Leucotriene B4 Research Articles

042 Epidermal leucotriene B4 receptor expression as a marker of regulatory T-cell–driven responses in resolved psoriasis

Pathogenic memory T cells are implicated in the local memory of chronic skin diseases. The factors underlying their persistence and function in human resolved epidermis are not understood. Lipid composition and transcriptional programs of lipid metabolism are known to be altered in active and non-lesional psoriasis, and the faculty of resident T cells to uptake fatty acids is essential to their local survival. Here, we wished to correlate the functionality of epidermal T cells in resolved skin of psoriasis patients to the lipid metabolism using transcriptomic data.

Eicosanoids in Nonalcoholic Fatty Liver Disease (NAFLD) Progression. Do Serum Eicosanoids Profile Correspond with Liver Eicosanoids Content during NAFLD Development and Progression?

Nonalcoholic fatty liver disease (NAFLD) is becoming a major public health problem worldwide. The study aimed to evaluate the concentration of eicosanoids in serum and liver tissue during steatosis progression and to assess whether eicosanoid change scores may predict liver tissue remodeling. Thirty six eight-week-old male Sprague Dawley rats were enrolled and sacrificed at different stages of NAFLD. Eicosanoid concentrations, namely lipoxin A4, hydroxyeicosatetraenoic acids (HETE), hydroxyloctadecadienoic acids (HODE), protectin DX, Maresine1, leucotriene B4, prostaglandin E2, and resolvin D1 measurement in serum and liver tissue with Agilent Technologies 1260 liquid chromatography were evaluated. For the liver and serum concentrations of 9-HODE and 13-HODE, the correlations were found to be strong and positive (r > 0.7, p < 0.05). Along with NAFLD progression, HODE concentration significantly increased, and change scores were more abundant in the liver. The moderate positive correlation between liver and serum (r = 0.52, p < 0.05) was also observed for resolvin E1. The eicosanoid concentration decreased during NAFLD progression, but mostly in serum. There were significant correlations between HETE concentrations in liver and serum, but their associations were relatively low and changes the most in liver tissue. Eicosanoids profile, predominantly 9-HODE and 13-HODE, may serve as a potential biomarker for NAFLD development.

Cytokine and eicosanoid profiles of phosphate mine workers.

Professional exposures to respirable dusts from phosphate mines are associated with the development of an inflammatory response and airways diseases. This study was performed on 12 phosphate workers versus 8 unexposed controls, including smokers and non-smokers. It consisted of assessing the incidence of phosphate dusts exposure associated or not with smoking on the plasmatic inflammatory status of phosphate mine workers versus controls. The following parameters were studied: hematological profile and plasma level of seven cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12, tumor necrosis Factor (TNF-α), macrophage inflammatory protein (MIP-1β)) and two eicosanoids (leucotriene B-4 (LTB-4) and 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE)) measured by a multiplexed flow cytometric method (CBA: Cytometric Bead Array) or ELISA. In phosphate workers, mainly smokers, the level of white blood cells (WBCs) and lymphocytes (LYM) was significantly higher as compared with controls. This was associated with enhanced levels of IL-1β, IL-6, IL-8, MIP-1β, and LTB-4. In smokers (including phosphate mine workers and controls), the level of LYM was also significantly higher than in controls. Based on a logistic regression analysis, smoker phosphate mine workers have a higher relative risk than controls to have an increase concentration of some cytokines, especially IL-1β, IL-6, IL-8, TNF-α, and MIP-1β. Moreover, the combined effect of smoking and phosphate dusts exposure increases the level of leucocytes as well as the concentration of IL-1β, IL-6, IL-8, MIP1-β, and LTB-4. The present study demonstrates that phosphate dusts are able to trigger a systemic inflammatory reaction characterized by enhanced levels of circulating immunocompetent cells, plasmatic cytokines and eicosanoids, and it establishes that these side effects are enhanced by smoking.

Cooperative role of endogenous leucotrienes and platelet‐activating factor in ischaemia–reperfusion‐mediated tissue injury

Insufficient oxygen delivery to organs leads to tissue dysfunction and cell death. Reperfusion, although vital to organ survival, initiates an inflammatory response that may both aggravate local tissue injury and elicit remote organ damage. Polymorphonuclear neutrophil (PMN) trafficking to remote organs following ischaemia/reperfusion (I/R) is associated with the release of lipid mediators, including leucotriene (LT) B4, cysteinyl-LTs (CysLTs) and platelet-activating factor (PAF). Yet, their potentially cooperative role in regulating I/R-mediated inflammation has not been thoroughly assessed. The present study aimed to determine the cooperative role of lipid mediators in regulating PMN migration, tissue oedema and injury using selective receptor antagonists in selected models of I/R and dermal inflammation. Our results show that rabbits, pre-treated orally with BIIL 284 and/or WEB 2086 and MK-0571, were protected from remote tissue injury following I/R or dermal inflammation in an additive or synergistic manner when the animals were pre-treated with two drugs concomitantly. The functional selectivity of the antagonists towards their respective agonists was assessed in vitro, showing that neither BIIL 284 nor WEB 2086 prevented the inflammatory response to IL-8, C5a and zymosan-activated plasma stimulation. However, these agonists elicited LTB4 biosynthesis in isolated rabbit PMNs. Similarly, a cardioprotective effect of PAF and LTB4 receptor antagonists was shown following myocardial I/R in mice. Taken together, these results underscore the intricate involvement of LTB4 and PAF in each other’s responses and provide further evidence that targeting both LTs and PAF receptors provides a much stronger anti-inflammatory effect, regulating PMN migration and oedema formation.

Phototherapeutic hardening modulates systemic cytokine levels in patients with polymorphic light eruption

The etiopathogenesis of polymorphic light eruption (PLE) has been linked to impaired UV-immunosuppression, Langerhans cell (LC) retention, and an absence of neutrophil infiltration into UV-exposed PLE skin. We have previously shown that photohardening restores the impaired neutrophil responsiveness to the chemoattractants leucotriene B4 and formyl-methionyl-leucyl-phenylalanin in PLE patients. The aim of this study was to investigate whether photohardening modulates baseline chemokine and cytokine levels which would alter chemoresponsiveness and hence immune function in PLE patients. Sixteen PLE patients received photohardening therapy for 4-9 weeks by 311 nm UVB. Plasma samples were taken both before and within 48 h of the penultimate phototherapeutic exposure. Plasma from these 16 patients, 8 non-irradiated PLE patients, and 14 control subjects was analyzed for IL-1β, CXCL8 (IL-8), IL-10, IL-17, TNF, CCL2 (MCP-1), CCL5 (RANTES), CCL11 (eotaxin), and CCL22 (MDC). These cytokines and chemokines were measured in early spring (March to April) and again in late spring (April to June). PLE patients had a significantly elevated level of CCL11 (p = 0.003) and IL-1β (p = 0.002) in early spring (before phototherapy). In late spring, after phototherapy, PLE patients had significantly elevated CCL2 (p = 0.002) and TNF (p = 0.002) but a trend for lowered plasma levels of CXCL8 (p = 0.021). When comparing the cytokine shifts from early to late spring, while healthy controls and non-UV-irradiated PLE patients showed an increase, PLE patients undergoing photohardening exhibited a trend for decrease in IL-1β (p = 0.012). Taken together, our results indicate that photohardening may alter the complex cytokine milieu in PLE, in particular via IL-1β, helping to normalise the pathophysiologic response to subsequent UV exposure.

Abstract 4589: Gamma-tocopherol and mixed tocopherols inhibit AOM-induced colon carcinogenesis that was promoted by moderate but not severe colon inflammation caused by dextran sodium sulfate

Abstract Our previous studies indicate that specific forms of vitamin E such as gamma-tocopherol (gT), the predominant form of vitamin E in US diets, have anti-inflammatory activities by inhibition of proinflammatory eicosanoids including prostaglandin E2 and leucotriene B4. These eicosanoids are known to promote carcinogenesis of different types of cancer including colon cancer. We therefore hypothesize that gT may be an effective anticancer agent against colon cancer. In male BALC mice, we examined potential effect of gT and mixed tocopherols at 1000mg/kg diet on AOM induced colon carcinogenesis which was promoted by 3-cycle DSS (dextrane sodium sulfate, 1.5%, 2.5% and 2%). The results show that two months after carcinogenesis was induced, all the AOM-DSS mice developed tumors located in the distal colon with ∼12 tumors per mouse. Supplementation of gT or gT-rich mixed tocopherols had no significant effects on tumor incidence or tumor size. In a subsequent study, potential effect of gT and gT rich mixed tocopherols were examined in the AOM induced colon cancer that was promoted by moderate colon inflammation caused by one-cycle 1.5% DSS. GT supplementation, although had no effects on total tumor incidence, significantly (P &amp;lt; 0.05) suppressed the incidence of large tumor (&amp;gt;2 mm2) by 60%. Mixed tocopherols showed strong tendency in attenuation of tumor development (50%, P = 0.06). Interestingly, gT but not mixed tocopherols significantly attenuated DSS-induced colon inflammation. These results indicate that gT appears to have anticancer activities via anti-inflammatory mechanisms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4589. doi:10.1158/1538-7445.AM2011-4589

Genes Involved in the Metabolism of Poly-Unsaturated Fatty-Acids (PUFA) and Risk for Crohn's Disease in Children &amp; Young Adults

Background and ObjectivesEpidemiological evidence for the role of polyunsaturated fatty-acids (PUFA) in Crohn's disease (CD) is unclear, although the key metabolite leucotriene B4 (LTB4) is closely linked to the inflammatory process. We hypothesized that inherited variation in key PUFA metabolic enzymes may modify susceptibility for CD.Methods and Principal ResultsA case-control design was implemented at three pediatric gastroenterology clinics in Canada. Children ≤20 yrs diagnosed with CD and controls were recruited. 19 single nucleotide polymorphisms (SNPs) across the ALOX5 (4) CYP4F3 (5) and CYP4F2 (10) genes, were genotyped. Associations between SNPs/haplotypes and CD were examined. A total of 431 cases and 507 controls were studied. The mean (±SD) age of the cases was 12.4 (±3.3) years. Most cases were male (56.4%), had ileo-colonic disease (L3±L4, 52.7%) and inflammatory behavior (B1±p, 87%) at diagnosis. One genotyped CYP4F3 SNP (rs2683037) not in Hardy-Weinberg Equilibrium was excluded. No associations with the remaining 4 CYP4F3 SNPs with CD were evident. However haplotype analysis revealed associations with a two-marker haplotype (TG) (rs3794987 & rs1290617) (p = 0.02; permuted p = 0.08). CYP4F2 SNPs, rs3093158 (OR (recessive) = 0.56, 95% CI = 0.35–0.89; p = 0.01), rs2074902 (OR (trend) = 1.26, 95% CI = 1.00–1.60; p = 0.05), and rs2108622 (OR (recessive) = 1.6, 95% CI = 1.00–2.57; p = 0.05) were significantly associated whereas rs1272 (OR (recessive) = 0.58, 95% CI = 0.30–1.13; p = 0.10) showed suggestions for associations with CD. A haplotype comprising these 4 SNPs was significantly associated (p = 0.007, permuted p = 0.02) with CD. Associations with SNP rs3780901 in the ALOX5 gene were borderline non-significant (OR (dominant) = 1.29, 95% CI = 0.99–1.67; p = 0.056). A haplotype comprising the 4 ALOX5 SNPs (TCAA, p = 0.036) was associated with CD, but did not withstand corrections for multiple comparisons (permuted p = 0.14).ConclusionsInherited variation in enzymes involved in the synthesis/metabolism of LTB4 may be associated with CD. These findings implicate PUFA metabolism as a important pathway in the CD pathogenesis.

Histopathology and bronchoalveolar lavage

Although neither lung biopsy nor bronchoalveolar lavage (BAL) is recommended for routine clinical use in patients with SSc, studies employing lung biopsy material and BAL fluid (BALF) have provided insight into the pathogenesis of scleroderma-associated interstitial lung disease (SSc-ILD). Most often, SSc-ILD is classified as a non-specific interstitial pneumonia, with abundant myofibroblasts and evidence of both epithelial cell and endothelial cell injury. Recently, SSc-ILD fibroblasts have been shown to express reduced levels of the caveolin-1 protein which, in turn, may lead to activation of the signalling molecules associated with increased collagen production and overexpression of alpha-smooth muscle cell actin (alpha-SMA). BALF often contains increased numbers of inflammatory cells as well as myofibroblasts expressing alpha-SMA. Analysis of BALF suggests an imbalance between pro-fibrotic and anti-fibrotic factors, e.g. an overabundance of TGF-beta, connective tissue growth factor (CTGF), PDGF, leucotriene B4, etc. and in some cases a deficiency of hepatocyte growth factor, 15-hydroxyeicosatetraenoic acid (15-HETE), lipoxin A, etc. Until the pathogenesis is fully understood, lung biopsy and BAL will remain useful research tools to better understand the inflammatory and fibrosing processes that underlie SSc-ILD.

Effects of atorvastatin added to inhaled corticosteroids on lung function and sputum cell counts in atopic asthma

Background:Statins have anti-inflammatory properties that may be beneficial in the treatment of asthma. A study was undertaken to test the hypothesis that atorvastatin added to inhaled corticosteroids improves lung function...

Oxygreen Process Applied on Nongerminated and Germinated Wheat: Role of Hydroxamic Acids

Wheat samples were taken at different stages of germination characterized by their falling number (which is a relevant indicator of germination) from 400 to 60 s. Each batch was treated by the Oxygreen process, a treatment by ozone, in a closed sequential batch reactor. Leucotriene B4 (LTB 4) was induced by germination, but ozone treatment did not increase this effect. Extract obtained from these wheat batches was applied on human epithelial bronchial cells. Wheat extract from nongerminated wheat did not induce any DNA adduct. More the wheat germination gets underway, more DNA adducts are observed. In contrast, germination did not affect the cell viability. Ozonization of wheat exemplified genotoxic effects only if the wheat was germinated. The implication of hydroxamic acids is discussed. In conclusion, ozonization of wheat, of high milling quality, does not pose any problem.

Inter-relationships between inflammatory markers in patients with stable COPD with bronchitis: intra-patient and inter-patient variability

Background:Measurements of pulmonary biomarkers can be used to monitor airway inflammation in chronic obstructive pulmonary disease (COPD), but the variability of sampled biomarkers and their inter-relationships are poorly understood. A...

Systemic and bronchial inflammation following LPS inhalation in asthmatic and healthy subjects

Background: Inhaled endotoxin is known to induce airway inflammation, causing bronchial hyper-reactivity.Objective: We characterized the response to lipopolysaccharide-inhalation by measuring exhaled nitric oxide (eNO) and inflammatory mediators.Patients and Methods : A total of 43 adult volunteers (13 asthmatics, 30 healthy controls) inhaled stepwise LPS every 30 min up to a cumulative dose of 100 µg (2.5, 10.5, 42, 45 µg). After each provocation and up to 24 h later, FEV1was determined; the procedure was stopped when FEV1declined more than 12.5%. We measured eNO, leucocytes, eosinophils, polymorphonuclear neutrophils (PMNs), C-reactive protein (CrP), lipopolysaccharide binding protein (LBP), eosinophilic cationic protein (ECP), leucotriene B4 (LTB4), thromboxane B2 (TXB2), and body temperature.Results: Initial eNO values were higher in asthmatics ( P &lt; 0.01), but only increased in an asthmatic subgroup. Marked differences were observed in the systemic response to LPS inhalation. Significant increases were found for CrP, LBP, and PMNs. There was no correlation between FEV1decrease and basal eNO levels.Conclusions: Inhalation of endotoxin was followed by clinical and laboratory signs of systemic inflammation, with asthmatics responding to the challenge similar as healthy subjects. Bronchial eNO increased only temporarily in asthmatics.

Systemic and bronchial inflammation following LPS inhalation in asthmatic and healthy subjects

Inhaled endotoxin is known to induce airway inflammation, causing bronchial hyperreactivity. We characterized the response to lipopolysaccharide-inhalation by measuring exhaled nitric oxide (eNO) and inflammatory mediators. A total of 43 adult volunteers (13 asthmatics, 30 healthy controls) inhaled stepwise LPS every 30 min up to a cumulative dose of 100 microg (2.5, 10.5, 42, 45 microg). After each provocation and up to 24 h later, FEV(1) was determined; the procedure was stopped when FEV(1) declined more than 12.5%. We measured eNO, leucocytes, eosinophils, polymorphonuclear neutrophils (PMNs), C-reactive protein (CrP), lipopolysaccharide binding protein (LBP), eosinophilic cationic protein (ECP), leucotriene B4 (LTB4), thromboxane B2 (TXB2), and body temperature. Initial eNO values were higher in asthmatics (P < 0.01), but only increased in an asthmatic subgroup. Marked differences were observed in the systemic response to LPS inhalation. Significant increases were found for CrP, LBP, and PMNs. There was no correlation between FEV(1) decrease and basal eNO levels. Inhalation of endotoxin was followed by clinical and laboratory signs of systemic inflammation, with asthmatics responding to the challenge similar as healthy subjects. Bronchial eNO increased only temporarily in asthmatics.

The effect of single‐dose naproxen on eicosanoid formation in human gastroduodenal mucosa

In animal studies, aspirin and non-aspirin non-steroidal anti-inflammatory drugs contribute to gastroduodenal damage via cyclo-oxygenase inhibition and consecutive leucotriene formation (COX-LOX eicosanoid shunt). Ten Helicobacter pylori-negative healthy volunteers received a single dose of 500 mg naproxen to address two questions: (i) is there a crosstalk between eicosanoids before medication in the human gastroduodenal mucosa and (ii) can we demonstrate a COX-LOX shunt following single-dose naproxen? Significant correlations in the stomach mucosa before medication were obtained between leucotriene B4 (LTB4) and thromboxane B(2) (TxB(2); r = -0.38, P = 0.05), as well as LTB4 and prostaglandin E(2) (PGE(2); r = 0.71, P < 0.0001). In serum, a >90% inhibition of TxB(2) and PGE(2) occurred within 30 min of naproxen administration. In gastric mucosa, a significant decrease of TxB(2) occurred already at 15 min and preferably in the antrum. For LTB4 there was a non-significant trend towards a transient increase. Mucosal PGE(2) was unchanged in all regions; transcript levels of both cyclo-oxygenases/5-lipoxygenase were unaffected (except for a trend of increasing cyclo-oxygenase-2 in the corpus). Baseline correlations between LTB4-TxB(2) and LTB4-PGE(2) reflect a crosstalk between these eicosanoids. A COX-LOX shunt; however, cannot be demonstrated following single-dose naproxen in a low-risk population.

Synthesis and activity of 4-(2',4'-difluorobiphenylyl)-2-methylbutyric acid (deoxoflobufen) and its derivatives

The series of 4-(2',4'-difluorobiphenylyl)-2-methylbutyric acid (deoxoflobufen, 1) and its four amides and two salts were prepared and tested for anti-inflammatory activity in rats and mice, using as models carrageenan-induced paw oedema, pleuritis, and arachidonic acid-induced ear inflammation, and on leucotriene B4 production in cells.

Clinical Snippets

In addition to epithelial cancers, people with Xeroderma Pigmentosum have increased melanin pigmentation. Whether this pigmentation is protective is unknown. Yamzucki and coworkers generated XP knockout mice and mice that had a transgene increased stem cell factor (SCF). SCF is the ligand for the c-kit receptor on melanocytes. In the XP/SCF mouse, increased pigmentation protected the epidermis against Ultraviolet B irradiation. This mouse is an important step in the quest for the grail of increased skin pigmentation to protect against UV exposure. J Invest Dermatol 123:220–228, 2004. Intradermal nociceptin, a 17 amino acid peptide, caused a 30-minute paroxysm of itching in mice, as reported by Kuraishi and coworkers. Nociceptin causes itching via the eicosanoid binding leucotriene B4 receptor. Defining new mediators for itching opens up important therapeutic avenues for this vexing symptom of many skin diseases. J Invest Dermatol 123:196–201, 2004. Hair follicle melanocytes synthesize opiate receptors and their ligand, β-endorphin. In a study by Tobin and colleagues, β-endorphin upregulated melanogenesis and melanocytic proliferation. Unfortunately, the physiological and social effects of opiates may prevent this interesting field of research from being fully exploited. J Invest Dermatol 123:184–195, 2004. Sunscreens, if used as advised, might be an important source of exogenously derived chemicals by percutaneous absorption. Detailed pharmacological studies by Janjua and colleagues show that three active ingredients from sunscreens can be measured in the blood and urine. Whether these chemicals could alter reproductive functions was determined by measuring FSH, LH, testosterone, estradiol, and inhibin A levels. None was altered, decreasing the possibility that sunscreens might be an important source for environmental estrogens. Other physiological functions possibly altered by sunscreens remain to be studied. J Invest Dermatol 123:57–61, 2004. Graves and coworkers studied diabetic mice with dermal infections caused by Porphyromonas gingivalis, an organism associated with bites and oral disorders. The infected skin showed increased and prolonged levels of TNF-α and the chemokines MCP-1 and MIP-2. The prolonged chemokine expression was significantly decreased when mice were treated with the TNF-α-specific inhibitor Embrel. Studies on non-healing ulcers in this model system might lead to relevant studies for treating the non-infected wounds of diabetes. J Invest Dermatol 123:87–92, 2004. Hair loss, a vexing side-effect and often a barrier to acceptance of chemotherapy, is under intensive study. Chemotactic peptide agonists prevented etoposide hair loss in neonatal rats. Furthermore, this hair loss was inhibited by an H1 receptor antagonist. If histamine pathways are involved in humans with this kind of hair loss, these findings are encouraging, since large numbers of histamine agonists and antagonists have been synthesized by pharmaceutical companies. J Invest Dermatol 123:242–243, 2004.

Effect of Dietary Lipids on Macrophage Function, Stress Susceptibility and Disease Esistance in Atlantic Salmon (Salmo salar)

As the supply of marine fish oil is becoming a limiting factor in the production of Atlantic salmon (Salmo salar), new diets and alternative sources of energy are being tested. Plant oils are natural potential candidates to replace fish oil, but the different levels of essential polyunsaturated fatty acids may influence the health and growth of salmon. In this study, we have investigated the resistance to transport stress and bacterial infection, phagocytic activity in head kidney macrophages and eicosanoid metabolism in salmon fed three different diets. In high-energy fishmeal based diets, 50% and 100% of the supplementary fish oil (FO) was replaced with soybean oil (SO). The three dietary groups were fed for 950 day-degrees at 5 � C (27 weeks) and 12 � C (11 weeks) before challenging the fish with Aeromonas salmonicida, analyzing the lipid composition of head kidney and examining macrophage function in vivo and in vitro. Dietary fatty acids affected the lipid composition of the kidney. The level of eicosanoid precursor’s 20:4n-6 and 20:3n-6 were 3 and 7-fold higher in the 100% SO group compared with the FO group. The total fraction of n-3 lipids in kidney was 19% in the SO group, compared to 16% and 12% in the 50% or 100% SO groups, respectively. However, the production of leucotriene B4 (LTB) and prostaglandin E2 (PGE) immunoreactive materiel from exogenously added arachidonic acid in head kidney macrophages was only affected by the composite diet (increased) at 5 � C. In addition, the phagocytic activity of kidney macrophages in vivo and in vitro was not affected by diet. No effect of diet was observed on transport stress or susceptibility to a bacterial infection with Aeromonas salmonicida. Atlantic salmon therefore seems to tolerate a diet solely based on soybean oil as lipid source, without any detrimental effects on growth, health and immune functions.

Platelets may inhibit leucotriene biosynthesis by human neutrophils at the integrin level.

Polymorphonuclear leucocytes and blood platelets co-operate in several pathophysiological processes, and arachidonic acid (AA) metabolites produced in response to the activation of these cells are potent mediators of their functions. We studied the role of platelets in the formation of 5-lipoxygenase products from AA by autologous neutrophils, especially the chemotactic agent leucotriene (LT) B4. The formation of all products, namely 5-hydroxy-eicosatetraenoic acid (5-HETE), LTB4 and the other LTA4-derived metabolites, in response to the calcium ionophore A23187 was evaluated by high-performance liquid chromatography. All the 5-lipoxygenase products were significantly diminished by physiological concentrations of platelets. This inhibitory effect was lost when platelets were previously degranulated by thrombin in non-aggregating conditions. Peptides containing the Arg-Gly-Asp-Ser or His-His-Leu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val sequence, which prevent the adhesion of platelets to neutrophils via the fibrinogen released from platelet granules and the integrin glycoprotein IIb/IIIa, markedly decreased the inhibitory effect of non-degranulated platelets. The production of transcellular metabolites of AA such as LTC4, the dual 5- and 12-lipoxygenase product 5,12-diHETE and lipoxins could not account for the decreased formation of 5-HETE and LTA4-derived metabolites. It is concluded that platelets may inhibit the neutrophil 5-lipoxygenase activity at the integrin level and in turn may play a role in slowing down the production of LTB4 in the course of inflammation.

Clinical, biochemical and molecular genetic characteristics of 19 patients with the Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS) is an autosomal recessively inherited neurocutaneous disorder caused by a deficiency of the microsomal enzyme fatty aldehyde dehydrogenase (FALDH). We report the clinical characteristics and the results of molecular studies in 19 SLS patients. Patients 1-17 show the classical triad of severe clinical abnormalities including ichthyosis, mental retardation and spasticity. Most patients were born preterm, and all patients exhibit ocular abnormalities and pruritus. Electro-encephalography shows a slow background activity, without other abnormalities. MRI of the brain shows an arrest of myelination, periventricular signal abnormalities of white matter and mild ventricular enlargement. Cerebral (1)H-MR spectroscopy reveals a characteristic, abnormal lipid peak. The degree of white matter abnormality in the MRIs and the height of the lipid peak in (1)H-MR spectra do not correlate with the severity of the neurological signs. The clinical presentation and the clinical course is strikingly similar in these patients. Patient 18 shows a mild phenotype that essentially contains the same, but less severe, clinical features. Patient 19 exhibits the typical, but very mild, dermatological and ocular abnormalities, without any clinical neurological involvement. The diagnosis of SLS was confirmed by demonstration of the enzyme defect in cultured skin fibroblasts. Furthermore, as might be predicted from the essential role of FALDH in leucotriene B(4) (LTB(4)) metabolism, elevated urinary concentrations of LTB(4) and 20-OH-LTB(4) were found in all patients studied. Molecular studies of the FALDH gene revealed eight different mutations, including three new ones: a large 26-base pair deletion (21-46del), a missense mutation (80C-->T) and an insertion mutation (487-488insA). The vast majority of SLS patients seem to be severely affected independent of their genotype.

Interactions between Candida species and platelets.

Candida spp. are able to cause disseminated disease in immunocompromised patients. This study examined the interactions of Candida spp. with platelets, complement and polymorphonuclear leucocytes (PMNLs). With the exception of C. albicans, all other Candida spp., including a C. albicans strain previously classified as C. stellatoidia, aggregated human platelets at a ratio of yeast cells: platelets of 1:80. Usually, those species and strains that aggregated platelets were either killed or prevented from growing in platelet-rich plasma indicating that the aggregation released microbicidal or microbistatic substances that were active against Candida spp. All Candida spp. were resistant to attack by complement in 50% serum. However, all species activated complement as determined by the presence of C3 fragments on their surface, in particular a 195-kDa fragment corresponding to C3c, two fragments at 67 and 40 kDa corresponding to iC3b, and a 33-kDa fragment corresponding to C3d. When strains were tested for their ability to stimulate the release of pro-inflammatory substances from platelets and PMNLs, it was found that most strains stimulated PMNLs to release interleukin(IL)-8 but not IL-1beta or leucotriene B4. The ability of C. albicans to evade complement-mediated killing and not to aggregate platelets may contribute to the survival of this species in the blood during vascular infections.