Nitric oxide (NO) has been shown to elicit both favorable and unfavourable effects on gastrointestinal (GI) system. NO is generated from L-arginine by two different types of NO synthase (NOS) . One type of NOS, constitutive NOS (cNOS), is con-stitutively expressed by endothelial cells (eNOS) and by neural cells (nNOS) . cNOS-derived NO causes a variety of physiogical effects by stimulating guanylate cyclase-cylic GMP system, effects genereally beneficial to GI system. For example, nNOS-derived NO modulates GI motility. eNOS-derived NO increases mucosal blood flow, and stimulates production of mucus and HCO₃^-, all of which enhance mucosal defense and repair system. Based on these background, several attemps have been made to use NO as a therapeutic drugs. For example, tetraprenylacetone (teprenone) has been shown to enhance gastric mucosal restitution by upregulating cNOS activity. NO-releasing NSAIDs have been developed to mitigate NSAIDs induced mucosal injury by protection afforded by NO. In contrast, other type of NOS, inducible NOS (iNOS), is transiently expressed in macrophages in response to stimuli, such as bacterial invasion. iNOS generates huge amount of NO, that pre-vents invasion of bacteria, but causes serious injury in host tissues. For example, Helicobacter pylori upregulates iNOS expression in gastric mucosa, and enhances release of NO, thereby accelerating epithelial cell apoptosis. In chronic inflammatory bowel diseases, inceased expression of mucosal iNOS is closely associated with developement of mucosal injury. However, it should be noted that in certain circum-stances iNOS affords mucosal protection against noxious stimuli, and promotes mucosal repair after injury.

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Sulfite is a major air pollutant which can cause inflammatory reactions in the respiratory tract characterized by an influx of neutrophils. In addition, sulfating agents are widely used in the food and beverages industries as antimicrobials or antioxidants. Sulfite is also an important intermediatory compound in the metabolic pathway from sulfur containing amino acids to sulfate in mammalians. Human serum contains some amounts of sulfite. But the production and physiological role of sulfite in mammalians are still unclear. We have recently shown that human neutro-phils produced significant amounts of sulfite in vitro in response to lipopolysaccharide (LPS) stimulation. In a rat model of sepsis induced by in vivo injection of LPS, sulfite concentration in serum was significantly increased. These results suggest that sulfite can be actively generated by mammalian cells in vivo and in vitro. In this brief review article, we discuss a potential role of sulfite as an endogenous mediator of inflammation.

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The effects of diesel exhaust particles (DEP) on Th 1/Th 2 balance and collagen-induced arthritis (CIA) in mice were investigated. Oral administration of neither DEP nor the antigen hen egg lysozyme (HEL) alone produced the Th 1 cytokine IFN-γ and the Th 2 cytokine IL-4. DEP administered orally together with HEL increased the secretion of IFN-γ as well as IL-4 in a dose -related fashion, although IL-4 appeared to be more efficiently secreted in mice given lower doses of DEP. Similar results were obtained when anti-HEL IgG 2 a and IgG 1 antibodies which were Th 1 and Th 2 cell-dependently produced, respectively, were measured. Intraperitoneal injection of HEL alone induced marked Th 2 responses including anti-HEL IgG 1 and IL-4 production, while negligible induction of Th 1 responses including anti-HEL IgG 2 a and IFN-γ. were observed in mice injected with the antigen in the same manner. DEP plus HEL administered intraperitoneally further facilitated the Th 2 responses, but the Th 1 responses remained unchanged. HEL emulsified with complete Freund's adjuvant induced both the Th 1 and Th 2 responses. Furthermore, nasal administration of DEP led to the augmentation of CIA that was associated with anti-type II collagen IgG antibody production. Antigenspecific IgG 2 a and IgG 1 antibodies as well as IFN-γ and IL-4 were also markedly produced. Thus, DEP appear to modulate Th 1/Th 2 balance and have ability to influence autoim-mune diseases.

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In total joint replacement, particle induced inflammatory reactions cause periprosthetic bone resorption. Using an air pouch model in rats, we investigated the inflammatory reaction by alumina and polyethylene particles, and also investigated the anti-inflammatory effects of indometacin farnesil (IMF) . Irrigation fluid from the air pouch was collected and the total protein (TP) concentration and the prostaglandin E₂ (PG E₂) level were measured. To eliminate the effects of dilution, PG E₂/TP was used. The pouch tissue was histologically evaluated. Without IMF, PG E₂/TP was significantly higher by injecting alumina and polyethylene particles. In the polyethylene particles injected group, the level diminished with IMF 3 mg/kg/day, and was significantly lower with IMF 10 mg/kg/day. On the other hand, the level was not affected by IMF administration in the alumina particle injected group. A similar tendency was observed in the histology of pouch tissues. These results indicated that both alumina and polyethylene particles induced inflammatory reactions, however the anti-inflammatory effects of IMF depended on the characteristics of the particles.

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In order to clarify the differences of the signaling pathways utilized by G-CSF, GM-CSF and TNF, we investigated activation of MAPK subtype cascades in human neutrophils stimulated by these cytokines. G-CSF exclusively activates the MEK-ERK cascade. GM-CSF activates the MEK-ERK cascade strongly and the MKK 3/ 6-p 38 MAPK cascade weakly, whereas TNF activates the MKK 3/6-p 38 MAPK cascade strongly and the MEK-ERK cascade weakly. The potency of these cytokines to activate the MEK-ERK cascade was GM-CSF>G-CSF>TNF, whereas that to activate the MKK 3/6-p 38 MAPK cascade was TNF>GM-CSF. JNK was not tyrosine-phosphorylated by any cytokine in spite of the existence of JNK proteins in human neutrophils, whereas it was tyrosine-phosphorylated by TNF in undifferentiated and all-trans retinoic acid-differentiated HL-60 cells. Increased phosphorylation of ERK or p 38 MAPK was detected within 1-5 minutes after stimulation with each cytokine and was dependent on the concentrations of cytokines used. GM-CSF-or TNF-induced superoxide (O₂^-) release was inhibited by p 38 MAPK inhibitor (SB203580) in a dose-dependent manner. The results indicate that G-CSF, GM-CSF and TNF activate the overlapping but distinct MAPK subtype cascades in human neutrophils and p 38 MAPK may be involved in GM -CSF-or TNF-induced O₂^- release.

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