Epidemiologic investigations and experimental studies on the nose suggest that diesel exhaust particles (DEP) may be implicated in the increasing severity and prevalence of allergic diseases. However, there is no experimental evidence for the relation of DEP to allergic asthma. The present study investigated the effects of DEP inoculated intratracheally on antigen induced airway inflammation, hyperresponsiveness, local expression of cytokine proteins and antigen-specific immunoglobulin production in mice. DEP aggravated ovalbumin-induced airway inflammation characterized by infiltration of eosinophils and lymphocytes, airway hyperresponsiveness to acetylcholine, and an increase in goblet cells in bronchial epithelium. DEP with antigen markedly increased interleukin (IL) -5 protein levels in lung tissue and bronchoalveolar lavage supernatants compared to either antigen or DEP alone. The combination of DEP and antigen induced significant increases in local expression of IL-4, granulocyte macrophagecolony stimulating factor (GM-CSF) and IL-2. In addition, DEP exhibited adjuvant activity for the antigen-specific production of IgG₁. These results provide experimental evidence that DEP can enhance the manifestations of allergic asthma. The enhancement may be mediated mainly by the increased local expression of IL-5, and also by the modulated expression of IL-4, GM-CSF and IL-2.

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A population of CD4⁺ T cells with TCR β-chain without TCRα (CD4⁺, α-β⁺ T cells) increased in the mucosal and peripheral lymphoid tissues of TCRα^-/- mice with inflammatory bowel disease (IBD) . Depletion of the CD4⁺, α^-β⁺ T cells by the treatment of TCRα^-/- mice with mAb against TCRβ suppressed the onset of IBD.
We further assessed the clonotypes of the infiltrated CD4⁺, α^-β⁺ T cells in TCRα^-/- mice with IBD by using a polymerase chain reaction singlestrand conformation polymorphism (PCR-SSCP) analysis of CDR3 segment of TCRβ chain. SSCP analyses of PCR-amplified TCR Vβ chain transcripts indicated that TCR Vβ repertoire of CD4⁺, α^-β⁺ T cell populations in the diseased mice was relatively monoclonal to oligoclonal, and that the repertoire in the diseased colon exhibited nearly identical mobility among the individual IBD mice. However, the TCR Vβ repertoire in peripheral lymphoid tissues such as spleen and mesenteric lymph nodes (MLN) was more divergent compared to that of the colon, suggesting that the mucosal CD4⁺, α^-β⁺ T cells can be clonally expanded upon the stimulation with gutderived antigens. Thus, an oligoclonal population of the aberrant CD4⁺, α^-β⁺ T cells is positively selected and prominently expanded in the intestinal inflammatory lesion.

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Besides proteinase 3 and myeloperoxidase, various target antigens have been identified that anti -neutrophil cytoplasmic antibodies (ANCA) can recognize. We have isolated a new member of perinuclear ANCA (P-ANCA) . Previously, we found that patients with ulcerative colitis (UC) had a novel P-ANCA against neutrophil 28-kD protein. Here, we purified the same antigens from HL-60 lysates by using reversed-phase HPLC. The N-terminus amino acids of these proteins were identical with those of high mobility group (HMG) non-histone chromosomal proteins HMG1 and HMG2. The 28-kD band detected by immunoblotting analysis using patient's serum completery disappeared after preincubation with HMG1/HMG2. A mono-clonal antibody to HMGI/HMG2 stained neutrophils selectivery in a P-ANCA pattern. These results indicate that HMG1/HMG2 can serve as the target antigens of P-ANCA. We then examined serum anti-HMG1/HMG2 antibodies by ELISA. The prevalence of the antibodies were 89% in autoimmune hepatitis, 70% in primary biliary cirrhosis, 48% in rheumatoid arthritis, 45% in systemic lupus erythematosus, and 35% in UC. The occurrence of the antibodies in these diseases seemed to be associated with the disease activity. Thus, anti-HMG1/HMG2 antibodies appear to be useful P-ANCA in some inflammatory diseases, especially in autoimmune liver diseases.

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Mast cells are known to degranulate and release several kinds of chemical mediators, including histamine, when they are sensitized with IgE antibodies and exposed to the appropriate antigen. Histamine, released from the mast cells, acts on their specific receptors located on the surface membrane of the endothelial and smooth muscle cells, and causes immediate allergic and inflammatory reactions. In this review, we introduce an application of in vivo microdialysis technique to monitoring of the plasma and subcutaneous levels of histamine in the jugular vein and the hind paw of urethane anesthetized rats, respectively. In the IgE pretreated rats, plasma histamine level increased immediately after intravenous administration of DNP-BSA, as an antigen, and the decrease in the mean blood pressure was found simultaneously with this treatment. Subplantar injection of compound 48/80, a mast cell degranulator, induced both the rapid increase in histamine release and the relatively gradual development of paw edema. These results, however, were not observed in genetically mast cell deficient Ws/Ws rats with the same treatments. We concluded that the present methods were useful and suitable for determining the release of mast cell histamine in situ, related to the experimental model of allergic and inflammatory diseases.

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Transcription factor nuclear factor κB (NF-κB) controls gene expression of a number of genes including endothelial cell adhesion molecules such as E-selection and ICAM-1. These cell adhesion molecules are known to play important roles in a critical step of acute lung injury. We tested the hypothesis that TNFα-induced ICAM-1 and E-selectin gene expression requires perturbation of cellular redox equilibrium, and the subsequent activation of redox sensitive transcription factor NF-κB that binds to its cognate promoter sequences leading to increased transcription of ICAM-1 and E-selectin genes in pulmonary artery endothelial cells. Stimulation of human pulmonary artery endothelial (HPAE) cells with TNFα (100 U/ml) decreased intracellular glutathione (GSH) content (-80%) with a concomitant increase in oxidized GSH (GSSG), activated NF-κB, and enhanced the transcription of ICAM-1 and E-selectin genes. Pretreatment with N-acetyl-L-cysteine (NAC), an antioxidant and precursor for GSH synthesis, for 0.5 h prevented the decrease in GSH content, inhibited the activation of NF-κB, and the lack of activated NF-κB prevented the activation of the ICAM-1 and E-selectin promoters and thereby the transcription of these genes. These results indicate the involvement of oxidant-dependent NF-κB activation in this pathway and the feasibility of using antioxidant or anti-NF-κB reagents in preventing acute lung injury associated with TNFα release.

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New quinolone (NQ) antimicrobials have strong bactericidal effects and a broad spectrum of antimicrobial activities. In this study, we investigated the in vitro effects of grepafloxacin (GPFX), a newly developed fluoroquinolone, on neutrophil functions. Superoxide production by neutrophils was measured using the ferricytochrome reduction assay. Enhancement of Superoxide production was observed in the presence of more than 10μg/ml of GPFX when stimulated with formyl-methionyl-leucyl-phenylalanine (FMLP) and more than 3μg/ml when stimulated with phorbol myristate acetate (PMA) . Neutrophils pretreated with more than 30μg/ml of GPFX also showed enhancement of superoxide production in response to both of the two stimuli. On the other hand, GPFX had no effect on FMLP-induced neutrophil chemotaxis at any of the concentrations (1 to 100μg/ml) . These results suggest that GPFX facilitates the improvement of bacterial infections with the combination of its bactericidal effect and the activation of neutrophils in vivo.

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