leukotriene-b4 and Skin-Diseases

The present paper examines evidence for the identity of low molecular weight eosinophil chemotactic factor (ECF) and of leukotriene B4 (LTB4) and its metabolites. Total congruity between the two entities is found regarding (1) cells of origin; (2) conditions for in vitro generation and pharmacological modulation; (3) physiochemical properties; (4) in vitro chemotaxis towards human monocytes, fibroblasts and guinea pig eosinophils; (5) in vivo activities in humans, and (6) occurrence of the factors in various dermatological diseases. Quantitative differences were observed only for in vitro neutrophil migration which may be due to neutrophil chemotactic mono-HETEs and possibly platelet activating factor in the ECF preparations. The name ECF should therefore be replaced by LTB4 and its metabolites, as has happened for SRS which is now called LTC4/D4.

Topics: Anaphylaxis; Animals; Chemical Phenomena; Chemistry; Chemotactic Factors; Chemotactic Factors, Eosinophil; Epidermis; Guinea Pigs; Humans; Leukotriene B4; Neutrophils; Skin Diseases

Topics: Acne Vulgaris; Bacteria; Chemotactic Factors; Chemotaxis, Leukocyte; Child; Communicable Diseases; Complement C3; Complement C5; Disease Susceptibility; HLA Antigens; Humans; Hypersensitivity; Leukotriene B4; Neutrophils; Psoriasis; Skin Diseases; Wiskott-Aldrich Syndrome

Topics: Anti-Inflammatory Agents; Arachidonic Acid; Arachidonic Acids; Arthritis; Chemical Phenomena; Chemistry; Chemotactic Factors; Humans; Inflammation; Intestinal Diseases; Leukotriene B4; Lipoxygenase; Lung Diseases; Lymphocytes; Mast Cells; Neutrophils; Receptors, Cell Surface; Skin Diseases; SRS-A

The cross-linking of the IgA Fc receptor (FcαRI) by IgA induces release of the chemoattractant LTB4, thereby recruiting neutrophils in a positive feedback loop. IgA autoantibodies of patients with autoimmune blistering skin diseases therefore induce massive recruitment of neutrophils, resulting in severe tissue damage. To interfere with neutrophil mobilization and reduce disease morbidity, we developed a panel of specific peptides mimicking either IgA or FcαRI sequences. CLIPS technology was used to stabilize three-dimensional structures and to increase peptides' half-life. IgA and FcαRI peptides reduced phagocytosis of IgA-coated beads, as well as IgA-induced ROS production and neutrophil migration in in vitro and ex vivo (human skin) experiments. Since topical application would be the preferential route of administration, Cetomacrogol cream containing an IgA CLIPS peptide was developed. In the presence of a skin permeation enhancer, peptides in this cream were shown to penetrate the skin, while not diffusing systemically. Finally, epitope mapping was used to discover sequences important for binding between IgA and FcαRI. In conclusion, a cream containing IgA or FcαRI peptide mimetics, which block IgA-induced neutrophil activation and migration in the skin may have therapeutic potential for patients with IgA-mediated blistering skin diseases.

Topics: Administration, Topical; Antigens, CD; Autoantibodies; Autoimmune Diseases; Cetomacrogol; Epitope Mapping; Half-Life; Humans; Immune System Diseases; Immunoglobulin A; Leukocyte Disorders; Leukotriene B4; Neutrophil Activation; Neutrophil Infiltration; Neutrophils; Peptide Library; Peptidomimetics; Phagocytosis; Protein Binding; Reactive Oxygen Species; Receptors, Fc; Skin; Skin Absorption; Skin Diseases

Leukotrienes constitute a group of lipid mediators, which may be subdivided into two groups, with leukotriene B4 on the one hand and cysteinyl leukotrienes on the other. Although leukotrienes are abundantly expressed in skin affected by diverse chronic inflammatory diseases, including atopic dermatitis, psoriasis, pemphigus vulgaris and bullous pemphigoid, their pathological roles in these diseases have remained elusive. Recent data now reveal that both leukotriene B4 and cysteinyl leukotrienes are indispensable in the pathogenesis of atopic dermatitis, with leukotriene B4 initiating the recruitment of inflammatory cells, particularly neutrophils and TH 2 cells into the skin, and cysteinyl leukotrienes later inducing characteristic structural alterations of chronically affected skin, specifically skin fibrosis and keratinocyte proliferation. Thus, these results reveal a sequential cooperation of LTB4 and cysteinyl leukotrienes to initiate and perpetuate allergic skin inflammation. These new insights highlight leukotrienes as promising therapeutic targets in allergic skin inflammation and should encourage more research into the role of leukotrienes in other inflammatory skin diseases.

Topics: Animals; Cell Proliferation; Dermatitis, Atopic; Fibrosis; Humans; Hypersensitivity; Inflammation; Keratinocytes; Leukotriene B4; Lipids; Mice; Neutrophils; Receptors, Leukotriene; Skin; Skin Diseases; Th2 Cells

To discover new 5-lipoxygenase (5-LO) inhibitors applicable to inflammation-related skin disease, we identified and examined antiinflammatory properties of a novel 5-LO inhibitor, KR-33749, in vitro and in vivo.. 5-LO enzyme activity was assayed using insect cell lysates overexpressing rat 5-LO. The leukotriene B(4) (LTB(4)) level was assayed in rat basophilic leukemia (RBL-1) cell line. Mouse ear edema was induced by topical application of arachidonic acid. Atopic dermatitis-like skin lesion was induced by topical application of 1-chloro-2,4-dinitrobenzene (DNCB) to NC/Nga mice.. KR-33749 inhibited 5-LO activity with an IC(50) value of 70.5 +/- 6.0 nmol/l in parallel with LTB(4) inhibition in RBL-1 cells. The compound exhibited a >1,000-fold selectivity against 12-LO and 15-LO. KR-33749 showed in vivo protective effects against arachidonic acid-induced ear edema and DNCB-induced atopic dermatitis-like symptoms in NC/Nga mice.. Our results show that KR-33749, a new 5-LO inhibitor exhibits potent antiinflammatory activities in vitro as well as in vivo.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Cell Line, Tumor; Dermatitis, Atopic; Dinitrochlorobenzene; Dose-Response Relationship, Drug; Edema; Isoenzymes; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mice; Mice, Inbred BALB C; Osmolar Concentration; Rats; Recombinant Proteins; Skin; Skin Diseases; Thiazoles; Time Factors; Xylenes

The aim of the present study was to investigate the role of the adhesion pathway alpha4 integrins/vascular cell adhesion molecule type 1 (VCAM-1) in rapid eosinophil accumulation induced by the chemoattractants PAF and LTB4. For this purpose we have used an in vivo model of local 111In-eosinophil accumulation to quantify eosinophil accumulation induced by intradermal administration of platelet-activating factor (PAF) and leukotriene B4 (LTB4) in rats. Initial experiments carried out over 4 hr demonstrated that intravenous administration of an anti-VCAM-1 monoclonal antibody (mAb; 5F10) or an anti-alpha4 integrin mAb (TA2) caused a significant reduction in PAF- or LTB4-induced 111In-labelled eosinophil accumulation. Time-course experiments demonstrated that the anti-VCAM-1 mAb was effective at suppressing early phases of the 111In-labelled eosinophil accumulation induced by PAF and LTB4 (e.g. within the first 60 min). In contrast, 111In-labelled eosinophil accumulation induced by these chemoattractants was unaffected by the local administration of the transcriptional inhibitor actinomycin D, suggesting a role for basally expressed VCAM-1. Indeed, basal expression of VCAM-1 in rat skin sites was demonstrated by the localization of intravenously administered radiolabelled mAb. The localization of the radiolabelled antibody was not altered in skin sites injected with PAF or LTB4. Finally, the inhibitory effects seen with the anti-VCAM-1 mAb were enhanced when the antibody was co-injected into rats with an anti-intercellular adhesion molecule-1 (ICAM-1) mAb (1A29). The combination of these two mAb also caused a significant inhibition of PAF-induced oedema, as quantified by the local accumulation of 125I-labelled human serum albumin. The results indicate a role for alpha4 integrins/VCAM-1 and ICAM-1, in PAF- and LTB4-induced eosinophil accumulation in vivo and suggest that basally expressed VCAM-1 may have a functional role in rapid accumulation of eosinophils induced by chemoattractants.

Topics: Animals; Antibodies, Monoclonal; Antigens, CD; Chemotaxis, Leukocyte; Dactinomycin; Edema; Eosinophils; Immunoenzyme Techniques; Integrin alpha4; Integrins; Leukotriene B4; Male; Platelet Activating Factor; Protein Synthesis Inhibitors; Rats; Rats, Sprague-Dawley; Skin; Skin Diseases; Vascular Cell Adhesion Molecule-1

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bromodeoxyuridine; Cell Division; Chronic Disease; Edema; Humans; Isoxazoles; Leflunomide; Leukotriene B4; Male; Mice; Mice, Inbred Strains; Neutral Red; Peroxidase; Phorbol Esters; Skin Diseases

In this study we report on functional characteristics of pustule as well as blood polymorphonuclear neutrophils (PMN) in a patient suffering from relapsing bullous staphyloderma. Large numbers of viable PMN from newly formed pustules as well as from the peripheral blood were investigated. During the course of disease chemotactic migration, enzyme degranulation, superoxide-anion generation and leukotriene B4 production were determined simultaneously. The results revealed C5a- and NAP-1/IL-8-specific dysfunction of pustule PMN as compared with blood PMN. In contrast, FMLP-elicited functional activities of pustule PMN were only slightly affected. Our findings provide evidence that in inflamed tissue invading PMN are regulated by in situ generated mediators. C5a produced by staph, aureus-induced activation of the alternative pathway of the complement cascade represents a predominant regulatory factor in situ. Furthermore, the results substantiate previous observations concerning different modulation of C5a and f-met-peptide receptors on human PMN.

Topics: Chemotaxis, Leukocyte; Complement C5a; Glucuronidase; Humans; Interleukin-8; Leukotriene B4; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Skin Diseases; Superoxides

In vivo experiments have shown that magnesium deficiency elicits characteristic skin lesions in the hairless rat. However, the mechanism of the involvement is not clarified. From the results of previous studies, a product derived from arachidonic acid, but not via the cyclooxygenase pathway, has been considered as an etiological cause. In this study, the inhibitory effect of newly produced leukotriene B4 (LTB4) receptor antagonist (LTBRA) against these skin manifestation was examined in hairless mutants given a hypomagnesic diet. Control animals with treatment of LTBRA developed eruptions on their bodies with increasing serum levels of LTB4, but LTBRA-treated animals did not suffer from the cutaneous disorder. Increased serum levels of LTB4 in control rats were significantly higher than those in the pre-treated condition. The diminution of skin lesions by LTBRA strongly indicated that magnesium deficiency dermatitis may involve a lipoxygenase-mediated metabolite of arachidonic acid, presumably LTB4, and that the cutaneous changes in hairless rats fed with hypomagnesic diet might provide an easily identifiable indicator of LTB4-mediated dermatitis.

Topics: Animals; Female; Leukotriene B4; Magnesium Deficiency; Phenylpropionates; Rats; Rats, Nude; Receptors, Immunologic; Receptors, Leukotriene B4; Skin Diseases

Topics: Administration, Oral; Administration, Topical; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Cell Degranulation; Chromatography, Gel; Disease Models, Animal; Edema; Glucuronidase; Leukotriene B4; Mice; Mice, Inbred BALB C; Neutrophils; Novobiocin; Rabbits; Skin Diseases; Streptomyces

Topics: Calcimycin; Dinoprostone; HEPES; Humans; Inflammation; Leukotriene B4; Luminescent Measurements; Neutrophils; Psoriasis; Reference Values; Skin Diseases; Taurine

Peripheral-blood polymorphonuclear cells from 36 donors with or without eosinophilia were studied for their in vitro responsiveness towards a wide range of concentrations of leukotriene B4 (LTB4) and platelet-activating factor (PAF). The mean percentage of migrated eosinophils was 17.6 for PAF, 21.1 for LTB4, 20.1 for buffer controls with cells from eosinophil patients, and 1.1 for PAF, 8.9 for LTB4 and 3.2 for buffer control with noneosinophil donors. The quantitative response of eosinophils towards PAF was lower than that towards LTB4 on a molar basis. The data showed high interindividual variations for eosinophil responsiveness towards mediators and buffer and suggest disease-dependent alterations of receptor expression or of basic metabolic activity of eosinophils as possible reasons for this variability.

Topics: Cell Movement; Chemotaxis, Leukocyte; Eczema; Eosinophilia; Eosinophils; Humans; In Vitro Techniques; Leukotriene B4; Neutrophils; Platelet Activating Factor; Skin Diseases

Intensive studies of the molecular pathways involved in common inflammatory skin disorders, coupled with detailed pharmacologic evaluation of the responses of skin to the end products of these pathways, have resulted in a much clearer understanding of the mode of action of nonsteroidal anti-inflammatory drugs. In particular the development of lipoxygenase inhibitors is prompting intense interest in their possible role as anti-inflammatory agents in psoriasis and other dermatoses. Because of the potency of these and other classes of new anti-inflammatory drugs, careful monitoring of their pharmacokinetics in individual patients, especially those at risk for adverse reactions, will prove necessary, especially in the early stages of treatment. Meanwhile, currently available nonsteroidal anti-inflammatory drugs have a limited but significant place in the treatment of certain dermatoses. Current experience of the high incidence of adverse reactions to existing nonsteroidal anti-inflammatory drugs suggests that this will be no less a problem with new agents under development. The skin is frequently involved in adverse reactions to this class of drug, and past experience suggests that cutaneous reactions are among the earliest unwanted side effects reported in a new drug of this type. The dermatologist, therefore, has an important responsibility to observe, document, and report such "early warning signs" to the appropriate licensing authority and the manufacturer.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Aspirin; Cyclooxygenase Inhibitors; Dermatitis; Eicosanoic Acids; Humans; Ibuprofen; Leukotriene B4; Lipoxygenase Inhibitors; Propionates; Prostaglandins; Skin; Skin Diseases

The percentage of non-diploid epidermal cells was determined by flow cytometry following application of leukotriene B4 (LTB4) to human skin. Doses in the range 35-500 ng were shown to cause a marked increase in proliferation, the non-diploid cells reaching a maximum between 72 and 96 h after LTB4 application. No difference was observed between the response of healthy controls and the uninvolved skin of psoriatic patients. We suggest, therefore, that the hyperproliferation is a consequence of the physical disruption of the stratum corneum accompanying the rupture of microabscesses.

Topics: Abscess; Cell Division; Epidermis; Humans; Leukotriene B4; Psoriasis; Skin Diseases

Topics: Acne Vulgaris; Arachidonic Acid; Arachidonic Acids; Capillary Permeability; Dermatitis, Atopic; Dermatitis, Contact; Humans; Leukotriene B4; Lipoxygenase; Lymphocytes; Phagocytes; Psoriasis; Skin; Skin Diseases; SRS-A; Urticaria

In order to evaluate the significance of chemotactic leukotrienes in cutaneous disease, synthetic leukotriene B4 and its metabolites were examined during in vitro chemotaxis. Leukotriene B4, and less so 20-OH-leukotriene B4, were chemotactic for neutrophils and eosinophils, with a preferential attraction of eosinophils. The responsiveness of human monocytes towards leukotriene B4 was relatively low. Normal cells and cells from different patients varied in their quantitative response. Cells from patients with eczema and T-cell lymphoma tended to migrate less than those from patients with other inflammatory diseases. Leukotrienes are generated from several types of peripheral leukocytes. In order to examine whether resident cells of the skin can also produce these factors, isolated human and murine epidermal cells were examined for their ability to generate leukotriene B4 and leukotriene C4 in vitro. Arachidonic acid, and less so the ionophore A 23187, induced the generation of both types of factors, based on the finding in the bioassay, reverse-phase high-pressure liquid chromatography and radioimmunoassays. The same factors were demonstrated by either or all of these methods in skin biopsies, scales, blisters or suction blisters of patients with psoriasis, pitysiasis rubra pilaris, dyshidrosis, bullous pemphigoid, pressure urticaria, urticaria pigmentosa and drug reactions, but not in Sézary syndrome nor in callus and skin biopsies of normal controls. These findings underline the fact that the leukotrienes are potent inflammatory mediators in diverse skin diseases, but that they are not limited to any specific disease. Furthermore, a relationship between leukotrienes and tissue eosinophilia does not exist.

Topics: Animals; Chemotactic Factors; Chemotaxis, Leukocyte; Chromatography, High Pressure Liquid; Eosinophils; Humans; Leukotriene B4; Mice; Neutrophils; Skin; Skin Diseases; SRS-A

Leukotriene B4 is a highly potent leukocyte chemotactic compound. It has been identified in chamber fluid and scale from psoriatic skin lesions, in which epidermal neutrophil infiltration is reported to be one of the earliest pathologic events. The ability of leukotriene B4 to reproduce the inflammatory events of psoriasis, by topical application to the skin of normal human volunteers, was thus studied. Persistent visible inflammatory reactions were elicited by application of amounts of leukotriene B4 as low as 5 ng, and the maximum diameters of the reactions were dose-related up to at least 500 ng. The visible reactions appeared 12-24 h after initial application of leukotriene B4, and persisted for several days, leaving brownish pigmentation and scaling at 7 days. Histologic examination showed intraepidermal neutrophil microabscesses at 24 h, but these had resolved by 48 h. A mixed, perivascular neutrophil and mononuclear cell infiltrate was seen in the dermis at 24 h, becoming predominantly mononuclear after 24 h. Nonspecific chemical irritant contact dermatitis was excluded by the absence of reactions to high doses of two chemically similar metabolites of arachidonic acid which lack significant in vitro chemokinetic activity. These experiments provide further evidence for the role of leukotriene B4 in the pathogenesis of psoriasis, and may lead to the development of an experimental model of the inflammatory events in psoriasis, and of a simple in vivo test of neutrophil function.

Topics: Abscess; Adult; Dose-Response Relationship, Drug; Epidermis; Female; Humans; Leukotriene B4; Male; Middle Aged; Neutrophils; Skin Diseases

The relevance of arachidonic acid metabolites in inflammatory skin diseases has been expanded by recent developments in analytical chemistry. The metabolites include prostaglandins, leukotrienes and monohydroxy fatty acids. In ultraviolet light-induced inflammation the concentrations of arachidonic acid, prostaglandin E2, prostaglandin F2 alpha and 6-oxo-prostaglandin F1 alpha are elevated. Indomethacin totally suppresses the evoked prostaglandin increase, but erythema is only partially suppressed. This indicates that prostaglandins are partially involved in erythema production. In psoriasis the first histological change is an infiltration into the epidermis by neutrophilic leucocytes. It has been suggested that chemotactic factors, such as complement derived factors or leukotriene B4 play a role in the pathogenesis of psoriasis.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Arachidonic Acids; Cyclic AMP; Humans; Leukotriene B4; Leukotrienes; Mast Cells; Prostaglandins; Psoriasis; Skin; Skin Diseases; SRS-A; Ultraviolet Rays

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Arachidonic Acid; Arachidonic Acids; Humans; Leukotriene B4; Lipoxygenase; Lipoxygenase Inhibitors; Phospholipases A; Propionates; Prostaglandins; Psoriasis; Skin; Skin Diseases; Thromboxanes