MJ Thomassen, LT Buhrow, MJ Connors, FT Kaneko, SC Erzurum and MS Kavuru
Department of Pulmonary and Critical Care Medicine, The Cleveland Clinic Foundation, Ohio 44195-5038, USA. thomasm@cesmtp.ccf.org

High levels of nitric oxide (NO) have been reported in exhaled air of asthmatic individuals. Because alveolar macrophages (AM) are major producers of cytokines, and bronchoalveolar lavage fluid (BALF) from asthmatic individuals contains increased levels of inflammatory cytokines, this study was undertaken to determine whether NO modified the production of inflammatory cytokines by human AM. AM were obtained from normal volunteers by fiberoptic bronchoscopy. Tumor necrosis factor-alpha (TNF-alpha) production stimulated by lipopolysaccharide (LPS; 0.5 microg/ml) was measured with an enzyme-linked immunosorbent assay (ELISA). NO generated from 2,2-(hydroxynitrosohydrazono)-bis- ethanamine (DETA NONOate) (0.1 to 1.0 mM) inhibited TNF-alpha secretion in a dose-dependent manner. At 1 mM DETA NONOate, mean inhibition (+/- SEM) of TNF-alpha secretion was 56 +/- 4% (P = 0.002). To determine whether this effect was cytokine specific, interleukin-1beta (IL-1beta) and macrophage inflammatory protein-1alpha (MIP-1alpha) were evaluated, and DETA NONOate was also found to inhibit both of these cytokines. Basal cytokine levels from unstimulated AM were unaffected by NO. These findings indicate that NO is a potent inhibitor of cytokine production by stimulated human AM.

This article has been cited by other articles:

				H. Meurs, R. Gosens, and J. Zaagsma Airway hyperresponsiveness in asthma: lessons from in vitro model systems and animal models Eur. Respir. J., August 1, 2008; 32(2): 487 - 502. [Abstract] [Full Text] [PDF]

				M. J. Thomassen, B. P. Barna, A. G. Malur, T. L. Bonfield, C. F. Farver, A. Malur, H. Dalrymple, M. S. Kavuru, and M. Febbraio ABCG1 is deficient in alveolar macrophages of GM-CSF knockout mice and patients with pulmonary alveolar proteinosis J. Lipid Res., December 1, 2007; 48(12): 2762 - 2768. [Abstract] [Full Text] [PDF]

				S. M. Wells and A. Holian Asymmetric Dimethylarginine Induces Oxidative and Nitrosative Stress in Murine Lung Epithelial Cells Am. J. Respir. Cell Mol. Biol., May 1, 2007; 36(5): 520 - 528. [Abstract] [Full Text] [PDF]

				W. E. Truog, P. L. Ballard, M. Norberg, S. Golombek, R. C. Savani, J. D. Merrill, L. A. Parton, A. Cnaan, X. Luan, R. A. Ballard, et al. Inflammatory Markers and Mediators in Tracheal Fluid of Premature Infants Treated With Inhaled Nitric Oxide Pediatrics, April 1, 2007; 119(4): 670 - 678. [Abstract] [Full Text] [PDF]

				T. Cui, F. J. Schopfer, J. Zhang, K. Chen, T. Ichikawa, P. R. S. Baker, C. Batthyany, B. K. Chacko, X. Feng, R. P. Patel, et al. Nitrated Fatty Acids: Endogenous Anti-inflammatory Signaling Mediators J. Biol. Chem., November 24, 2006; 281(47): 35686 - 35698. [Abstract] [Full Text] [PDF]

				D. C. Look, L. L. Stoll, S. A. Romig, A. Humlicek, B. E. Britigan, and G. M. Denning Pyocyanin and Its Precursor Phenazine-1-Carboxylic Acid Increase IL-8 and Intercellular Adhesion Molecule-1 Expression in Human Airway Epithelial Cells by Oxidant-Dependent Mechanisms J. Immunol., September 15, 2005; 175(6): 4017 - 4023. [Abstract] [Full Text] [PDF]

				J. Wu, M. Kobayashi, E. A. Sousa, W. Liu, J. Cai, S. J. Goldman, A. J. Dorner, S. J. Projan, M. S. Kavuru, Y. Qiu, et al. Differential Proteomic Analysis of Bronchoalveolar Lavage Fluid in Asthmatics following Segmental Antigen Challenge Mol. Cell. Proteomics, September 1, 2005; 4(9): 1251 - 1264. [Abstract] [Full Text] [PDF]

				R Ratnawati and P S Thomas Exhaled nitric oxide in paediatric asthma Chronic Respiratory Disease, July 1, 2005; 2(3): 163 - 174. [Abstract] [PDF]

				M. Peters-Golden, C. Canetti, P. Mancuso, and M. J. Coffey Leukotrienes: Underappreciated Mediators of Innate Immune Responses J. Immunol., January 15, 2005; 174(2): 589 - 594. [Abstract] [Full Text] [PDF]

				H. L. Attalah, S. Honore, S. Eddahibi, E. Marcos, C.-J. Soussy, S. Adnot, and C. Delclaux Decreased exhaled nitric oxide as a marker of postinsult immune paralysis J Appl Physiol, October 1, 2004; 97(4): 1188 - 1194. [Abstract] [Full Text] [PDF]

				M. Peters-Golden The Alveolar Macrophage: The Forgotten Cell in Asthma Am. J. Respir. Cell Mol. Biol., July 1, 2004; 31(1): 3 - 7. [Full Text] [PDF]

				F. L. M. Ricciardolo, P. J. Sterk, B. Gaston, and G. Folkerts Nitric Oxide in Health and Disease of the Respiratory System Physiol Rev, July 1, 2004; 84(3): 731 - 765. [Abstract] [Full Text] [PDF]

				T. Waldow, K. Alexiou, W. Witt, F. M. Wagner, V. Gulielmos, K. Matschke, and M. Knaut Attenuation of Reperfusion-Induced Systemic Inflammation by Preconditioning With Nitric Oxide in an In Situ Porcine Model of Normothermic Lung Ischemia Chest, June 1, 2004; 125(6): 2253 - 2259. [Abstract] [Full Text] [PDF]

				D. A. Culver, B. P. Barna, B. Raychaudhuri, T. L. Bonfield, S. Abraham, A. Malur, C. F. Farver, M. S. Kavuru, and M. J. Thomassen Peroxisome Proliferator-Activated Receptor {gamma} Activity Is Deficient in Alveolar Macrophages in Pulmonary Sarcoidosis Am. J. Respir. Cell Mol. Biol., January 1, 2004; 30(1): 1 - 5. [Abstract] [Full Text] [PDF]

				T. L. Bonfield, C. F. Farver, B. P. Barna, A. Malur, S. Abraham, B. Raychaudhuri, M. S. Kavuru, and M. J. Thomassen Peroxisome Proliferator-Activated Receptor-{gamma} Is Deficient in Alveolar Macrophages from Patients with Alveolar Proteinosis Am. J. Respir. Cell Mol. Biol., December 1, 2003; 29(6): 677 - 682. [Abstract] [Full Text] [PDF]

				T. L. Bonfield, B. Raychaudhuri, A. Malur, S. Abraham, B. C. Trapnell, M. S. Kavuru, and M. J. Thomassen PU.1 regulation of human alveolar macrophage differentiation requires granulocyte-macrophage colony-stimulating factor Am J Physiol Lung Cell Mol Physiol, November 1, 2003; 285(5): L1132 - L1136. [Abstract] [Full Text] [PDF]

				J. Sokol, S. E. Jacobs, and D. Bohn Inhaled Nitric Oxide for Acute Hypoxic Respiratory Failure in Children and Adults: A Meta-analysis Anesth. Analg., October 1, 2003; 97(4): 989 - 998. [Abstract] [Full Text] [PDF]

				A. Rachlis, J. L. Watson, J. Lu, and D. M. McKay Nitric oxide reduces bacterial superantigen-immune cell activation and consequent epithelial abnormalities J. Leukoc. Biol., August 1, 2002; 72(2): 339 - 346. [Abstract] [Full Text] [PDF]

				J. L. Kang, W. Park, I. S. Pack, H. S. Lee, M. J. Kim, C.-M. Lim, and Y. Koh Inhaled nitric oxide attenuates acute lung injury via inhibition of nuclear factor-kappa B and inflammation J Appl Physiol, February 1, 2002; 92(2): 795 - 801. [Abstract] [Full Text] [PDF]

				P L Clark, I I Ekekezie, H A Kaftan, C A Castor, and W E Truog Safety and efficacy of nitric oxide in chronic lung disease Arch. Dis. Child. Fetal Neonatal Ed., January 1, 2002; 86(1): F41 - 45. [Abstract] [Full Text] [PDF]

				O. Nohara, M. Kulka, R. E. Dery, F. L. Wills, N. S. Hirji, M. Gilchrist, and A. D. Befus Regulation of CD8 Expression in Mast Cells by Exogenous or Endogenous Nitric Oxide J. Immunol., November 15, 2001; 167(10): 5935 - 5939. [Abstract] [Full Text] [PDF]

				R. Hammermann, M. D. M. Dreißig, J. Mössner, M. Fuhrmann, L. Berrino, M. Göthert, and K. Racké Nuclear Factor-kappa B Mediates Simultaneous Induction of Inducible Nitric-Oxide Synthase and Up-Regulation of the Cationic Amino Acid Transporter CAT-2B in Rat Alveolar Macrophages Mol. Pharmacol., April 13, 2001; 58(6): 1294 - 1302. [Abstract] [Full Text]

				L. Connelly, M. Palacios-Callender, C. Ameixa, S. Moncada, and A. J. Hobbs Biphasic Regulation of NF-{{kappa}}B Activity Underlies the Pro- and Anti-Inflammatory Actions of Nitric Oxide J. Immunol., March 15, 2001; 166(6): 3873 - 3881. [Abstract] [Full Text] [PDF]

				C. M. Calkins, D. D. Bensard, J. K. Heimbach, X. Meng, B. D. Shames, E. J. Pulido, and R. C. McIntyre Jr. L-Arginine attenuates lipopolysaccharide-induced lung chemokine production Am J Physiol Lung Cell Mol Physiol, March 1, 2001; 280(3): L400 - L408. [Abstract] [Full Text] [PDF]

				S. A. A. Comhair, M. J. Thomassen, and S. C. Erzurum Differential Induction of Extracellular Glutathione Peroxidase and Nitric Oxide Synthase 2 in Airways of Healthy Individuals Exposed to 100% O2 or Cigarette Smoke Am. J. Respir. Cell Mol. Biol., September 1, 2000; 23(3): 350 - 354. [Abstract] [Full Text]

				B. Raychaudhuri, R. Dweik, M. J. Connors, L. Buhrow, A. Malur, J. Drazba, A. C. Arroliga, S. C. Erzurum, M. S. Kavuru, and M. J. Thomassen Nitric Oxide Blocks Nuclear Factor-kappa B Activation in Alveolar Macrophages Am. J. Respir. Cell Mol. Biol., September 1, 1999; 21(3): 311 - 316. [Abstract] [Full Text]

				R. A. Schroeder, C. Cai, and P. C. Kuo Endotoxin-mediated nitric oxide synthesis inhibits IL-1beta gene transcription in ANA-1 murine macrophages Am J Physiol Cell Physiol, September 1, 1999; 277(3): C523 - C530. [Abstract] [Full Text] [PDF]

				C. E. Howlett, J. S. Hutchison, J. P. Veinot, A. Chiu, P. Merchant, and H. Fliss Inhaled nitric oxide protects against hyperoxia-induced apoptosis in rat lungs Am J Physiol Lung Cell Mol Physiol, September 1, 1999; 277(3): L596 - L605. [Abstract] [Full Text] [PDF]

				P. KAUL, I. SINGH, and R. B. TURNER Effect of Nitric Oxide on Rhinovirus Replication and Virus-Induced Interleukin-8 Elaboration Am. J. Respir. Crit. Care Med., April 1, 1999; 159(4): 1193 - 1198. [Abstract] [Full Text] [PDF]