Enhanced nitric oxide production associated with airway hyporesponsiveness in the absence of IL-10.

Interleukin (IL)-10 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 (-/-) mice compared with wild-type C57BL/6 (C57) mice, in which airway NO production was measured as exhaled NO (E(NO)), 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(-/-) mice by 25-50%, which was associated with elevated E(NO) 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(-/-) mice decreased E(NO) by an average of 50%, which was associated with increased AR, to levels similar to C57 mice. E(NO) in IL-10(-/-) 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.

[1]  J. Drazen,et al.  Expression of nitric oxide synthase-2 in the lungs decreases airway resistance and responsiveness. , 2004, Journal of applied physiology.

[2]  E. Gelfand,et al.  Surfactant protein D regulates airway function and allergic inflammation through modulation of macrophage function. , 2003, American journal of respiratory and critical care medicine.

[3]  A. Choi,et al.  Low-dose carbon monoxide reduces airway hyperresponsiveness in mice. , 2003, American journal of physiology. Lung cellular and molecular physiology.

[4]  P. O'Byrne,et al.  Airway hyperresponsiveness. , 2003, Chest.

[5]  J. Bates,et al.  A reevaluation of the validity of unrestrained plethysmography in mice. , 2002, Journal of applied physiology.

[6]  D. Spina,et al.  Role of cytokines and chemokines in bronchial hyperresponsiveness and airway inflammation. , 2002, Pharmacology & therapeutics.

[7]  P. R. Mayeux,et al.  Effect of inhibitors of nitric oxide synthase on acetaminophen-induced hepatotoxicity in mice. , 2002, Nitric oxide : biology and chemistry.

[8]  O. Moss,et al.  Pulmonary function assessment by whole-body plethysmography in restrained versus unrestrained mice. , 2002, Journal of pharmacological and toxicological methods.

[9]  M. Grunstein,et al.  Autocrine signaling by IL-10 mediates altered responsiveness of atopic sensitized airway smooth muscle. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[10]  B. Ameredes,et al.  Increased nitric oxide production by airway cells of sensitized and challenged IL‐10 knockout mice , 2001, Journal of leukocyte biology.

[11]  K. Leong,et al.  Understanding the pathogenesis of allergic asthma using mouse models. , 2001, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[12]  P. Huang,et al.  Regulation of murine airway responsiveness by endothelial nitric oxide synthase. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[13]  T. Karachi,et al.  Noninvasive measurement of exhaled nitric oxide in a spontaneously breathing mouse. , 2001, American journal of respiratory and critical care medicine.

[14]  Y. Shibata,et al.  IL-10 gene knockout attenuates allergen-induced airway hyperresponsiveness in C57BL/6 mice. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[15]  S. Kunkel,et al.  Acute inhibition of nitric oxide exacerbates airway hyperresponsiveness, eosinophilia and C-C chemokine generation in a murine model of fungal asthma , 2000, Inflammation Research.

[16]  M. Jordana,et al.  IL-10 is necessary for the expression of airway hyperresponsiveness but not pulmonary inflammation after allergic sensitization. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[17]  J. Curtis,et al.  Repeated Intratracheal Challenge with Particulate Antigen Modulates Murine Lung Cytokines1 2 , 2000, The Journal of Immunology.

[18]  E. Enright,et al.  IL-10 reduces Th2 cytokine production and eosinophilia but augments airway reactivity in allergic mice. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[19]  J. Hankinson,et al.  Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. , 2000, American journal of respiratory and critical care medicine.

[20]  M. Jordana,et al.  Interleukin-10 gene transfer to the airway regulates allergic mucosal sensitization in mice. , 1999, American journal of respiratory cell and molecular biology.

[21]  G. Cieslewicz,et al.  The late, but not early, asthmatic response is dependent on IL-5 and correlates with eosinophil infiltration. , 1999, The Journal of clinical investigation.

[22]  J. Drazen,et al.  Contribution of Nitric Oxide Synthases 1, 2, and 3 to Airway Hyperresponsiveness and Inflammation in a Murine Model of Asthma , 1999, The Journal of experimental medicine.

[23]  P. Barnes,et al.  Effect of endogenous nitric oxide inhibition on airway responsiveness to histamine and adenosine-5′-monophosphate in asthma , 1998, Thorax.

[24]  K. Chung,et al.  Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma. , 1998, Thorax.

[25]  E. Gelfand,et al.  Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. , 1997, American journal of respiratory and critical care medicine.

[26]  I. Adcock,et al.  Inducible nitric oxide synthase after sensitization and allergen challenge of Brown Norway rat lung , 1997, British journal of pharmacology.

[27]  S. Wenzel,et al.  Interleukin-10 regulation in normal subjects and patients with asthma. , 1996, Journal of Allergy and Clinical Immunology.

[28]  D. Berg,et al.  Interleukin-10 gene knock-out mice: a model of chronic inflammation. , 1995, Clinical Immunology and Immunopathology.

[29]  K. Rajewsky,et al.  Interleukin-10-deficient mice develop chronic enterocolitis , 1993, Cell.

[30]  S. Moncada,et al.  Interleukin-10 (IL-10) inhibits the induction of nitric oxide synthase by interferon-gamma in murine macrophages. , 1992, Biochemical and biophysical research communications.

[31]  T. Loscher.  Endothelium-derived nitric oxide: the endogenous nitrovasodilator in the human cardiovascular system. , 1991 .

[32]  P. Bruneval,et al.  Aetiology of surgically treated mitral regurgitation. , 1991, European heart journal.

[33]  T. Lüscher.  Endothelium-derived nitric oxide: the endogenous nitrovasodilator in the human cardiovascular system. , 1991, European heart journal.

[34]  M. Jordana,et al.  Late-phase airway reaction and inflammation. , 1989, The Journal of allergy and clinical immunology.