Atopic dermatitis (AD) usually develops in patients with an individual or family history of allergic diseases, and is characterized by chronic relapsing inflammation seen especially in childhood, association with IgE hyperproduction and precipitation by environmental factors. However, the exact etiology of AD has been unclear. To further explore the pathogenesis and treatment of AD, a suitable animal model is required. We found that skin lesions, which were clinically and histologically very similar to human AD, spontaneously appeared on the face, neck, ears and dorsal skin of inbred NC/Nga mice when they were raised in non-sterile (conventional) circumstances, but not under specific pathogen-free conditions. Plasma levels of total IgE in conventional NC/Nga mice were markedly elevated from 8 weeks of age, correlating with clinical skin severity of dermatitis. Immunohistochemical examination of the skin lesion showed increased numbers of mast cells and CD4+ T cells containing IL-4 necessary for IgE synthesis. Thus, NC/Nga mice suffered from dermatitis very similar to human AD with IgE hyperproduction, which may be triggered by some environmental factor(s).

Development of atopic dermatitis-like skin lesion with IgE hyperproduction in NC/Nga mice.

Asthma and inflammation.

/pdf/the-biologically-active-leukotrienes-biosynthesis-metabolism-mx1hvulmll.pdf

The biologically active leukotrienes. Biosynthesis, metabolism, receptors, functions, and pharmacology.

Eosinophilia of lung and blood associated with injury to the mucociliary escalator and excessive shedding of bronchial epithelium are hallmarks of both allergic and nonallergic asthma. In vitro, the eosinophil granule major basic protein (MBP) is toxic to helminths and to mammalian cells, including human respiratory epithelium. The MBP-mediated damage to the respiratory epithelium consists of desquamation and frank destruction of ciliated cells. Increased sputum MBP concentration is a good marker for asthma, and patients treated for acute asthma have high levels of MBP in their sputa, which decrease after treatment. Peak sputum MBP levels approximate concentrations toxic to respiratory epithelium in vitro. In the lungs of patients who had died of asthma, MBP has been localized outside of the eosinophil in association with damage to the epithelium. Overall, these and other findings suggest the hypothesis that the eosinophil mediates damage to the respiratory epithelium and is the prime effector cell in the pathophysiology of asthma.

The eosinophil and the pathophysiology of asthma

Asthma and inflammation

Horse eosinophils stimulated with the calcium ionophore A23187 were examined by transmission and scanning electron microscopy. Secretion was characterized by granule movement to the cell periphery and fusion of adjacent granules. The granules became swollen and less electron-dense as their contents were released into large intracellular vacuoles, which opened to the outside of the cell through surface pores. A23187-induced eosinophil peroxidase (EPO) release, as measured by guaiacol oxidation, was blocked by eicosa-5,8,11,14-tetraynoic acid (ETYA) (which inhibits both the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism) but not by indomethacin (which inhibits only the cyclooxygenase pathway). Highly purified porcine phospholipase A2 induced noncytotoxic eosinophil degranulation (as measured by the release of EPO without the concomitant release of the cytoplasmic marker lactate dehydrogenase), which was blocked by pretreatment of the enzyme with the phospholipase A2 inhibitor 4-bromophenacyl bromide. These results suggest that calcium-dependent activation of phospholipase A2 and generation of lipoxygenase products of arachidonic acid metabolism are important in the initiation of eosinophil degranulation.

Horse eosinophil degranulation induced by the ionophore A23187. Ultrastructure and role of phospholipase A2

Cidal mechanisms and their dependence on hydrogen peroxide

Horse eosinophils purified to greater than 98% generated slow reacting substance (SRS) when incubated with the calcium ionophore A23187. On a per cell basis, eosinophils generated four to five times the SRS produced by similarly treated horse neutrophils. Eosinophil SRS production was inhibited by 5,8,11,14-eicosatetraynoic acid and augmented by indomethacin and arachidonic acid, suggesting that it was a product(s) of the lipoxygenase pathway of arachidonic acid metabolism. Compounds with SRS activity were purified by high-pressure liquid chromatography (HPLC) and identified by ultraviolet spectra, spectral shift on treatment with lipoxygenase, incorporation of [14C]arachidonic acid, gas chromatography-mass spectrometry, and comparison of retention times on HPLC to authentic standards. The eosinophil products characterized were 5-(S), 12-(R)-dihydroxy-6-cis-8, 10-trans-14-cis-eicosatetraenoic acid (leukotriene B4) and its 5-(S), 12-(R)-6-trans and 5-(S), 12-(S)-6-trans isomers, 5-(S)-hydroxy-6-(R)-S-glutathionyl-7,9-trans-11, 14-cis-eicosatetraenoic acid (leukotriene C4) and its 11-trans isomer, and 5-(S)-hydroxy-6-(R)-S-cysteinylglycine-7,9-trans-11,14-cis-eicosatetraenoic acid (leukotriene D4).

https://rupress.org/jem/article-pdf/155/2/390/1092354/390.pdf

Leukotriene generation by eosinophils.

The slow-reacting substance (SRS) bioactivity of leukotrienes C4 (LTC4) and D4 (LTD4) was rapidly decreased by incubation with eosinophil peroxidase (EPO), H2O2, and iodide, bromide, or to a lesser degree, chloride, LTB4 chemotactic activity was also decreased by the EPO-H2-H2-halide system, although at a slower rate. Myeloperoxidase could substitute for EPO in these reactions. Leukotriene inactivation was greatly decreased or abolished by deletion of any of the components of the system or by the addition of the hemeprotein inhibitors, azide, cyanide, or aminotriazole, indicating a requirement for peroxidase. The H2O2 concentration employed in the above studies was 10(-4) M. H2O2 at higher concentrations (5 x 10(-4) to 10(-2) M) inactivated LTC4 and LTD4 in the absence of EPO and a halide but had no effect on the chemotactic activity of LTB4. We have previously shown that horse eosinophils stimulated with the calcium ionophore A23187 generate SRS. In the present study, eosinophils stimulated in this way were found to release extracellularly both H2O2 and EPO. Incubation of eosinophils with azide that inhibits EPO, and catalase that degrades H2O2, significantly increased the amount of SRS activity detected in the extracellular medium after A23187 stimulation. These findings suggests eosinophils may play an important modulating role in hypersensitivity reactions both by the production of leukotrienes and by their inactivation through the release of H2O2 and EPO.

Eosinophil peroxidase-mediated inactivation of leukotrienes B4, C4, and D4.

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Horse eosinophil degranulation induced by the ionophore A23187. Ultrastructure and role of phospholipase A2

Cidal mechanisms and their dependence on hydrogen peroxide

Leukotriene generation by eosinophils.

Eosinophil peroxidase-mediated inactivation of leukotrienes B4, C4, and D4.