Am. J. Respir. Cell Mol. Biol., Volume 21, Number 3, September, 1999 311-316

Nitric Oxide Blocks Nuclear Factor-B Activation in Alveolar Macrophages

Baisakhi Raychaudhuri, Raed Dweik, Mary J. Connors, Lisa Buhrow, Anagha Malur, Judith Drazba, Alejandro C. Arroliga, Serpil C. Erzurum, Mani S. Kavuru, and Mary Jane Thomassen

Departments of Pulmonary and Critical Care Medicine, Neurosciences, Cancer Biology, and Immunology, The Cleveland Clinic Foundation, Cleveland, Ohio

Nitric oxide (NO) is an important endogenous regulatory molecule implicated in both proinflammatory and antiinflammatory processes in the lung. Previously, we demonstrated that in human alveolar macrophages (AM), NO decreased inflammatory cytokine production, including that of interleukin-1, tumor necrosis factor- and macrophage inflammatory protein-1. One mechanism by which NO could regulate such diverse cytokine production is through effects on the transcription factor nuclear factor-B (NF-B), which controls the expression of the genes for these inflammatory cytokines and growth factors. We therefore investigated whether NO affects NF-B activation in AM in vitro and in vivo. In vitro studies with AM showed that NF-B activation by lipopolysaccharide (LPS) is decreased by NO in a dose-dependent manner. NO prevented an LPS-mediated decrease in the NF-B inhibitory protein IB-. In asthma, airway NO levels are increased, whereas in primary pulmonary hypertension (PPH), airway NO levels are lower than in healthy lungs. In vivo investigations were conducted with freshly isolated AM from healthy controls, asthmatic individuals, and PPH patients. Healthy individuals had airway NO levels of 8 ± 2 ppb (mean ± SEM), which is associated with low NF-B activation. Asthma patients with airway NO levels > 17 ppb showed minimal NF-B activation, whereas asthmatic individuals with NO levels  17 ppb showed greater NF-B activation. PPH patients with low NO (1 ± 1 ppb) had prominent NF-B activation. These in vivo studies in asthma and PPH support the in vitro observation of an inverse relationship between NO and NF-B activation. One mechanism by which NO blocks cytokine production involves IB.

This article has been cited by other articles:

				J. Huang, P. M. Kaminski, J. G. Edwards, A. Yeh, M. S. Wolin, W. H. Frishman, M. H. Gewitz, and R. Mathew Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotaline-induced pulmonary artery hypertension Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1250 - L1259. [Abstract] [Full Text] [PDF]

				M. Hagen, K. Fagan, W. Steudel, M. Carr, K. Lane, D. M. Rodman, and J. West Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1473 - L1479. [Abstract] [Full Text] [PDF]

				D. El Kebir, B. Hubert, R. Taha, E. Troncy, T. Wang, D. Gauvin, M. Gangal, and G. Blaise Effects of Inhaled Nitric Oxide on Inflammation and Apoptosis After Cardiopulmonary Bypass Chest, October 1, 2005; 128(4): 2910 - 2917. [Abstract] [Full Text] [PDF]

				X. Baur and L. Barbinova Latex allergen exposure increases exhaled nitric oxide in symptomatic healthcare workers Eur. Respir. J., February 1, 2005; 25(2): 309 - 316. [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]

				B. Raychaudhuri, S. Abraham, T. L. Bonfield, A. Malur, A. Deb, J. A. DiDonato, M. S. Kavuru, and M. J. Thomassen Surfactant Blocks Lipopolysaccharide Signaling by Inhibiting both Mitogen-Activated Protein and I{kappa}B Kinases in Human Alveolar Macrophages Am. J. Respir. Cell Mol. Biol., February 1, 2004; 30(2): 228 - 232. [Abstract] [Full Text] [PDF]

				T. Okamoto, K. Gohil, E. I. Finkelstein, P. Bove, T. Akaike, and A. van der Vliet Multiple contributing roles for NOS2 in LPS-induced acute airway inflammation in mice Am J Physiol Lung Cell Mol Physiol, January 1, 2004; 286(1): L198 - L209. [Abstract] [Full Text] [PDF]

				K. S. Mark, A. R. Burroughs, R. C. Brown, J. D. Huber, and T. P. Davis Nitric oxide mediates hypoxia-induced changes in paracellular permeability of cerebral microvasculature Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H174 - H180. [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]

				S. B. Khatri, J. Hammel, M. S. Kavuru, S. C. Erzurum, and R. A. Dweik Temporal association of nitric oxide levels and airflow in asthma after whole lung allergen challenge J Appl Physiol, July 1, 2003; 95(1): 436 - 440. [Abstract] [Full Text] [PDF]

				I. Jibiki, S. Hashimoto, S. Maruoka, Y. Gon, A. Matsuzawa, H. Nishitoh, H. Ichijo, and T. Horie Apoptosis Signal-Regulating Kinase 1-Mediated Signaling Pathway Regulates Nitric Oxide-Induced Activator Protein-1 Activation in Human Bronchial Epithelial Cells Am. J. Respir. Crit. Care Med., March 15, 2003; 167(6): 856 - 861. [Abstract] [Full Text] [PDF]

				C.-L. Chen, C.-T. Lee, Y.-C. Liu, J.-Y. Wang, H.-Y. Lei, and C.-K. Yu House Dust Mite Dermatophagoides farinae Augments Proinflammatory Mediator Productions and Accessory Function of Alveolar Macrophages: Implications for Allergic Sensitization and Inflammation J. Immunol., January 1, 2003; 170(1): 528 - 536. [Abstract] [Full Text] [PDF]

				B. Raychaudhuri, A. Malur, T. L. Bonfield, S. Abraham, R. J. Schilz, C. F. Farver, M. S. Kavuru, A. C. Arroliga, and M. J. Thomassen The Prostacyclin Analogue Treprostinil Blocks NFkappa B Nuclear Translocation in Human Alveolar Macrophages J. Biol. Chem., August 30, 2002; 277(36): 33344 - 33348. [Abstract] [Full Text] [PDF]

				D. W. Porter, L. Millecchia, V. A. Robinson, A. Hubbs, P. Willard, D. Pack, D. Ramsey, J. McLaurin, A. Khan, D. Landsittel, et al. Enhanced nitric oxide and reactive oxygen species production and damage after inhalation of silica Am J Physiol Lung Cell Mol Physiol, August 1, 2002; 283(2): L485 - L493. [Abstract] [Full Text] [PDF]

				T. Wang, D. El-Kebir, B. Hubert, R. A.W Veldhuizen, D. Gauvin, and G. Blaise EFFECT OF INHALED NITRIC OXIDE (INO) ON SURFACTANT IN PIGS Can J Anesth, June 1, 2002; 49(90001): A99 - 99. [Full Text]

				J. Pfeilschifter, R. Koditz, M. Pfohl, and H. Schatz Changes in Proinflammatory Cytokine Activity after Menopause Endocr. Rev., February 1, 2002; 23(1): 90 - 119. [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]

				I. M. Robbins, R. J. Barst, L. J. Rubin, S. P. Gaine, P. V. Price, J. D. Morrow, and B. W. Christman Increased Levels of Prostaglandin D2 Suggest Macrophage Activation in Patients With Primary Pulmonary Hypertension Chest, November 1, 2001; 120(5): 1639 - 1644. [Abstract] [Full Text] [PDF]

				R. A. Dweik, D. Laskowski, M. Özkan, C. Farver, and S. C. Erzurum High Levels of Exhaled Nitric Oxide (NO) and NO Synthase III Expression in Lesional Smooth Muscle in Lymphangioleiomyomatosis Am. J. Respir. Cell Mol. Biol., April 1, 2001; 24(4): 414 - 418. [Abstract] [Full Text]

				R. A. Dweik, S. A. A. Comhair, B. Gaston, F. B. J. M. Thunnissen, C. Farver, M. J. Thomassen, M. Kavuru, J. Hammel, H. M. Abu-Soud, and S. C. Erzurum NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response PNAS, February 15, 2001; (2001) 51629498. [Abstract] [Full Text]

				M. J. Coffey, S. M. Phare, and M. Peters-Golden Prolonged Exposure to Lipopolysaccharide Inhibits Macrophage 5-Lipoxygenase Metabolism Via Induction of Nitric Oxide Synthesis J. Immunol., October 1, 2000; 165(7): 3592 - 3598. [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]

				F. H. Guo, S. A. A. Comhair, S. Zheng, R. A. Dweik, N. T. Eissa, M. J. Thomassen, W. Calhoun, and S. C. Erzurum Molecular Mechanisms of Increased Nitric Oxide (NO) in Asthma: Evidence for Transcriptional and Post-Translational Regulation of NO Synthesis J. Immunol., June 1, 2000; 164(11): 5970 - 5980. [Abstract] [Full Text] [PDF]

				H. E. Marshall and J. S. Stamler Exhaled Nitric Oxide (NO), NO Synthase Activity, and Regulation of Nuclear Factor (NF)-kappa B Am. J. Respir. Cell Mol. Biol., September 1, 1999; 21(3): 296 - 297. [Full Text]

				R. A. Dweik, S. A. A. Comhair, B. Gaston, F. B. J. M. Thunnissen, C. Farver, M. J. Thomassen, M. Kavuru, J. Hammel, H. M. Abu-Soud, and S. C. Erzurum NO chemical events in the human airway during the immediate and late antigen-induced asthmatic response PNAS, February 27, 2001; 98(5): 2622 - 2627. [Abstract] [Full Text] [PDF]