Ken-ichiro Inoue

15-deoxy-delta(12,14)-PGJ(2) induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats.

Peroxisome proliferator–activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and have a dominant regulatory role in adipocyte and monocyte differentiation. PPAR-γ agonists are also negative regulators of macrophage activation and have modulatory effects on tumorigenesis. In this study we demonstrate that synovial tissue localized expression of PPAR-γ in patients with rheumatoid arthritis (RA). We detected markedly enhanced expression of PPAR-γ in macrophages, as well as modestly enhanced expression in the synovial lining layer, fibroblasts, and endothelial cells. Activation of the PPAR-γ by 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and the synthetic PPAR-γ ligand (troglitazone) induced RA synoviocyte apoptosis in vitro. Moreover, intraperitoneal administration of these PPAR-γ ligands ameliorated adjuvant-induced arthritis with suppression of pannus formation and mononuclear cell infiltration in female Lewis rats. Anti-inflammatory effects of 15d-PGJ2 were more potent than troglitazone. These findings suggest that PPAR-γ may be an important immunoinflammatory mediator and its ligands, especially 15d-PGJ2, may be useful in the treatment of RA.

Extract of Perilla frutescens Enriched for Rosmarinic Acid, a Polyphenolic Phytochemical, Inhibits Seasonal Allergic Rhinoconjunctivitis in Humans

Extract of Perilla frutescens enriched for rosmarinic acid, a polyphenolic phytochemical, suppresses allergic immunoglobulin responses and inflammation caused by polymorphonuclear leukocytes (PMNL) in mice. However, few placebo-controlled clinical trials have examined the efficacy and safety of polyphenolic phytochemicals for treatment of allergic inflammatory diseases in humans. The present study determined whether oral supplementation with rosmarinic acid is an effective intervention for patients with seasonal allergic rhinoconjunctivitis (SAR). In this 21-day, randomized, double-blind, age-matched, placebo-controlled parallel group study, patients with mild SAR were treated daily with extract of Perilla frutescens enriched for rosmarinic acid (200 mg [n = 10] or 50 mg [n = 9]) or placebo (n = 10). Patients recorded symptoms daily in a diary. Profiles of infiltrating cells and concentrations of eotaxin, IL-1β, IL-8, and histamine were measured in nasal lavage fluid. Serum IgE concentrations and routine blood tests were also examined. As compared with placebo supplementation, supplementation with extract of Perilla frutescens enriched for rosmarinic acid resulted in a significant increase in responder rates for itchy nose, watery eyes, itchy eyes, and total symptoms (P < 0.05). Active treatment significantly decreased the numbers of neutrophils and eosinophils in nasal lavage fluid (P < 0.05 vs. placebo). Patients reported no adverse events, and no significant abnormalities were detected in routine blood tests. In conclusion, extract of Perilla frutescens enriched for rosmarinic acid can be an effective intervention for mild SAR at least partly through inhibition of PMNL infiltration into the nostrils. Use of this alternative treatment for SAR might reduce treatment costs for allergic diseases.

Rosmarinic acid in perilla extract inhibits allergic inflammation induced by mite allergen, in a mouse model

Background Perilla and its constituent rosmarinic acid have been suggested to have anti‐allergic activity. However, few studies have examined the effects on allergic asthma.

Rosmarinic acid inhibits lung injury induced by diesel exhaust particles

Epidemiological and experimental studies have suggested that diesel exhaust particles (DEP) may be involved in recent increases in lung diseases. DEP has been shown to generate reactive oxygen species. Intratracheal instillation of DEP induces lung inflammation and edema in mice. Rosmarinic acid is a naturally occurring polyphenol with antioxidative and anti-inflammatory activities. We investigated the effects of rosmarinic acid on lung injury induced by intratracheal administration of DEP (500 microg/body) in mice. Oral supplementation with administration of rosmarinic acid (2 mg/body for 3 d) inhibited DEP-induced lung injury, which was characterized by neutrophil sequestration and interstitial edema. DEP enhanced the lung expression of keratinocyte chemoattractant (KC), interleukin-1beta, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1alpha, which was inhibited by treatment with rosmarinic acid. DEP enhanced expression of iNOS mRNA and formation of nitrotyrosine and 8-OHdG in the lung, which was also inhibited by rosmarinic acid. These results suggest that rosmarinic acid inhibits DEP-induced lung injury by the reduction of proinflammatory molecule expression. Antioxidative activities of rosmarinic acid may also contribute to its protective effects.

Components of Diesel Exhaust Particles Diversely Enhance a Variety of Respiratory Diseases Related to Infection or Allergy: Extracted Organic Chemicals and the Residual Particles after Extraction Differently Affect Respiratory Diseases

Experimental and epidemiological studies have reported that diesel exhaust particles (DEP) can aggravate a variety of respiratory diseases including infection or allergy. However, the responsible components in DEP for the enhancement have not been identified. The present review demonstrates the different effects of the components of DEP on the respiratory diseases related to infection or allergy. We exposed mice to the organic chemicals (DEP-OC) and the residual carbonaceous nuclei (washed DEP) derived from DEP in the presence or absence of bacterial endotoxin (lipopolysaccharide: LPS) or allergen. In our first series of experiments, washed DEP combined with LPS synergistically exacerbated lung injury, which was concomitant with the enhanced lung expression of proinflammatory cytokines and chemokines, whereas DEP-OC combined with LPS did not. In contrast, our second series of experiments showed that DEP-OC, rather than washed DEP, enhanced allergen-related eosinophilic inflammation and proliferation of goblet cells in the airway epithelium, which was paralleled by the enhanced lung expression of eotaxin and interleukin-5. However, washed DEP with ovalbmin showed less change and increased the lung expression of interferon-γ. It is suggested that DEP components diversely affect various types of respiratory diseases, while the combination of organic chemicals and carbonaceous nuclei (whole DEP) mostly aggravate respiratory diseases.

A NOVEL WATER-SOLUBLE VITAMIN E DERIVATIVE PREVENTS ACUTE LUNG INJURY BY BACTERIAL ENDOTOXIN

1. Various chemokines, such as keratinocyte chemoattractant (KC), macrophage inflammatory protein (MIP)‐1α and macrophage chemoattractant protein (MCP)‐1, are involved in the pathogenesis of acute lung injury induced by bacterial endotoxin (lipopolysaccharide; LPS). Oxidative stress is an important regulator of the expression of these chemokines, whereas vitamin E protects against LPS‐induced insults. In the present study, we determined the effects of 2‐(α‐d‐glucopyranosyl) methyl‐2,5,7,8‐tetramethylchroman‐6‐ol (TMG), a novel water‐soluble vitamin E derivative with excellent anti‐oxidant activity, on acute lung injury induced by intratracheal instillation of LPS (125 µg/kg) in mice.

Cacao liquor proanthocyanidins inhibit lung injury induced by diesel exhaust particles.

Epidemiological and experimental studies have suggested that diesel exhaust particles (DEPs), which generate reactive oxygen species, may be involved in the recent increase in the prevalence of lung diseases. Cacao liquor proanthocyanidins (CPs) are naturally occurring polyphenols with antioxidative activities. We carried out a study in mice to investigate the effects of dietary supplementation of CPs on lung injury induced by intratracheal administration of DEPs (500 μg/body). Dietary supplementation with 1.0% CPs inhibited DEP-induced lung injury, characterized by neutrophil sequestration and edema. Immunohistochemical analyses showed that CPs prevented enhanced expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 caused by DEPs in the lung injury. Numerous adducts of nitrotyrosine, N-(hexanonyl) lysine, 4-hydroxy-2-nonenal, and 8-OHdG were also observed immunohistochemically in the lungs of mice treated with DEPs. However, these indicators of oxidative stress were barely visible in mice pretreated with CP supplementation. In addition, the level of thiobarbituric acid reactive substances in the lung was decreased by CP supplementation in the presence of DEPs. These results suggest that CPs inhibit DEP-induced lung injury by reducing oxidative stress, in association with a reduction in the expression of adhesion molecules.

Effects of 15-deoxy-Δ12,14-prostaglandin J2 on the expression of toll-like receptor 4 and 2 in the murine lung in the presence of lipopolysaccharide

1. Previously, we have demonstrated that 15‐deoxy‐Δ12,14‐prostaglandin J2 (15d‐PGJ2) enhances acute lung injury induced by lipopolysaccharide (LPS) in mice. The enhancement in acute lung injury by 15d‐PGJ2 was concomitant with the enhanced expression of several pro‐inflammatory cytokines in the lung. However, other underlying mechanisms of this enhancement remain to be elucidated. The present study investigated the effects of 15d‐PGJ2 on the expression of Toll‐like receptor (TLR) 4 and 2 in the lung in the absence or presence of LPS.

Urinary Trypsin Inhibitor, an Alternative Therapeutic Option for Inflammatory Disorders

Urinary trypsin inhibitor (UTI), a serine protease inhibitor, has been widely (and sometimes experiencely) used as a supportive drug for patients with inflammatory disorders such as pancreatitis, shock, and disseminated intravascular coagulation (DIC). Also, previous in vitro studies have demonstrated that serine protease inhibitors may have anti-inflammatory properties at sites of inflammation. However, the therapeutic effects of UTI in vivo remain unclarified, since commercial UTI have been developed to act against human, with the activity and selectivity toward the relevant animal UTI being less characterized. In this review, we introduce the roles of UTI mainly in experimental endotoxin (lipopolysaccharide: LPS)-related inflammatory disorders using UTI-deficient (-/-) and corresponding wild-type (WT) mice. Our experiments employing genetic approach suggest that endogenous UTI can serve protection against the systemic inflammatory response and subsequent organ injury induced by LPS, at least partly, through the inhibition of proinflammatory cytokine and chemokine expression, which provide important in vivo evidence and understanding about a protective role of UTI in inflammatory conditions. Using genetically targeted mice selectively lacking UTI, UTI has been evidenced to provide an attractive “rescue” therapeutic option for endotoxin-related inflammatory disorders such as DIC, acute lung injury, and acute liver injury.