RL Warner, R Paine 3rd, PJ Christensen, MA Marletta, MK Richards, SE Wilcoxen and PA Ward
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602, USA.

Products of inducible nitric oxide synthase (iNOS) are known to be involved in lung injury following intrapulmonary deposition of immunoglobulin G immune complexes (IgG-ICx). In the current studies rat alveolar macrophages stimulated in vitro with murine interferon gamma (IFN-gamma), tumor necrosis factor alpha, interleukin 1 alpha, (IL-1 alpha), lipopolysaccharide (LPS), or IgG-ICx immunostained for iNOS and produced nitrite/nitrate- (NO2-/NO3-) in a dose- and time-dependent manner requiring availability of L-arginine. Under the same conditions, IL-4 and IL-10 reduced NO2-/NO3- generation. Type II alveolar epithelial cells, which were obtained from normal rat lungs and stimulated in vitro with IgG-ICx, LPS, or IFN-gamma, also immunostained for iNOS and generated NO2-/NO3-. Special techniques of bronchoalveolar lavage (BAL) were used to retrieve alveolar macrophages and type II alveolar epithelial cells. Under these conditions, intrapulmonary deposition of LPS yielded BAL fluids containing increased amounts of NO2-/NO3- and macrophages that spontaneously released NO2-/NO3- and stained for iNOS. After intrapulmonary deposition of IgG both macrophages as well as type II cells (retrieved by BAL) spontaneously produced NO2-/NO3- and both cell types immunostained for iNOS (approximately 20% of all type II cells and 35% of all alveolar macrophages). Using dual fluorescence staining for cell identification, frozen sections of lung tissue after IgG immune complex deposition revealed iNOS in both alveolar macrophages and type II cells. Finally, in the immune complex model of alveolitis, the appearance of iNOS in macrophages as well as macrophage production in vitro of NO2-/NO3- was dependent on the in vivo availability of tumor necrosis factor alpha, IL-1, and IFN-gamma. These studies suggest a dual cell source for nitric oxide in inflamed lungs and the requirements for iNOS of several cytokines.

This article has been cited by other articles:

				M. T. Saavedra, A. D. Patterson, J. West, S. H. Randell, D. W. Riches, K. C. Malcolm, C. D. Cool, J. A. Nick, and C. A. Dinarello Abrogation of Anti-Inflammatory Transcription Factor LKLF in Neutrophil-Dominated Airways Am. J. Respir. Cell Mol. Biol., June 1, 2008; 38(6): 679 - 688. [Abstract] [Full Text] [PDF]

				J A Frank, J-F Pittet, C Wray, and M A Matthay Protection from experimental ventilator-induced acute lung injury by IL-1 receptor blockade Thorax, February 1, 2008; 63(2): 147 - 153. [Abstract] [Full Text] [PDF]

				C. Keen, A.-C. Olin, A. Edentoft, E. Gronowitz, and B. Strandvik Airway Nitric Oxide in Patients With Cystic Fibrosis Is Associated With Pancreatic Function, Pseudomonas Infection, and Polyunsaturated Fatty Acids Chest, June 1, 2007; 131(6): 1857 - 1864. [Abstract] [Full Text] [PDF]

				R. Loi, T. Beckett, K. K. Goncz, B. T. Suratt, and D. J. Weiss Limited Restoration of Cystic Fibrosis Lung Epithelium In Vivo with Adult Bone Marrow-derived Cells Am. J. Respir. Crit. Care Med., January 15, 2006; 173(2): 171 - 179. [Abstract] [Full Text] [PDF]

				B. N. Chorley, Y. Li, S. Fang, J.-A. Park, and K. B. Adler (R)-Albuterol Elicits Antiinflammatory Effects in Human Airway Epithelial Cells via iNOS Am. J. Respir. Cell Mol. Biol., January 1, 2006; 34(1): 119 - 127. [Abstract] [Full Text] [PDF]

				S. Zheng, W. Xu, S. Bose, A. K. Banerjee, S. J. Haque, and S. C. Erzurum Impaired nitric oxide synthase-2 signaling pathway in cystic fibrosis airway epithelium Am J Physiol Lung Cell Mol Physiol, August 1, 2004; 287(2): L374 - L381. [Abstract] [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]

				H. Watarai, H. Warita, and K. Soma Effect of Nitric Oxide on the Recovery of the Hypofunctional Periodontal Ligament J. Dent. Res., April 1, 2004; 83(4): 338 - 342. [Abstract] [Full Text] [PDF]

				D.V. Pechkovsky, G. Zissel, C. Stamme, T. Goldmann, H. Ari Jaffe, M. Einhaus, C. Taube, H. Magnussen, M. Schlaak, and J. Muller-Quernheim Human alveolar epithelial cells induce nitric oxide synthase-2 expression in alveolar macrophages Eur. Respir. J., April 1, 2002; 19(4): 672 - 683. [Abstract] [Full Text] [PDF]

				N. C. Riedemann, R.-F. Guo, V. J. Sarma, I. J. Laudes, M. Huber-Lang, R. L. Warner, E. A. Albrecht, C. L. Speyer, and P. A. Ward Expression and Function of the C5a Receptor in Rat Alveolar Epithelial Cells J. Immunol., February 15, 2002; 168(4): 1919 - 1925. [Abstract] [Full Text] [PDF]

				J. A. Jordan, R.-F. Guo, E. C. Yun, V. Sarma, R. L. Warner, L. D. Crouch, G. Senaldi, T. R. Ulich, and P. A. Ward Role of IL-18 in Acute Lung Inflammation J. Immunol., December 15, 2001; 167(12): 7060 - 7068. [Abstract] [Full Text] [PDF]

				B. T. Ameredes, R. Zamora, K. F. Gibson, T. R. Billiar, B. Dixon-McCarthy, S. Watkins, and W. J. Calhoun Increased nitric oxide production by airway cells of sensitized and challenged IL-10 knockout mice J. Leukoc. Biol., November 1, 2001; 70(5): 730 - 736. [Abstract] [Full Text] [PDF]

				J. Fan, R. D. Ye, and A. B. Malik Transcriptional mechanisms of acute lung injury Am J Physiol Lung Cell Mol Physiol, November 1, 2001; 281(5): L1037 - L1050. [Abstract] [Full Text] [PDF]

				P. J. Christensen, M. B. Bailie, R. E. Goodman, A. D. O'Brien, G. B. Toews, and R. Paine III Role of diminished epithelial GM-CSF in the pathogenesis of bleomycin-induced pulmonary fibrosis Am J Physiol Lung Cell Mol Physiol, September 1, 2000; 279(3): L487 - L495. [Abstract] [Full Text] [PDF]

				S. Zhu, K. F. Basiouny, J. P. Crow, and S. Matalon Carbon dioxide enhances nitration of surfactant protein A by activated alveolar macrophages Am J Physiol Lung Cell Mol Physiol, May 1, 2000; 278(5): L1025 - L1031. [Abstract] [Full Text] [PDF]

				S. R. Thomas, S. A. Kharitonov, S. F. Scott, M. E. Hodson, and P. J. Barnes Nasal and Exhaled Nitric Oxide Is Reduced in Adult Patients With Cystic Fibrosis and Does Not Correlate With Cystic Fibrosis Genotype Chest, April 1, 2000; 117(4): 1085 - 1089. [Abstract] [Full Text] [PDF]

				J. Tamaoki, M. Kondo, K. Kohri, K. Aoshiba, E. Tagaya, and A. Nagai Macrolide Antibiotics Protect Against Immune Complex-Induced Lung Injury in Rats: Role of Nitric Oxide from Alveolar Macrophages J. Immunol., September 1, 1999; 163(5): 2909 - 2915. [Abstract] [Full Text] [PDF]

				T. Jilling, I. Y. Haddad, S. H. Cheng, and S. Matalon Nitric oxide inhibits heterologous CFTR expression in polarized epithelial cells Am J Physiol Lung Cell Mol Physiol, July 1, 1999; 277(1): L89 - L96. [Abstract] [Full Text] [PDF]

				B. J. Czermak, A. B. Lentsch, N. M. Bless, H. Schmal, H. P. Friedl, and P. A. Ward Synergistic Enhancement of Chemokine Generation and Lung Injury by C5a or the Membrane Attack Complex of Complement Am. J. Pathol., May 1, 1999; 154(5): 1513 - 1524. [Abstract] [Full Text] [PDF]

				S. Zhu, D. L. Kachel, W. J. Martin II, and S. Matalon Nitrated SP-A does not enhance adherence of Pneumocystis carinii to alveolar macrophages Am J Physiol Lung Cell Mol Physiol, December 1, 1998; 275(6): L1031 - L1039. [Abstract] [Full Text] [PDF]

				S. J. LINNANE, V. M. KEATINGS, C. M. COSTELLO, J. B. MOYNIHAN, C. M. O'CONNOR, M. X. FITZGERALD, and P. MCLOUGHLIN Total Sputum Nitrate plus Nitrite Is Raised during Acute Pulmonary Infection in Cystic Fibrosis Am. J. Respir. Crit. Care Med., July 1, 1998; 158(1): 207 - 212. [Abstract] [Full Text] [PDF]

				L. E. Olsson, M. A. Wheeler, W. C. Sessa, and R. M. Weiss Bladder Instillation and Intraperitoneal Injection of Escherichia coli Lipopolysaccharide Up-regulate Cytokines and iNOS in Rat Urinary Bladder J. Pharmacol. Exp. Ther., March 1, 1998; 284(3): 1203 - 1208. [Abstract] [Full Text]

				T. P. Shanley, R. L. Warner, L. D. Crouch, G. N. Dietsch, D. L. Clark, M. M. O'Brien, W. M. Gallatin, and P. A. Ward Requirements for {alpha}d in IgG Immune Complex-Induced Rat Lung Injury J. Immunol., January 15, 1998; 160(2): 1014 - 1020. [Abstract] [Full Text] [PDF]

				R. J. Folz, J. Guan, M. F. Seldin, T. D. Oury, J. J. Enghild, and J. D. Crapo Mouse Extracellular Superoxide Dismutase: Primary Structure, Tissue-specific Gene Expression, Chromosomal Localization, and Lung In Situ Hybridization Am. J. Respir. Cell Mol. Biol., October 1, 1997; 17(4): 393 - 403. [Abstract] [Full Text]

				B. Beck-Schimmer, R. C. Schimmer, R. L. Warner, H. Schmal, G. Nordblom, C. M. Flory, M. E. Lesch, H. P. Friedl, D. J. Schrier, and P. A. Ward Expression of Lung Vascular and Airway ICAM-1 after Exposure to Bacterial Lipopolysaccharide Am. J. Respir. Cell Mol. Biol., September 1, 1997; 17(3): 344 - 352. [Abstract] [Full Text]

				H.-W. LIU, A. ANAND, K. BLOCH, D. CHRISTIANI, and R. KRADIN Expression of Inducible Nitric Oxide Synthase by Macrophages in Rat Lung Am. J. Respir. Crit. Care Med., July 1, 1997; 156(1): 223 - 228. [Abstract] [Full Text]

				D. V. Pechkovsky, G. Zissel, T. Goldmann, M. Einhaus, C. Taube, H. Magnussen, M. Schlaak, and J. Muller-Quernheim Pattern of NOS2 and NOS3 mRNA expression in human A549 cells and primary cultured AEC II Am J Physiol Lung Cell Mol Physiol, April 1, 2002; 282(4): L684 - L692. [Abstract] [Full Text] [PDF]