Signal transduction and oxidative processes in sinonasal polyposis

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Signal transduction and oxidative processes in sinonasal polyposis Steven B. Cannady, MD, Pete S. Batra, MD, Rachel Leahy, BS, Martin J. Citardi, MD, Allison Janocha, BSE, Kristin Ricci, BA, Suzy A.A. Comhair, PhD, Melanie Bodine, MS, Zeneng Wang, PhD, Stanley L. Hazen, MD, PhD, Serpil C. Erzurum, MD Journal of Allergy and Clinical Immunology Volume 120, Issue 6, Pages 1346-1353 (December 2007) DOI: 10.1016/j.jaci.2007.07.067 Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Increased phospho-STAT1 (pSTAT1) and iNOS expression in nasal polyps. A, Increased expression of phospho-STAT1 (91 kd) and iNOS (130 kd) in lysates of freshly obtained polyps compared with healthy nasal tissue (30 μg of protein per lane). Epithelial cells were stimulated with IFN-γ as a positive control. Cytokeratin confirms the epithelial nature of cell brushings, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) confirms protein integrity. NL, Healthy tissue. B, Means ± SEMs. CK, Cytokeratin. Journal of Allergy and Clinical Immunology 2007 120, 1346-1353DOI: (10.1016/j.jaci.2007.07.067) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Nuclear localization of phospho-STAT1 in epithelial and endothelial cells. A, E, and I, Hematoxylin and eosin stain. B, F, and J, Immunostaining for cytokeratin to identify epithelial cells. C, G, and K, Phospho-STAT1. D, H, and L, Von Willebrand factor to identify endothelial cells. Journal of Allergy and Clinical Immunology 2007 120, 1346-1353DOI: (10.1016/j.jaci.2007.07.067) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Nuclear localization of phospho-STAT1 in epithelial and endothelial cells. A, E, and I, Hematoxylin and eosin stain. B, F, and J, Immunostaining for cytokeratin to identify epithelial cells. C, G, and K, Phospho-STAT1. D, H, and L, Von Willebrand factor to identify endothelial cells. Journal of Allergy and Clinical Immunology 2007 120, 1346-1353DOI: (10.1016/j.jaci.2007.07.067) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Nuclear localization of phospho-STAT1 in epithelial and endothelial cells. A, E, and I, Hematoxylin and eosin stain. B, F, and J, Immunostaining for cytokeratin to identify epithelial cells. C, G, and K, Phospho-STAT1. D, H, and L, Von Willebrand factor to identify endothelial cells. Journal of Allergy and Clinical Immunology 2007 120, 1346-1353DOI: (10.1016/j.jaci.2007.07.067) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Nitrate and nitrite levels in nasal lavage fluid of 8 healthy control subjects and 7 patients with polyps. Means ± SEMs for nitrite and nitrate (in micromoles) are shown. ∗Significant. Journal of Allergy and Clinical Immunology 2007 120, 1346-1353DOI: (10.1016/j.jaci.2007.07.067) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Nitrotyrosine (NY) levels in control and polyp epithelial cells. Lysates of freshly obtained nasal airway epithelial cells (30 μg of protein per lane) from healthy control subjects and patients with polyps are shown in panel A, along with a positive control of in vitro nitrated proteins (lane NY+). B, Means ± SEMs of control and polyp tissue nitrotyrosine. ∗Significant. Journal of Allergy and Clinical Immunology 2007 120, 1346-1353DOI: (10.1016/j.jaci.2007.07.067) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 SOD activity in healthy control and polyp epithelium (in units per milligram of protein). Journal of Allergy and Clinical Immunology 2007 120, 1346-1353DOI: (10.1016/j.jaci.2007.07.067) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 NO biochemical pathways. L-arginine is metabolized by urea cycle enzymes and through the enzyme iNOS, which produces NO. NO reacts with superoxide to form peroxynitrite, which ultimately generates nitrotyrosine (NY). SOD, endogenous inhibitors of iNOS (asymmetric dimethylarginine [ADMA] and NGmonomethyl-L-arginine [L-NMMA]), and the bacterial enzymes nitrite reductase (NiR) and nitrate reductase (NaR) modulate NO levels in the sinonasal passages. Journal of Allergy and Clinical Immunology 2007 120, 1346-1353DOI: (10.1016/j.jaci.2007.07.067) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 L-arginine metabolism. The substrate L-arginine is enzymatically converted to asymmetric dimethylarginine (ADMA), NGmonomethyl-L-arginine (L-NMMA), or symmetric dimethylarginine (SDMA) by protein arginine methylases (PRMT) in the presence of S-adenosylmethionine (forming S-adenylhomocysteine [SAH]). All methylarginines are excreted by the renal system or, in the case of ADMA and L-NMMA, enzymatically converted to methylamines by dimethylaminohydrolase (DDAH), resulting in formation of citrulline. ADMA, L-NMMA, and SDMA reduce NO production. Journal of Allergy and Clinical Immunology 2007 120, 1346-1353DOI: (10.1016/j.jaci.2007.07.067) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions