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Increased Pulmonary Neuroendocrine Cells with Bombesin-Like Immunoreactivity in Adult Patients with Eosinophilic Granuloma

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Increased Pulmonary Neuroendocrine Cells with Bombesin-Like Immunoreactivity in Adult Patients with Eosinophilic Granuloma Increased pulmonary neuroendocrine cells with bombesin-like immunoreactivity in adult patients with eosinophilic granuloma. S M Aguayo, … , M A Kane, Y E Miller J Clin Invest. 1990;86(3):838-844. https://doi.org/10.1172/JCI114782. Research Article Cigarette smoking is associated with hyperplasia of pulmonary neuroendocrine cells and variably increased levels of bombesin-like peptides in the lower respiratory tract. Because the neuropeptide bombesin is a chemoattractant for monocytes and a mitogen for 3T3 fibroblasts, we hypothesized that an excess of neuroendocrine cells and bombesin-like peptides could contribute to lung inflammation and fibrosis in certain cigarette smokers. Eosinophilic granuloma is a fibrotic lung disease of unknown etiology that in adults occurs almost invariably in cigarette smokers. We quantitated neuroendocrine cells with bombesin-like immunoreactivity in open lung biopsies from patients with eosinophilic granuloma (n = 6) and compared these with cigarette smokers (n = 6) who underwent lung resection for reasons other than primary lung disease. In addition, we compared them with patients with idiopathic pulmonary fibrosis (n = 8), a disease not associated with cigarette smoking. Finally, we also examined the mitogenic effect of bombesin on cultured human adult lung fibroblasts. The patients with eosinophilic granuloma exhibited a 10-fold increase in neuroendocrine cells with bombesin-like immunoreactivity compared to both smokers (P = 0.005) and patients with idiopathic pulmonary fibrosis (P = 0.005). In addition, bombesin produced a significant mitogenic effect on cultured human adult lung fibroblasts at concentrations of 1 nM and above. We conclude that increased numbers of pulmonary neuroendocrine cells with bombesin-like immunoreactivity are commonly found […] Find the latest version: https://jci.me/114782/pdf Increased Pulmonary Neuroendocrine Cells with Bombesin-like Immunoreactivity in Adult Patients with Eosinophilic Granuloma Samuel M. Aguayo,**1II Talmadge E. King, Jr.,**II James A. Waldron, Jr.,' Karen M. Sherritt,* Madeleine A. Kane,111** and York E. Miller~fll**# *Pulmonary Sciences Division, Department ofMedicine, Veterans Administration Medical Center, Denver, Colorado 80220; WNational Jewish Centerfor Immunology and Respiratory Medicine; 1University ofColorado Cancer Center; 1 University ofColorado Health Sciences Center; 'Veterans Administration Medical Center, University ofArkansas for Medical Sciences; **Medical Oncology Division, Veterans Administration Medical Center; and t$Eleanor Roosevelt Institute for Cancer Research, Denver, Colorado 80220 Abstract Introduction Cigarette smoking is associated with hyperplasia of pulmonary neuroendocrine cells and variably increased levels of bombe- We have reported that cigarette smoking is associated with sin-like peptides in the lower respiratory tract. Because the markedly increased levels of bombesin-like peptides (BLP)' in neuropeptide bombesin is a chemoattractant for monocytes and the lower respiratory tract of some individuals (1). BLP is the a mitogen for 3T3 fibroblasts, we hypothesized that an excess name given to the family of peptides having carboxy-terminal of neuroendocrine cells and bombesin-like peptides could con- homology with the structure of bombesin, a tetradecapeptide tribute to lung inflammation and fibrosis in certain cigarette originally isolated by Erspamer from the skin ofthe amphibian smokers. Bombina bombina (2, 3). These include gastrin-releasing pep- Eosinophilic granuloma is a fibrotic lung disease of un- tide (GRP) and neuromedin B, the only BLP fully character- known etiology that in adults occurs almost invariably in ciga- ized in humans (4). In susceptible subjects, the increased levels rette smokers. We quantitated neuroendocrine cells with bom- of BLP in the lower respiratory tract are presumably due to a besin-like immunoreactivity in open lung biopsies from pa- smoking induced hyperplasia of pulmonary neuroendocrine tients with eosinophilic granuloma (n = 6) and compared these (NE) cells. Such a relationship has been demonstrated in an with cigarette smokers (n = 6) who underwent lung resection animal model by Tabassian and colleagues (5). Furthermore, for reasons other than primary lung disease. In addition, we BLP have been reported to be chemotactic for monocytes (6) compared them with patients with idiopathic pulmonary fi- and mitogenic for 3T3 fibroblasts (7). Thus, we hypothesized brosis (n = 8), a disease not associated with cigarette smoking. that an excess of NE cells and BLP could contribute to lung Finally, we also examined the mitogenic effect of bombesin on inflammation and fibrosis in susceptible cigarette smokers cultured human adult lung fibroblasts. who demonstrate the greatest degree of NE cell hyperplasia. The patients with eosinophilic granuloma exhibited a 10- Eosinophilic granuloma (EG) of the lung, also known as fold increase in neuroendocrine cells with bombesin-like immu- pulmonary histiocytosis X or Langerhans' cell granulomatosis noreactivity compared to both smokers (P = 0.005) and pa- (8-10), is a fibrotic disorder of the lower respiratory tract. tients with idiopathic pulmonary fibrosis (P = 0.005). In addi- Although the pathogenesis of EG is unknown, an abnormal tion, bombesin produced a significant mitogenic effect on accumulation of mononuclear phagocytes and Langerhans' cultured human adult lung fibroblasts at concentrations of I cells is thought to play a major role (1 1). However, the mecha- nM and above. We conclude that increased numbers of pulmo- nisms modulating the increase in the numbers of alveolar mac- nary neuroendocrine cells with bombesin-like immunoreactiv- rophages and Langerhans' cells in the lungs remain to be elu- ity are commonly found in patients with eosinophilic granu- cidated. Interestingly, in adults, EG occurs almost invariably loma and, since bombesin-like peptides are chemotactic for in current or former cigarette smokers (12). This suggests that monocytes and mitogenic for human lung fibroblasts, we spec- cigarette smoke may play an important role in the pathogene- ulate that neuroendocrine cell hyperplasia may be important in sis of EG. the pathogenesis of eosinophilic granuloma in adult cigarette The purpose of this study was to determine whether open smokers. (J. Clin. Invest. 1990. 86:838-844.) Key words: lung biopsies from patients with EG have increased NE cells bombesin-like peptides * growth factors * fibroblasts * histio- with bombesin-like immunoreactivity when compared to nor- mal cigarette smokers who underwent lung resection for rea- cytosis X - cigarette smoking sons other than primary lung disease. In addition, we com- pared the EG patients to patients with idiopathic pulmonary Presented in part at the Annual Meeting of the American Thoracic fibrosis (IPF), a disease in which lung inflammation and fi- Society 20-24 May 1990 (Am. Rev. Respir. Dis. [Abstr.] 141:4 [Suppl. brosis is not associated with cigarette smoking. Finally, we 872]). tested whether bombesin is for human adult K. Sheritt's present address is University of Pennsylvania School of mitogenic lung Medicine, Philadelphia, PA. Address reprint requests to Dr. Samuel fibroblasts, thus providing a potential direct link between pul- M. Aguayo, Respiratory Care (1 1 lA), Denver Veterans Administra- monary NE cells, BLP, and the pathogenesis of EG. tion Medical Center, 1055 Clermont Street, Denver, CO 80220. Received for publication 2 February 1990 and in revised form 11 April 1990. 1. Abbreviations used in this paper: BAL, bronchoalveolar lavage; BLP, bombesin-like peptides; EG, eosinophilic granuloma; GRP, gastrin- The Journal of Clinical Investigation, Inc. releasing peptides; IPF, idiopathic pulmonary fibrosis; NE, neuroendo- Volume 86, September 1990, 838-844 crine. 838 Aguayo, King, Waldron, Sherritt, Kane, Miller Table I. Characteristics ofPatients with Pulmonary Fibrosis Tissue examined NE cells Subject BLP in Airway (per 10 cm of No. Age Smoking history Diagnosis BAL fluid Slides Airways length airway length) yr pk/yr pmol/ml mm 1 22 6 EG 42 7 51 313 98.12 2 30 10 EG 16 5 25 304 36.00 3 32 20 EG 22 5 41 950 195.00 4 29 10 EG 12 11 92 1,280 127.50 5 58 92 EG ND* 7 36 791 18.33 6 31 13 EG 6 7 49 982 20.00 7 67 Never smoked IPF ND* 4 15 146 NDt 8 55 45, stopped 5 yr ago IPF 0.63 6 24 272 3.00 9 43 Never smoked IPF 12 7 31 209 53.00 10 62 9, stopped 18 yrago IPF ND* 5 10 109 NDt 11 72 Never smoked IPF ND* 5 15 120 NDt 12 65 22, stopped 25 yr ago IPF 72 4 5 64 6.30 13 47 66 IPF 18 4 8 68 NDt 14 67 51, stopped 22 yrago IPF 8 5 12 132 4.66 * ND, nondetectable; for statistical purposes, equal 0.2; $ Nondetectable; for statistical purposes, equal 0. Methods in devitalized tissue obtained at necropsy. This control group was composed of five men and one woman with a mean age of40 yr, range, Subjects. Lung tissue samples were obtained by open lung biopsy from 16-68 yr. All were current smokers. patients enrolled in the National Heart, Lung, and Blood Interstitial The IPF control group consisted of eight untreated patients (seven Lung Diseases Specialized Centers of Research program, the Denver men, one woman; mean age of 60 yr; range, 43-72 yr). There were Veterans Administration Medical Center, AMI Presbyterian-St. three never smokers, four former smokers, and only one current Luke's Medical Center, and the University of Colorado Health smoker (Table I). IPF was diagnosed on the basis of a compatible Sciences Center Department of Pathology. The protocol was approved
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