leukotriene-b4 and Immune-System-Diseases

Topics: Animals; Asthma; Humans; Hypersensitivity; Immune System Diseases; Leukotriene B4; Leukotrienes; Membrane Proteins; Pulmonary Fibrosis; Receptors, Leukotriene; Receptors, Leukotriene B4; Signal Transduction

Topics: Animals; Arteries; Asthma; Biological Assay; Humans; Immune System Diseases; Inflammation; Leukotriene B4; Lung; Muscle, Smooth; SRS-A; Structure-Activity Relationship

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

Several emerging lines of evidence support an anti-inflammatory role for nicotinic acid (niacin); however, its role in the regulation of leukocyte migration in response to inflammatory stimuli has not been elucidated until now. Herein, we have examined the effect of nicotinic acid on neutrophil recruitment in experimentally induced inflammation. We demonstrated that nicotinic acid treatment inhibited interleukin (IL)-8-induced, leukotriene (LT)B4-induced, and carrageenan-induced neutrophil migration into the pleural cavity of BALB/c mice and reduced neutrophil rolling and adherence in a mouse cremaster muscle preparation. Surprisingly, nicotinic acid treatment increased the level of the neutrophil chemoattractant KC in response to carrageenan. These results suggest that nicotinic acid plays an important role in the regulation of inflammation due to its ability to inhibit the actions of the neutrophil chemoattractants IL-8 and LTB4. Further inhibition of chemoattractants leads to impairment of leukocyte rolling and adherence to the vascular endothelium in the microcirculation of inflamed tissues.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Cell Adhesion; Chemokine CXCL1; Disease Models, Animal; Immune System Diseases; Inflammation; Interleukin-8; Leukocyte Disorders; Leukocyte Rolling; Leukotriene B4; Male; Mice; Mice, Inbred BALB C; Neutrophil Infiltration; Niacin; Pleural Cavity

Platelet-activating factor (PAF) and its receptor (PAFR) have been shown to be involved in several inflammatory events, including neutrophil chemoattraction and nociception. The present study addressed the role of PAF in the genesis of articular hyperalgesia in a model of joint inflammation. Zymosan-induced articular hyperalgesia, oedema and neutrophil migration were dose-dependently reduced following pretreatment with selective PAFR antagonists, UK74505 (5, 10 and 20 mg/kg) and PCA4248 (3, 10, 30 mg/kg). These parameters were also reduced in PAF receptor-deficient mice (PAFR(-/-)). The hyperalgesic action of PAF was further confirmed by the demonstration that joint injection of PAF induces a dose- (0.3, 1 and 3 μg/joint), time- and PAFR-dependent articular hyperalgesia and oedema. The PAF hyperalgesic mechanisms were dependent on prostaglandins, leukotrienes and neutrophils, as PAF-induced articular hyperalgesia was inhibited by indomethacin (COX inhibitor), MK886 (leukotrienes synthesis inhibitor) or fucoidan (leukocyte rolling inhibitor). Furthermore, PAF-induced hyperalgesia was reduced in 5-lypoxigenase-null mice. In corroboration of these findings, intra-articular injection of PAF promotes the production of LTB(4) as well as the recruitment of neutrophils to the joint. These results suggest that PAF may participate in the cascade of events involved in the genesis of articular inflammatory hyperalgesia via stimulation of prostaglandins, leukotrienes and neutrophil migration. Finally, targeting PAF action (e.g., with a PAFR antagonist) might provide a useful therapeutic approach to inhibit articular inflammatory hyperalgesia.

Topics: Animals; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Hyperalgesia; Imidazoles; Immune System Diseases; Inflammation; Joint Diseases; Leukocyte Disorders; Leukotriene B4; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Neutrophils; Platelet Activating Factor; Platelet Membrane Glycoproteins; Prostaglandins; Receptors, G-Protein-Coupled; Time Factors; Zymosan