Relation of epidermal growth factor receptor expression to goblet cell hyperplasia in nasal polyps Pierre-Regis Burgel, MDa, Estelle Escudier, MDb, Andre.

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Relation of epidermal growth factor receptor expression to goblet cell hyperplasia in nasal polyps Pierre-Regis Burgel, MDa, Estelle Escudier, MDb, Andre Coste, MDc, Trang Dao-Pick, BAa, Iris F. Ueki, BAa, Kiyoshi Takeyama, MDa, Jae Jeong Shim, MDa, Andrew H. Murr, MDd, Jay A. Nadel, MDa Journal of Allergy and Clinical Immunology Volume 106, Issue 4, Pages 705-712 (October 2000) DOI: 10.1067/mai.2000.109823 Copyright © 2000 Mosby, Inc. Terms and Conditions

Fig. 1 Percentage of AB/PAS- and MUC5AC-stained areas of epithelium in control (open columns) and nasal polyp (filled columns) epithelium. In control epithelium (n = 6) and in polyp epithelium (n = 8), AB/PAS- and MUC5AC-stained areas were not different from one another (P > .05). However, AB/PAS- and MUC5AC-stained areas were larger in polyp epithelium than in control epithelium (*P = .002 and †P = .003, respectively). Values are expressed as mean percentage areas ± SEM occupied by AB/PAS- and MUC5AC-stained cells. Journal of Allergy and Clinical Immunology 2000 106, 705-712DOI: (10.1067/mai.2000.109823) Copyright © 2000 Mosby, Inc. Terms and Conditions

Fig. 2 Comparison of AB/PAS staining (left panels) and MUC5AC protein immunolocalization (right panels) in control and polyp nasal epithelium. In control nasal epithelium (upper panels) , staining with AB/PAS (for mucous glycoconjugates: left panel ) and staining for mucin MUC5AC protein (right panel) was positive in only a few goblet cells. In polyp epithelium (lower panels) AB/PAS and MUC5AC staining was also positive in goblet cells; the stained areas were larger than in control epithelium (bar = 50 μm). Journal of Allergy and Clinical Immunology 2000 106, 705-712DOI: (10.1067/mai.2000.109823) Copyright © 2000 Mosby, Inc. Terms and Conditions

Fig. 3 Comparison of MUC5AC protein immunolocalization (left panels) , EGFR protein immunolocalization (middle panels) , and in situ hybridization for EGFR messenger RNA (right panels) in control nasal tissue (upper panels) and in two types of nasal polyps (EGFR-positive and EGFR-negative, middle and lower panels ). In the epithelium of EGFR-positive control subjects (upper panels) , the MUC5AC antibody stained few goblet cells (insert, arrows) . EGFR gene and EGFR protein expression was weak; no EGFR expression was seen in the basal epithelium. In the epithelium of EGFR-positive polyps (middle panels) , MUC5AC staining was greater than in control epithelium. Some goblet cells were seen secreting (insert, arrows) , suggesting active goblet cell degranulation. EGFR gene and EGFR protein expression was strong and concentrated in the basal epithelium. In the epithelium of EGFR-unstained polyps (lower panels) , the MUC5AC-stained goblet cell area was larger than in EGFR-positive polyps and extended throughout the elongated cells (arrows) . EGFR in situ hybridization showed little expression (insert, arrows ; bar = 50 μm; original picture magnification, 200×; inserts, same area, 1000×). Journal of Allergy and Clinical Immunology 2000 106, 705-712DOI: (10.1067/mai.2000.109823) Copyright © 2000 Mosby, Inc. Terms and Conditions

Fig. 4 TNF-α immunolocalization in nasal polyps. After staining with a polyclonal antibody to TNF-α, both EGFR-positive and EGFR-negative tissues showed immunoreactivity in stromal inflammatory cells. However, EGFR-positive polyps contained more cells expressing TNF-α immunoreactivity than EGFR-negative polyps (P = .02). Among the cells that showed immunoreactivity, eosinophils (arrows) with characteristic bilobed nuclei were the most common cells (bar , 50 μm; original picture magnification, 200×; inserts, 1000×). Journal of Allergy and Clinical Immunology 2000 106, 705-712DOI: (10.1067/mai.2000.109823) Copyright © 2000 Mosby, Inc. Terms and Conditions

Fig. 5 Comparison of MUC5AC- and EGFR-stained areas in pseudostratified and hyperplastic epithelium in polyps. In EGFR-stained polyps (n = 4) hyperplastic epithelium contained a greater area of MUC5AC-stained cells (upper columns , *P < .05) and a greater area of EGFR-stained cells (lower columns , †P < .05) than in pseudostratified epithelium. Results are expressed as mean percentage stained areas ± SEM. Journal of Allergy and Clinical Immunology 2000 106, 705-712DOI: (10.1067/mai.2000.109823) Copyright © 2000 Mosby, Inc. Terms and Conditions

Fig. 6 Percentage of MUC5AC-stained area of epithelium (upper) and neutrophil infiltration (lower) in EGFR-positive (left) and EGFR-unstained (right) polyps. Surprisingly, the EGFR-unstained polyps contained greater areas of epithelial MUC5AC staining (upper panel, right) than polyps with EGFR staining (upper panel, left , *P < .05). Neutrophils (lower panel) assessed by elastase-stained (filled circles) and CD16-stained (filled squares) cells were more concentrated in the epithelium of EGFR-positive polyps (n = 4) than in the epithelium of EGFR-unstained polyps (n = 4, P < .05). Data are reported as the number of positive cells per 0.25 mm of basal lamina. Journal of Allergy and Clinical Immunology 2000 106, 705-712DOI: (10.1067/mai.2000.109823) Copyright © 2000 Mosby, Inc. Terms and Conditions

Fig. 7 Hypothetical mechanism for goblet cell production in nasal polyps. 1, Eosinophils (EOS) , on recruitment and activation, release TNF-α, which induces EGFR expression in epithelial basal cells. 2, Neutrophils, on recruitment and activation, cause EGFR tyrosine kinase phosphorylation (eg, transphosphorylation by oxygen-free radicals). EGFR activation may also occur by the release of EGFR ligands (autophosphorylation) by various cells. 3, Activation of the EGFR cascade results in mucin synthesis and storage. 4, When the inflammatory process resolves, EGFR downregulation occurs. The goblet cells become quiescent (resting cells). 5, Subsequent inflammation induces the recruitment of inflammatory cells to the epithelium. Activated neutrophils may release elastase, which causes goblet cell degranulation. 6, After neutrophil-induced goblet cell degranulation, regranulation may occur through the same mechanism. Journal of Allergy and Clinical Immunology 2000 106, 705-712DOI: (10.1067/mai.2000.109823) Copyright © 2000 Mosby, Inc. Terms and Conditions