Inflammation in the Absence of IL10 Cytokine Production with Airway Alterations in Nitric Oxide and (original) (raw)
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Increased nitric oxide production by airway cells of sensitized and challenged IL-10 knockout mice
Journal of leukocyte biology, 2001
The anti-inflammatory cytokine interleukin (IL)-10 suppresses inducible nitric oxide synthase (iNOS); therefore, NO production should increase in the absence of IL-10. Production of NO (as nitrite) by bronchoalveolar lavage cells of IL-10 knockout ((-/-)) mice was assessed after ovalbumin sensitization and airway challenge (S/C) and was compared with the IL-10-sufficient, wild-type (WT) C57Bl6. Eosinophil recruitment occurred in S/C WT and IL-10(-/-) mice, suggesting allergic airway inflammation. Alveolar macrophages (per g mouse) were unchanged (approximately 3x10(4) cells) with the exception of a doubling in the S/C IL-10(-/-) mice (approximately 6x10(4) cells, P<0.05). NO production (per million cells) was doubled in cells from S/C IL-10(-/-) (15.3 microM) mice compared with WT (7.6 microM, P<0.05). Inhibition of iNOS by L-N(5)-(1-iminoethyl)-ornithine reduced NO production in all S/C mice, confirming that the increase was a result of up-regulation of iNOS. We conclude that...
Enhanced nitric oxide production associated with airway hyporesponsiveness in the absence of IL-10
American Journal of Physiology-lung Cellular and Molecular Physiology, 2005
is an anti-inflammatory cytokine implicated in the regulation of airway inflammation in asthma. Among other activities, IL-10 suppresses production of nitric oxide (NO); consequently, its absence may permit increased NO production, which can affect airway smooth muscle contractility. Therefore, we investigated airway reactivity (AR) in response to methacholine (MCh) in IL-10 knockout (Ϫ/Ϫ) mice compared with wild-type C57BL/6 (C57) mice, in which airway NO production was measured as exhaled NO (ENO), and NO production was altered with administration of either NO synthase (NOS)-specific inhibitors or recombinant murine (rm)IL-10. AR, measured as enhanced pause in vivo, and tracheal ring tension in vitro were lower in IL-10 Ϫ/Ϫ mice by 25-50%, which was associated with elevated ENO levels (13 vs. 7 ppb). Administration of NOS inhibitors N G-nitro-L-arginine methyl ester (8 mg/kg ip) or L-N 6-(1-iminoethyl)-lysine (3 mg/kg ip) to IL-10 Ϫ/Ϫ mice decreased ENO by an average of 50%, which was associated with increased AR, to levels similar to C57 mice. ENO in IL-10 Ϫ/Ϫ mice decreased in a dose-dependent fashion in response to administered rmIL-10, to levels similar to C57 mice (7 ppb), which was associated with a 30% increment in AR. Thus increased NO production in the absence of IL-10, decreased AR, which was reversed with inhibition of NO, either by inhibition of NOS, or with reconstitution of IL-10. These findings suggest that airway NO production can modulate airway smooth muscle contractility, resulting in airway hyporesponsiveness when IL-10 is absent.
Nitric oxide enhances Th9 cell differentiation and airway inflammation
Nature communications, 2014
Th9 cells protect hosts against helminthic infection but also mediate allergic disease. Here we show that nitric oxide (NO) promotes Th9 cell polarization of murine and human CD4 þ T cells. NO de-represses the tumour suppressor Q3 gene p53 via nitrosylation of Mdm2. NO also increases p53-mediated IL-2 production, STAT5 phosphorylation and IRF4 expression, all essential for Th9 polarization. NO also increases the expression of TGFbR and IL-4R, pivotal to Th9 polarization. OVA-sensitized mice treated with an NO donor developed more severe airway inflammation. Transferred Th9 cells induced airway inflammation, which was exacerbated by NO and blocked by anti-IL-9 antibody. Nos2 À / À mice had less Th9 cells and developed attenuated eosinophilia during OVA-induced airway inflammation compared with wild-type mice. Our data demonstrate that NO is an important endogenous inducer of Th9 cells and provide a hitherto unrecognized mechanism for NO-mediated airway inflammation via the expansion of Th9 cells.
Role of Nitric Oxide in Chronic Allergen-Induced Airway Cell Proliferation and Inflammation
Journal of Pharmacology and Experimental Therapeutics, 2003
Chronic cellular inflammation and airway wall remodeling with subepithelial fibrosis and airway smooth muscle thickening are features of chronic asthma. We determined the role of nitric oxide in the pathogenesis of allergen-induced airway cell proliferation and inflammation by studying the effects of a relatively selective prodrug inhibitor of nitric-oxide synthase type 2 (NOS2), L-N 6-(1-iminoethyl)-lysine-5-tetrazole amide (SC-51). Brown-Norway rats were sensitized to ovalbumin and were exposed to ovalbumin aerosol every 3rd day on six occasions and were treated orally with either vehicle or SC-51 (10 mg ⅐ kg Ϫ1 ; 12 doses). We measured inflammatory cell accumulation in the airways and proliferation of cells by incorporation of bromodeoxyuridine. There Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
Endogenous nitric oxide in allergic airway disease
Journal of Allergy and Clinical Immunology, 2000
There has been intense research into the role nitric oxide (NO) plays in physiologic and pathologic mechanisms. The presence of NO in exhaled breath and the high concentrations in nasal airways stimulated many studies examining exhaled and nasal NO as potential markers of airway inflammation, enabling repeated monitoring of airway inflammation not possible with invasive tests (eg, bronchoscopy). In airway inflammation, NO is not merely a marker but may have anti-inflammatory and proinflammatory effects. Nasal NO measurement may be used in the noninvasive diagnosis and monitoring of nasal disease. This review was compiled by speakers who gave presentations on NO at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in 1999 on exhaled and nasal NO, in vitro studies of NO, the chemistry of airway NO formation, and standardized measurement of exhaled mediators. (J Allergy Clin Immunol 2000;105:438-48.)
European Journal of Pharmacology, 2005
In the present study we investigated the lymphocytes infiltration and other parameters of allergic lung inflammation comparing mice submitted to acute suppression of nitric oxide synthesis with mice deficient in inducible nitric oxide synthase (NOS2 À/À ) gene. At weekly intervals C57Bl/6 mice, wild type and NOS2 À/À were sensitized twice with ovalbumin-alumen and challenged twice with ovalbumin aerosol and lungs examined 24 h later. In wild type mice, treatment with nitric oxide synthase inhibitor, N N -nitro-l-arginine-methyl-ester (l-NAME) or aminoguanidine (i.p., 30 min before each ovalbumin challenge) caused a significant decrease in bronchoalveolar lavage cell number: eosinophils (90%), lymphocytes NK1.1 + (70%), Tgy + (50%), CD4 + (55%), CD8 + (60%) and B220 + (65%). Both inhibitors abolished airway hyperreactivity and significantly reduced mucus secretion (l-NAME 64%; aminoguanidine 58%). Surprisingly, in NOS2 À/À mice these parameters of allergic lung inflammation were not significantly different when compared with wild type mice. In addition, treatment of NOS2 À/À mice with l-NAME or aminoguanidine did not affect these parameters. Thus, acute inhibition of NOS2 activity inhibits asthmalike responses but absence of NOS2 has no affect.