ganglia, and nodose ganglion. Cysteinyl leukotriene (LTC₄/D₄) stimulation of colonic submucosal venules elicited a greater permeability response in wild-type mice. In a dextran sulfate sodium-induced colon inflammation model, the disease activity index and colonic edema (measured by wet:dry weights and submucosal thickness) were significantly reduced in knockout (KO) mice compared to controls. Tumor necrosis factor-α levels in colon tissue were significantly lower in KO mice; however, myeloperoxidase activity was similar in both the KO and wild-type groups. Finally, patch-clamp recordings of basal neuronal activity of colonic-projecting nociceptive neurons from dorsal root ganglia (T9-13) revealed significantly higher excitability in KO neurons compared to wild type. These results suggest that a lack of neuronal expression of CysLT₂R in the murine colonic myenteric plexus attenuates colitis disease progression via a reduction in inflammation-associated tissue edema and increases neuronal sensitivity to nociceptive stimuli.

Quantitative measurement of cysteinyl leukotrienes and leukotriene B 4 in human sputum using ultra high pressure liquid chromatography–tandem mass spectrometry

The role of leukotrienes (LTs) in airway inflammatory diseases, such as asthma, has been extensively reported. The measurement of LTs in sputum supernatants, which is commonly done via enzyme immunoassays (EIAs), may prove to be useful for assessing airway inflammation. Despite the many advantages of EIA, these methods suffer from a lack of selectivity. Therefore, a selective and reliable method for the analysis of LTs in human sputum is needed. In this study we developed and validated a sensitive and specific method using ultra high pressure liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS), to measure simultaneously cysteinyl leukotrienes (CysLTs) and leukotriene B 4 (LTB 4) in human sputum. Sputum supernatants obtained by ultracentrifugation were stabilized by protease inhibitors, spiked with stable isotopic internal standards, and subjected to solid phase extraction (SPE) and UHPLC separation. Multiple reaction monitoring (MRM) transitions were optimized and measured on a mass spectrometer. The limit of detection (LOD) for LTE 4 and LTB 4 was 9.8 and 19.5 pg/mL, respectively. The lower limit of quantitation (LLOQ) for LTE 4 and LTB 4 was 19.5 and 39.0 pg/mL, respectively. The dynamic range of the LTE 4 assay was from 9.8 to 5000 pg/mL, whereas for the LTB 4 assay was from 19.5 to 10,000 pg/mL. The intra- and inter-day % coefficient of variation (%CV) was <6.5% and <10%, for both LTE 4 and LTB 4, respectively. Spike recovery ranged from 105% to 111% for both analytes. In addition, twenty-two sputum samples were analyzed for cysLTs and LTB 4. Fourteen of these samples were purchased commercially and eight were collected during the course of a clinical trial. LTB 4 was detectable in all samples tested and it ranged from 79 to 7220 pg/mL. LTE 4 was detectable in most of the sputum samples (12.3–891 pg/mL), whereas LTC 4 and LTD 4 were below limit of detection for majority of sputum samples. The in vitro conversion of LTC 4 and LTD 4 into LTE 4 was observed. The measurement of LTB 4 was sensitive to low pH and high temperature. The use of UHPLC–MS/MS method will allow a more accurate and reliable quantitation of LTs in human sputum, which in turn, may lead to a better understanding of the role of LTs in airway disease pathways and the application in associated clinical treatments.

Leukotriene modifiers for asthma treatment

Leukotrienes (LTs), including cysteinyl LTs (CysLTs) and LTB(4) , are potent lipid mediators that have a role in the pathophysiology of asthma. At least two receptor subtypes for CysLTs, CysLT(1) and CysLT(2) , have been identified. The activation of the CysLT(1) receptor is responsible for most of the pathophysiological effects of CysLTs in asthma, including increased airway smooth muscle activity, microvascular permeability, and airway mucus secretion. LTB(4) might have a role in severe asthma, asthma exacerbations, and the development of airway hyperresponsiveness. CysLT(1) receptor antagonists can be given orally as monotherapy in patients with mild persistent asthma, but these drugs are generally less effective than inhaled glucocorticoids. Combination of CysLT(1) receptor antagonists and inhaled glucocorticoids in patients with more severe asthma may improve asthma control and enable the dose of inhaled glucocorticoids to be reduced while maintaining similar efficacy. The identification of subgroups of asthmatic patients who respond to CysLT(1) receptor antagonists is relevant for asthma management as the response to these drugs is variable. CysLT(1) receptor antagonists have a potential anti-remodelling effect that might be important for preventing or reversing airway structural changes in patients with asthma. This review discusses the role of LTs in asthma and the role of LT modifiers in asthma treatment.

Role of leukotriene B 4 in celecoxib-mediated anticancer effect

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has anticancer effect on many cancers associated with chronic inflammation by both COX-2-dependent and COX-2-independent mechanisms. The non-COX-2 targets of celecoxib, however, are still a matter of research. Leukotriene B 4 (LTB 4) has been implicated in prostate and colon carcinogenesis, but little is known about the potential role of LTB 4 in celecoxib-mediated anticancer effect. In this study, we evaluated whether LTB 4 was involved in celecoxib-mediated inhibitory effect on human colon cancer HT-29 cells and human prostate cancer PC-3 cells. Our data showed that survival of both cell lines was obviously suppressed after celecoxib treatment for 72 h in a concentration-dependent manner. However, only in HT-29 cells, this inhibitory effect could be reversed by LTB 4, which promoted survival of HT-29 cells rather than PC-3 cells. Consistent with these results, lioxygenase (LOX) potent inhibitor nordihydroguaiaretic acid (NDGA) had a higher inhibitory effect on HT-29 cells than PC-3 cells. Additionally, ELISA results showed that celecoxib could suppress expression of LTB 4 in both cell lines, whereas, inhibition of PGE 2 was only detected in HT-29 cells. These results indicate that the anticancer effect of celecoxib is COX-2-independent in HT-29 and PC-3 cells and in HT-29 cells primarily via down-regulating LTB 4 production.

Interplay of cysteinyl leukotrienes and TGF-β in the activation of hepatic stellate cells from Schistosoma mansoni granulomas

Hepatic stellate cells (HSCs) have a critical role in liver physiology, and in the pathogenesis of liver inflammation and fibrosis. Here, we investigated the interplay between leukotrienes (LT) and TGF-β in the activation mechanisms of HSCs from schistosomal granulomas (GR-HSCs). First, we demonstrated that GR-HSCs express 5-lipoxygenase (5-LO), as detected by immunolocalization in whole cells and confirmed in cell lysates through western blotting and by mRNA expression through RT-PCR. Moreover, mRNA expression of 5-LO activating protein (FLAP) and LTC 4-synthase was also documented, indicating that GR-HSCs have the molecular machinery required for LT synthesis. Morphological analysis of osmium and Oil-Red O-stained HSC revealed large numbers of small lipid droplets (also known as lipid bodies). We observed co-localization of lipid droplet protein marker (ADRP) and 5-LO by immunofluorescence microscopy. We demonstrated that GR-HSCs were able to spontaneously release cysteinyl-LTs (CysLTs), but not LTB 4, into culture supernatants. CysLT production was highly enhanced after TGF-β-stimulation. Moreover, the 5-LO inhibitor zileuton and 5-LO gene deletion were able to inhibit the TGF-β-stimulated proliferation of GR-HSCs, suggesting a role for LTs in HSC activation. Here, we extend the immunoregulatory function of HSC by demonstrating that HSC from liver granulomas of schistosome-infected mouse are able to release Cys-LTs in a TGF-β-regulated manner, potentially impacting pathogenesis and liver fibrosis in schistosomiasis.

Leukotrienes modulate secretion of progesterone and prostaglandins during the estrous cycle and early pregnancy in cattle: an in vivo study

Recently, we showed that leukotrienes (LTs) regulate ovarian cell function in vitro. The aim of this study was to examine the role of LTs in corpus luteum (CL) function during both the estrous cycle and early pregnancy in vivo. mRNA expression of LT receptors (BLT for LTB(4) and CYSLT for LTC(4)), and 5-lipoxygenase (5-LO) in CL tissue and their localization in the ovary were studied during the estrous cycle and early pregnancy. Moreover, concentrations of LTs (LTB(4) and C(4)) in the CL tissue and blood were measured. 5-LO and BLT mRNA expression increased on days 16-18 of the cycle, whereas CYSLT mRNA expression increased on days 16-18 of the pregnancy. The level of LTB(4) was evaluated during pregnancy compared with the level of LTC(4), which increased during CL regression. LT antagonists influenced the duration of the estrous cycle: the LTC(4) antagonist (azelastine) prolonged the luteal phase, whereas the LTB(4) antagonist (dapsone) caused earlier luteolysis in vivo. Dapsone decreased progesterone (P(4)) secretion and azelastine increased P(4) secretion during the estrous cycle. In summary, LT action in the bovine reproductive tract is dependent on LT type: LTB(4) is luteotropic during the estrous cycle and supports early pregnancy, whereas LTC(4) is luteolytic, regarded as undesirable in early pregnancy. LTs are produced/secreted in the CL tissue, influence prostaglandin function, and serve as important factors during the estrous cycle and early pregnancy in cattle.

Arachidonic Acid, Eicosanoids, and Fracture Repair

Not all fractures heal well or rapidly in the adult skeleton, and basic scientists and clinicians continue to search for ways to make fractures heal more predictably. It is a fundamental tenet of orthopaedics that skeletal injury is followed by inflammation and that this inflammatory response is the first stage in a sequence of events that culminate in skeletal repair. Modulating this response can affect the inflammatory stage and in turn subsequent stages that are required for healing. Literally dozens of studies in animals dating back to the 1970s have investigated the effects of commonly used anti-inflammatory medications on prostaglandin synthesis and fracture repair with strikingly uniform results. More recently, investigators have begun examining other means of modulating the early inflammatory stages after fracture in an effort to enhance fracture healing. This article reviews recent investigations into the potential role of leukotrienes as negative regulators of fracture healing and potential pharmacologic use of medications that block this effect.

Exercise but not mannitol provocation increases urinary Clara cell protein (CC16) in elite swimmers

Elite swimmers have an increased risk of developing asthma, and exposure to chloramine is believed to be an important trigger factor. The aim of the present study was to explore pathophysiological mechanisms behind induced bronchoconstriction in swimmers exposed to chloramine, before and after swim exercise provocation as well as mannitol provocation. Urinary Clara cell protein (CC16) was used as a possible marker for epithelial stress. 101 elite aspiring swim athletes were investigated and urinary samples were collected before and 1h after completed exercise and mannitol challenge. CC16, 11β-prostaglandin (PG)F(2α) and leukotriene E(4) (LTE(4)) were measured. Urinary levels of CC16 were clearly increased after exercise challenge, while no reaction was seen after mannitol challenge. Similar to CC16, the level of 11β-PGF(2α) was increased after exercise challenge, but not after mannitol challenge, while LTE(4) was reduced after exercise. There was no significant difference in urinary response between those with a negative compared to positive challenge, but a tendency of increased baseline levels of 11β-PGF(2α) and LTE(4) in individuals with a positive mannitol challenge. The uniform increase of CC16 after swim exercise indicates that CC16 is of importance in epithelial stress, and may as such be an important pathogenic factor behind asthma development in swimmers. The changes seen in urinary levels of 11β-PGF(2α) and LTE(4) indicate a pathophysiological role in both mannitol and exercise challenge.

Leukotrienes and Atherosclerosis

Evidence from experimental and genetic studies suggest the existence of a potential link between the leukotrienes (LT) signalling cascade, and the pathogenesis/progression of atherosclerosis and its serious consequences such as acute myocardial infarction (AMI), stroke, aortic aneurysms, and intimal hyperplasia. LT biosynthetic enzymes are expressed within atherosclerotic lesion, leading to production of cysteinyl-leukotrienes (Cys-LTs) and LTB4 that exert potent pro-inflammatory action through interaction with CysLT and BLT receptor subtypes expressed on inflammatory and structural cells within the vascular wall. Genetic variants in the genes of the 5-LO pathway have been associated with the risk of developing AMI and stroke. As a result, anti-LT have recently received renewed interest for the treatment of atherosclerosis and its ischemic complications. The aim of this short review is to summarize our current understanding of the role of LTs and their receptors in the genesis and progression of atherosclerosis and review the recent developments on the use of antagonists.

ChemInform Abstract: A Versatile Approach to anti-Asthmatic Compound CMI-977 and Its Six-Membered Analogue.

The synthesis of the anti-asthmatic compound CMI-977 is described. The tetrahydrofuran ring was effectively constructed by involving olefin metathesis while the stereoselective introduc- tion of the 1-N-hydroxyureidylbut-3-yn-4-yl side-chain was achieved by C-alkylation of the 2-benzenesulfonyl derivative. The role of leukotrienes in inflammatory and allergic re- sponses including arthritis, asthma, psoriasis, and throm- botic disease has been well recognized. The urge to develop antagonists or inhibitors of leukotriene biosyn- thesis to prevent inflammatory responses is an ongoing process. 1 Various 2,5-disubstituted tetrahydrofuran deriv- atives have been reported with lipoxygenase inhibitory activity. 2 However, (2S,5S)-5-(4-fluorophenoxylmethyl)- 2-(1-N-hydroxyureidylbut-3-yn-4-yl)tetrahydrofuran (CMI-977) (1) is by far the most potent compound report- ed in this series. 3 In this communication, we report a new approach to 2,5-disubstituted tetrahydrofuran (CMI -977) as well as to the corresponding six-membered 2,6-disub- stituted pyran analogue 2 based on (i) the olefin metathesis 4 and (ii) a stereoselective alkylation of 2-ben- zenesulfonyl derivatives. 5

Is there a role for leukotriene antagonists in the prevention of recurrent nasal polyps?

The aim of this review is to provide the current available data for leukotriene receptor antagonists in the treatment of nasal polyps, the use in the postoperative therapy single or as an add-on to standard treatments. Surgical treatment of nasal polyps was refined in the last 30 years by the introduction of functional endoscopic sinus surgery and nasal endoscopy for monitoring nasal polyp patients. As the relapse is the main challenge and as nasal steroids only delay it, a more efficient treatment is needed. Leukotriene antagonists have effects on asthma and allergic rhinitis; preliminary data show some benefits in nasal polyps. In the surgery of nasal polyps, recurrence is the main problem. Steroids are the current standard therapy, but the limitations are obvious. The role of leukotrienes in the disorder of nasal polyps is well established now, and with the antagonists available, interest rose in treating nasal polyps. A total of 356 patients took part in several studies involving leukotriene antagonists in the nasal polyp population. Some studies have minor levels of evidence; the data show positive effects for patients in preoperative and postoperative studies and medical treatments. There were benefits as an add-on to steroids and data from allergic rhinitis studies also show possible synergism with antihistamines. There are hints for a positive effect on eosinophil inflammation, clinical symptom scores, nasal airflow, sneezing and postnasal drip. Although some effects are shown, more controlled studies are necessary for reliable data.

Impaired phagocytosis by alveolar macrophages from diabetic rats is related to the deficient coupling of LTs to the FcγR signaling cascade

Diabetic individuals are more susceptible to infections and this seems to be related to impaired phagocyte function. Alveolar macrophages (AMs) are the first barrier to prevent respiratory infections. Leukotrienes (LTs) increase AM phagocytic activity via FcγR. In this study, we compared AMs from diabetic and non-diabetic rats for phagocytosis via FcγR and the roles of LTs and insulin. Diabetes was induced in male Wistar rats by alloxan (42 mg/kg, i.v.); macrophages were obtained by bronchoalveolar lavage and IgG-opsonised sheep red blood cells (IgG-SRBC) were used as targets. LTs were added to the AMs 5 min before the addition of IgG-SRBC. AMs were treated with a LT synthesis inhibitor (zileuton, 10 μM), or antagonists of the LTB 4 receptor (CP105.696, 10 μM) or cys-LT receptor (MK571, 10 μM), 30 or 20 min before the addition of IgG-SRBC, respectively. We found that the phagocytosis of IgG-SRBC by AMs from diabetic rats is impaired compared with non-diabetic rats. Treatment with the LT inhibitor/antagonists significantly reduced AM phagocytosis in non-diabetic but not diabetic rats. During the phagocytosis of IgG-SRBC LTB 4 and LTC 4 were produced by AMs from both groups. The addition of exogenous LTB 4 or LTD 4 potentiated phagocytosis similarly in both groups. Phagocytosis was followed by the phosphorylation of PKC-δ, ERK and Akt. This was reduced by zileuton treatment in AMs from non-diabetic but not diabetic rats. The addition of insulin to AMs further increased the phagocytosis by increasing PKC-δ phosphorylation. These results suggest that the impaired phagocytosis found in AMs from diabetic rats is related to a deficient coupling of LTs to the FcγR signaling cascade and that insulin has a key role in this coupling. An essential role for insulin in innate immunity is suggested.

Involvement of leukotrienes in the pathogenesis of silica-induced pulmonary fibrosis in mice

ABSTRACTThe authors investigated the role of leukotrienes (LTs) in the pathogenesis of silica-induced pulmonary fibrosis in mice during the progression from acute to chronic phases. Intratracheal instillation of silica particles induced progressive pulmonary fibrosis. The tissue content of cysteinyl (Cys) LTs and LTB4 was markedly increased in the acute phase after silica instillation, concurrently with the up-regulation of LTB4 receptor, transforming growth factor (TGF)-β1, and tumor necrosis factor (TNF)-α, along with down-regulation of the CysLT type 2 receptor. Importantly, the tissue content of CysLTs and mRNA levels of TGF-β1 and TNF-α were increased in the fibrotic lung in the chronic phase. Furthermore, strong immunohistochemical staining for the CysLT type 1 receptor, TNF-α, and TGF-β1, but not for the CysLT type 2 receptor, was codetected in the pathological lesions during both acute and chronic phases. These findings suggest that an increase in LT production in the lung and modulation of homeostatic balance among LT receptors may contribute to the progression of pulmonary fibrosis.

Role of leukotrienes in resistance and susceptibility to infection by Histoplasma capsulatum

Role of leukotrienes in resistance and susceptibility to infection by Histoplasma capsulatum

5-Lipoxygenase inhibitors: a review of recent developments and patents

Importance to the field: Leukotrienes (LTs) are pivotal lipid mediators of inflammation and allergy and results from recent studies also suggest roles of LTs in cardiovascular diseases, cancer and osteoporosis. 5-Lipoxygenase (5-LO) catalyzes the first step in the biosynthesis of LTs from arachidonic acid, and based on the multiple potent pathophysiological actions of LTs, the pharmacological intervention with 5-LO is a challenge in the development of therapeutics.Areas covered in this review: We first summarize the biochemical regulation of 5-LO and the general pharmacological concepts in 5-LO inhibition by currently available compounds, and subsequently we report recent developments deduced from recent scientific publications and patents.What the reader will gain: A comprehensive overview about the different molecular pharmacological strategies to inhibit 5-LO and the most successful previous 5-LO inhibitors. The review also gives insights into novel concepts, for example, dual prostaglandin/LT synthesis inhibition and reveals novel compounds patented or developed within the past 5 years.Take home message: Despite the increasing therapeutic indications of anti-LT therapy, the progress in the development of novel 5-LO inhibitors is moderate. However, novel molecular concepts in the intervention with LT biosynthesis seem promising.

Sputum leukotrienes in chronic airway diseases and bronchial asthma attacks

To determine the pathogenetic role of leukotrienes in chronic airway diseases, sputum samples from patients with bronchial asthma (BA), diffuse panbronchiolitis (DPB), sinobronchial syndrome (SBS), and bronchiectasis (BE) were examined for the presence of leukotrienes (LT) C4, D4, E4, B4, all apparently derived from airway inflammatory cells. Sputum samples from 21 patients, including 10 with BA attack (5 atopic type, 5 non-atopic type) and 11 with chronic obstructive airway diseases (3 DPB, 6 SBS, and BE), were studied. Patients expectorated sputum directly into test-tubes containing 80% ethanol. Following ethanol extraction and partial purification by a C18 SEP-PAK column, LTs were further purified by high performance liquid chromatography (HPLC). Fractions from HPLC with elution times corresponding to synthetic LTC4, D4, E4, and B4 were used to quantify LTs by radioimmunoassay. Eosinophils and neutrophils in the sputum (0.5 ml) were counted following Papanicolaou staining. Percentages of eosinophils in sputum were higher in BA, while those of neutrophils were higher in DPB. Sputum levels of LTC4 were 1.2 +/- 1.6 in BA, 0.12 +/- 0.11 in SBS, and 0.42 +/- 0.14 ng/ml in DPB. Those of LTD4 were 0.21 +/- 0.27 in BA, 0.9 +/- 0.13 in DPB, and 0.10 +/- 0.07 in SBS. LTE4 levels were 5.06 +/- 3.83 in DPB and 2.66 +/- 4.32 in BA. Levels of LTB4 were 1.36 +/- 1.19 in DPB, 0.28 +/- 0.27 in BA, 0.12 +/- 0.07 in SBS, and 0.04 +/- 0.04 in BE. In asthmatics, peptide leukotriene content in sputum was higher than that in chronic airway disease patients.(ABSTRACT TRUNCATED AT 250 WORDS)

An update on the role of leukotrienes in asthma

Leukotrienes are lipid mediators involved in the pathogenesis of asthma. There is significant new information about the actions of leukotrienes in asthma and the evolving role of antileukotriene therapies. We review recent findings on regulation of leukotriene synthesis, biological function of leukotrienes in disease models, and use of leukotriene modifiers in clinical practice. Our understanding of the regulation of leukotriene synthesis at a molecular level has greatly advanced. Recent evidence indicates that genetic variation in the leukotriene synthetic pathway affects the clinical response to leukotriene modifiers. The participation of leukotriene B4 in the allergic sensitization process in animal models suggests a larger role for leukotriene B4 in asthma. Preclinical and in-vitro models suggest that the cysteinyl leukotrienes are important in airway remodeling. Leukotrienes are key mediators of exercise-induced bronchoconstriction with recent studies demonstrating that leukotriene modifiers reduce the severity of exercise-induced bronchoconstriction during short-term and long-term use. Leukotrienes are clearly involved in airway inflammation and certain clinical features of asthma. Evolving evidence indicates that leukotriene B4 has an important role in the development of asthma and that cysteinyl leukotrienes are key mediators of the airway remodeling process.

Leukotrienes Produced in Allergic Lung Inflammation Activate Alveolar Macrophages

It has been well-documented that leukotrienes (LTs) are released in allergic lung inflammation and that they participate in the physiopathology of asthma. A role for LTs in innate immunity has recently emerged: Cys-LTs were shown to enhance FcγR-mediated phagocytosis by alveolar macrophages (AMs). Thus, using a rat model of asthma, we evaluated FcγR-mediated phagocytosis and killing of Klebsiella pneumoniae by AMs. The effect of treatment with a cys-LT antagonist (montelukast) on macrophage function was also investigated. Male Wistar rats were immunized twice with OVA/alumen intraperitoneally and challenged with OVA aerosol. After 24 h, the animals were killed, and the AMs were obtained by bronchoalveolar lavage. Macrophages were cultured with IgG-opsonized red blood cells (50:1) or IgG-opsonized K. pneumoniae (30:1), and phagocytosis or killing was evaluated. Leukotriene C₄ and nitric oxide were quantified by the EIA and Griess methods, respectively. The results showed that AMs from sensitized and challenged rats presented a markedly increased phagocytic capacity via FcγR (10X compared to controls) and enhanced killing of K. pneumoniae (4X higher than controls). The increased phagocytosis was inhibited 15X and killing 3X by treatment of the rats with montelukast, as compared to the non-treated group. cys-LT addition increased phagocytosis in control AMs but had no effect on macrophages from allergic lungs. Montelukast reduced nitric oxide (39%) and LTC₄ (73%). These results suggest that LTs produced during allergic lung inflammation potentiate the capacity of AMs to phagocytose and kill K. pneumonia via FcγR.

Montelukast as a Treatment of Acute Lung Injury in Sepsis

Acute lung injury is a syndrome including acute and persistent lung inflammation with augmented vascular permeability. Sepsis is the most common reason for acute lung injury. The overall mortality rate of acute lung injury has been reported as 25 – 58%, although recent advances in the management of sepsis have been revealed. Many studies have pointed out the role of anti-inflammatory treatments of sepsis and sepsis-induced acute lung injury. But anti-inflammatory treatments such as N-acetylcysteine and TNF-alpha blockers have still limited value in the treatment of sepsis-induced lung injury. Sepsis and its effect on lung tissue is a kind of inflammatory storm and it is therefore not easy to control all steps in this inflammatory pathway. On the other hand, the leukotriene receptor antagonist, montelukast, has been shown to ameliorate sepsis induced hepatic and intestinal injury including oxidative stress in rats. Montelukast has also been used as an effective agent to decrease fibrosis and oxidative stress in lungs in some animal studies. Acute lung injury due to sepsis is related to some mediators and cytokines, including fibroblastic growth factor and tumor necrosis factor (TNF-alpha), both of which are released in the inflammatory process of acute lung injury and oxidative stress. Given the multiple lines of evidence that have emerged to support a central role of leukotrienes, we hypothesize that leukotriene receptor antagonist treatment, particularly with montelukast, may reduce the fibrotic phase of acute lung injury due to sepsis. We believe that if our hypothesis is correct, a new perspective will be opened for the medical management of sepsis-induced acute lung injury.

Involvement of Leukotriene Pathway in the Pathogenesis of Ischemia- Reperfusion Injury and Septic and Non-Septic Shock

The 5-lipoxygenase (5-LO) pathway is responsible for the production of leukotrienes (LTs), inflammatory lipid mediators which play a role in innate immunity. More recently, a pivotal role of LTs in ischemia-reperfusion and shock injury has been suggested. In fact, these pathological conditions are characterized by a severe neutrophil infiltration that gives rise to tissue injury and 5-LO metabolites control neutrophil recruitment in injured tissue by the modulation of adhesion molecule expression. The aim of this review is to analyze the results reported in the literature on the role of 5-LO pathway, with particular regard to LTs, in these pathological conditions. A better understanding of the mechanisms underlying the role of the 5-LO enzyme and/or its metabolites in the regulation of neutrophil trafficking, might open new perspectives in the therapy of organ dysfunction and/or injury associated with shock and ischemia-reperfusion injury.