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Asthma is an inflammatory lung disease, in which conventional [CD4.sup.+] T cells producing IL-4/IL-13 appear to play an obligatory pathogenic role. Here we show, in a mouse model of asthma, that activation of pulmonary IL-4/IL-13 producing invariant [TCR.sup.+] CD1d-restricted natural killer T (NKT) cells is sufficient for the development of airway hyperreactivity (AHR), a cardinal feature of asthma, in the absence of conventional [CD4.sup.+] T cells and adaptive immunity. Respiratory administration of glycolipid antigens that specifically activate NKT cells ([alpha]-GalactosylCeramide and a Sphingornonas bacterial glycolipid) rapidly induced AHR and inflammation typically associated with protein allergen administration. Naive MHC class II-deficient mice, which lack conventional [CD4.sup.+] T but have NKT cells, showed exaggerated baseline AI-IR and, when challenged with [alpha]-GalactosylCeramide, demonstrated even greater AHR. These studies demonstrate an expanded role for NKT cells, in which NKT cells not only produce cytokines that influence adaptive immunity but also function as critical effector cells that can induce AHR. These results suggest that NKT cells responding to glycolipid antigens, as well as conventional [CD4.sup.+] T cells responding to peptide antigens, may be synergistic in the induction of AHR, although in some cases, each may independently induce AHR. asthma | atopy | IgE

A p38 MAPK inhibitor, FR-167653, ameliorates murine bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 283: L103-L112, 2002. First published February 15, 2002; 10.1152/ajplung.00187.2001.--To elucidate the pathophysiology of pulmonary fibrosis, we investigated the involvement of p38 mitogen-activated protein kinase (MAPK), which is one of the major signal transduction pathways of proinflammatory cytokines, in a murine model of bleomycin-induced lung fibrosis, p38 MAPK and its substrate, activating transcription factor (ATF)-2, in bronchoalveolar lavage fluid cells were phosphorylated by intratracheal exposure of bleomycin, and the phosphorylation of ATF-2 was inhibited by subcutaneous administration of a specific inhibitor of p38 MAPK, FR-167653. FR-167653 also inhibited augmented expression of tumor necrosis factor -[alpha], connective tissue growth factor, and apoptosis of lung cells induced by bleomycin administration. Moreover, daily subcutaneous administration of FR-167653 (from 1 day before to 14 days after bleomycin administration) ameliorated pulmonary fibrosis and pulmonary cachexia induced by bleomycin. These findings demonstrated that p38 MAPK is involved in bleomycin-induced pulmonary fibrosis, and its inhibitor, FR-167653, may be a feasible therapeutic agent. phosphorylation of p38 mitogen-activated protein kinase; tumor necrosis factor-[alpha]; connective tissue growth factor; anti-apoptotic effect

Byline: Kin'ya Abe (1), Toru Arai (1), Masahide Mori (1), Hiroshi Kida (1), Sho Goya (1), Hiroto Matsuoka (1), Tadashi Osaki (1), Isao Tachibana (1), Seiji Hayashi (1) Abstract: The selectin family adhesion molecules exert a crucial role in accumulation of leukocytes at the site of inflammation. To test the biological effects of soluble selectin on lung inflammation, we introduced an expression plasmid vector of soluble selectin gene via HVJ-liposome into a murine model of LPS-induced lung injury. The myeloperoxidase activity in LPS-injected mice was suppressed by the in vivo injection of soluble P-selectin gene relative to control mice. On the contrary, soluble E- or L-selectin genes did not exert suppressive effects. Our observations suggest that P-selectin plays a crucial role in the initial steps of lung inflammation, and exogenous introduction of soluble P-selectin by in vivo gene transfer method may be a useful strategy for regulating inflammation of the lung. Author Affiliation: (1) Department of Molecular Medicine, Osaka University Medical School, 2-2 Yamada-oka, Suita-city, Osaka, 565--0871, Japan Article History: Registration Date: 30/09/2004

Introduction of the interleukin-10 gene into mice inhibited bleomycin-induced lung injury in vivo. Am J Physiol Lung Cell Mol Physiol 278: L914-L922, 2000.--Interleukin (IL)-10 has been shown to reduce many inflammatory reactions. We investigated the in vivo effects of IL-10 on a bleomycin-induced lung injury model. Hemagglutinating virus of Japan (HVJ)-liposomes containing a human IL-10 expression vector (hIL10-HVJ) or a balanced salt solution as a control (Cont-HVJ) was intraperitoneally injected into mice on day -3. This was followed by intratracheal instillation of bleomycin (0.8 mg/kg) on day 0. Myeloperoxidase activity of bronchoalveolar lavage fluid and tumor necrosis factor-[Alpha] mRNA expression in bronchoalveolar lavage fluid cells on day 7 and hydroxyproline content of the whole lung on day 21 were inhibited significantly by hILl0-HVJ treatment. However, Cont-HVJ treatment could not suppress any of these parameters. We also examined the in vitro effects of IL-10 on the human lung fibroblast cell line WI-38. IL-10 significantly reduced constitutive and transforming growth factor-[Beta]-stimulated type I collagen mRNA expression. However, IL-10 did not affect the proliferation of WI-38 cells induced by platelet-derived growth factor. These data suggested that exogenous IL-10 may be useful in the treatment of pulmonary fibrosis. transforming growth factor-[Beta]; pulmonary fibrosis; collagen