胃蛋白酶与咽喉反流性疾病:从致病机制到咽喉鳞状细胞癌的潜在风险因素

doi:10.6040/j.issn.1673-3770.0.2023.343

Abstract

Abstract: Laryngopharyngeal reflux disease(LPRD)is an inflammatory disease of the tissues of the upper aerodigestive tract caused by the direct or indirect action of reflux of gastroduodenal contents, with pepsin as the main causative agent. Numerous studies have shown a strong association between laryngeal reflux and squamous cell carcinoma of the pharynx and larynx. Nonetheless, the ongoing debate as to whether laryngeal reflux is a risk factor for laryngeal squamous cell carcinoma remains inconclusive. Pepsin, the main pathogenic factor of LPRD, has been shown to play a crucial role in the oncogenesis of squamous cell carcinoma of the pharynx and larynx. Possible mechanisms include damage to the epithelium of the pharyngeal and laryngeal mucosa, disruption of the epithelial defense barrier, induction of inflammation, and alterations in genes and miRNA. This article provides a comprehensive review of the role and mechanism of LPRD, with a special focus on pepsin, in terms of pathogenic mechanisms and potential risk factors for pharyngeal and laryngeal squamous cell carcinoma, with the aim of facilitating the explanation of oncogenesis and inspiring innovative therapeutic approaches in this disease.

Key words: Laryngopharyngeal reflux, Pepsin, Squamous cell carcinoma, Mucosal injury, Pathogenesis

CLC Number:

R767.6

ZHOU Shitong, YANG Yanyan, YANG Yucheng, FANG Hongyan. Pepsin and laryngopharyngeal reflux disease: from pathogenic mechanisms to potential risk factors for pharyngeal and laryngeal squamous cell carcinoma[J].Journal of Otolaryngology and Ophthalmology of Shandong University, 2024, 38(6): 55-60.

References

[1] 中华耳鼻咽喉头颈外科杂志编辑委员会咽喉组,中华医学会耳鼻咽喉头颈外科学分会咽喉学组,中华医学会耳鼻咽喉头颈外科学分会嗓音学组.咽喉反流性疾病诊断与治疗专家共识(2022年,修订版)[J].中华耳鼻咽喉头颈外科杂志, 2022, 57(10): 1149-1172. doi:10.3760/cma.j.cn115330-20220711-00428 Subspecialty Group of Laryngopharyngology,Editorial Board of Chinese Journal of Otorhinolaryngology Head and Neck Surgery; Subspecialty Group of Laryngopharyngology,Society of Otorhinolaryngology Head and Neck Surgery,Chinese Medical Association;Subspecialty Group of Voice,Society of Otorhinolaryngology Head and Neck Surgery,Chinese Medical Association. Experts consensus on diagnosis and treatment of laryngopharyngeal reflux disease(2022,revision)[J]. Chinese Journal of Otorhinolaryngology Head and Neck Surgery, 2022, 57(10): 1149-1172. doi:10.3760/cma.j.cn115330-20220711-00428
[2] Lechien JR, Akst LM, Hamdan AL, et al. Evaluation and management of laryngopharyngeal reflux disease: state of the art review[J]. Otolaryngol Head Neck Surg, 2019, 160(5): 762-782. doi:10.1177/0194599819827488
[3] 曾宪廷,王广科,孙占伟,等. 伴咽喉反流的难治性鼻窦炎术后应用质子泵抑制剂的疗效观察[J]. 山东大学耳鼻喉眼学报, 2022, 36(3): 189-194. doi:10.6040/j.issn.1673-3770.0.2021.512 ZENG Xianting, WANG Guangke, SUN Zhanwei, et al. Postoperative efficacy of proton pump inhibitor in the treatment of difficult-to-treat rhinosinusitis with laryngopharyngeal reflux[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2022, 36(3): 189-194. doi:10.6040/j.issn.1673-3770.0.2021.512
[4] Barsouk A, Aluru JS, Rawla P, et al. Epidemiology, risk factors, and prevention of head and neck squamous cell carcinoma[J]. Med Sci(Basel), 2023, 11(2): 42. doi: 10.3390/medsci11020042
[5] Du E, Mazul AL, Farquhar D, et al. Long-term survival in head and neck cancer: impact of site, stage, smoking, and human papillomavirus status[J]. Laryngoscope, 2019, 129(11): 2506-2513. doi:10.1002/lary.27807
[6] Wang SM, Freedman ND, Katki HA, et al. Gastroesophageal reflux disease: a risk factor for laryngeal squamous cell carcinoma and esophageal squamous cell carcinoma in the NIH-AARP diet and health study cohort[J]. Cancer, 2021, 127(11): 1871-1879. doi: 10.1002/cncr.33427
[7] Parsel Sean M,Iarocci Andrew L,Gasta?aduy Mariella et al. Reflux Disease and Laryngeal Neoplasia in Nonsmokers and Nondrinkers.[J].Otolaryngol Head Neck Surg, 2020, 163: 560-562.doi:10.1177/0194599820917669
[8] Krause AJ, Walsh EH, Weissbrod PA, et al. An update on current treatment strategies for laryngopharyngeal reflux symptoms[J]. Ann N Y Acad Sci, 2022, 1510(1): 5-17. doi:10.1111/nyas.14728
[9] Mishra P, Agrawal D, Chauhan K, et al. Prevalence of laryngopharyngeal reflux disease in Indian population[J]. Indian J Otolaryngol Head Neck Surg, 2022,74(2):1877-1881. doi:10.1007/s12070-020-01882-1
[10] Salihefendic N, Zildzic M, Cabric E. Laryngopharyngeal reflux disease-LPRD[J]. Med Arch, 2017, 71(3): 215-218. doi:10.5455/medarh.2017.71:215-218
[11] Kanemitsu Y, Kurokawa R, Takeda N, et al. Clinical impact of gastroesophageal reflux disease in patients with subacute/chronic cough[J]. Allergol Int, 2019, 68(4): 478-485. doi:10.1016/j.alit.2019.04.011
[12] 邵娜, 张青青, 刘小红, 等. 幽门螺旋杆菌感染对症状性咽喉反流患者唾液胃蛋白酶浓度的影响[J]. 山东大学耳鼻喉眼学报, 2022, 36(6): 89-95. doi:10.6040/j.issn.1673-3770.0.2022.350 SHAO Na, ZHANG Qingqing, LIU Xiaohong, et al. Effects of Helicobacter pylori infection on salivary pepsin concentration in patients with symptomatic laryn-gopharyngeal reflux[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2022, 36(6): 89-95. doi:10.6040/j.issn.1673-3770.0.2022.350
[13] 李超凡, 张立红, 王文伦, 等. 耳鼻咽喉科门诊患者咽喉反流性疾病、焦虑抑郁患病率及二者关系[J]. 中华耳鼻咽喉头颈外科杂志, 2020, 55(3): 241-248. doi:10.3760/cma.j.issn.1673-0860.2020.03.010 LI Chaofan, ZHANG Lihong, WANG Wenlun, et al. The prevalence and relationship between laryngopharyngeal reflux disease, anxiety and depression in otolaryngology outpatients[J]. Chinese Journal of Otorhinolaryngology Head and Neck Surgery, 2020, 55(3): 241-248. doi:10.3760/cma.j.issn.1673-0860.2020.03.010
[14] 崔小缓, 张延平, 阎小妍, 等. 耳鼻咽喉科门诊成年患者的睡眠状况与咽喉反流性疾病的相关性[J]. 中华耳鼻咽喉头颈外科杂志, 2019, 54(10): 754-759. doi:10.3760/cma.j.issn.1673-0860.2019.10.009 CUI Xiaohuan, ZHANG Yanping, YAN Xiaoyan, et al. Relationship between sleep status and laryngopharyngeal reflux disease in adult patients in otolaryngology clinic[J]. Chinese Journal of Otorhinolaryngology Head and Neck Surgery, 2019, 54(10): 754-759. doi:10.3760/cma.j.issn.1673-0860.2019.10.009
[15] 张晨彬, 李木, 张延平, 等. 慢性睡眠剥夺和高脂饮食与咽喉反流性疾病相关性的实验研究[J]. 听力学及言语疾病杂志, 2018, 26(1): 68-72. doi:10.3969/j.issn.1006-7299.2018.01.018 ZHANG Chenbin, LI Mu, ZHANG Yanping, et al. Upper gastrointestinal tract pH monitoring in rats with chronic sleep deprivation and high fat diet[J]. Journal of Audiology and Speech Pathology, 2018, 26(1): 68-72. doi:10.3969/j.issn.1006-7299.2018.01.018
[16] Gtari W, Bey H, Aschi A, et al. Impact of macromolecular crowding on structure and properties of pepsin and trypsin[J]. Mater Sci Eng C Mater Biol Appl, 2017, 72: 98-105. doi:10.1016/j.msec.2016.11.046
[17] Bardhan KD, Strugala V, Dettmar PW. Reflux revisited: advancing the role of pepsin[J]. Int J Otolaryngol, 2012: 646901. doi: 10.1155/2012/646901
[18] Tamhankar AP, Peters JH, Portale G, et al. Omeprazole does not reduce gastroesophageal reflux: new insights using multichannel intraluminal impedance technology[J]. J Gastrointest Surg, 2004, 8(7): 890-898. doi: 10.1016/j.gassur.2004.08.001
[19] Wang L, Liu X, Liu YL, et al. Correlation of pepsin-measured laryngopharyngeal reflux disease with symptoms and signs[J]. Otolaryngol Head Neck Surg, 2010, 143(6):765-771. doi: 10.1016/j.otohns.2010.08.018
[20] Pizzorni N, Ambrogi F, Eplite A, et al. Magnesium alginate versus proton pump inhibitors for the treatment of laryngopharyngeal reflux: a non-inferiority randomized controlled trial[J]. Eur Arch Otorhinolaryngol, 2022, 279(5): 2533-2542. doi:10.1007/s00405-021-07219-0
[21] Eells AC, MacKintosh C, Marks L, et al. Gastroesophageal reflux disease and head and neck cancers: a systematic review and meta-analysis[J]. Am J Otolaryngol, 2020, 41(6): 102653. doi:10.1016/j.amjoto.2020.102653
[22] Blaine-Sauer S, Samuels TL, Yan K, et al. The protease inhibitor amprenavir protects against pepsin-induced esophageal epithelial barrier disruption and cancer-associated changes[J]. Int J Mol Sci, 2023, 24(7): 6765. doi: 10.3390/ijms24076765
[23] Calvo-Henríquez C, Ruano-Ravina A, Vaamonde P, et al. Is pepsin a reliable marker of laryngopharyngeal reflux? A systematic review[J]. Otolaryngol Head Neck Surg, 2017, 157(3): 385-391. doi:10.1177/0194599817709430
[24] Katzka DA, Kahrilas PJ. Advances in the diagnosis and management of gastroesophageal reflux disease[J]. BMJ, 2020, 371: m3786. doi:10.1136/bmj.m3786
[25] Bevilacqua LA, Obeid NR, Yang J, et al. Incidence of GERD, esophagitis, Barrett’s esophagus, and esophageal adenocarcinoma after bariatric surgery[J]. Surg Obes Relat Dis, 2020, 16(11): 1828-1836. doi:10.1016/j.soard.2020.06.016
[26] Gong X, Wang XY, Yang L, et al. Detecting laryngopharyngeal reflux by immunohistochemistry of pepsin in the biopsies of vocal fold leukoplakia[J]. J Voice, 2018, 32(3): 352-355. doi:10.1016/j.jvoice.2017.06.010
[27] Sezen Goktas S, Dogan R, Yenigun A, et al. A new approach to vocal cord leukoplakia and evaluation of proton pump ınhibitor treatment[J]. Eur Arch Otorhinolaryngol, 2019, 276(2): 467-471. doi:10.1007/s00405-018-05273-9
[28] Parsel SM, Wu EL, Riley CA, et al. Gastroesophageal and laryngopharyngeal reflux AssociatedWith laryngeal malignancy: a systematic reviewand meta-analysis[J]. Clin Gastroenterol Hepatol, 2019, 17(7): 1253-1264. doi:10.1016/j.cgh.2018.10.028
[29] Yin CY, Zhang SS, Zhong JT, et al. Pepsin and laryngeal and hypopharyngeal carcinomas[J]. Clin Exp Otorhinolaryngol, 2021, 14(2): 159-168. doi:10.21053/ceo.2020.00465
[30] Lagergren J, Lindam A. Increased risk of laryngeal and pharyngeal cancer after gastrectomy for ulcer disease in a population-based cohort study[J]. Br J Cancer, 2012, 106(7): 1342-1345. doi:10.1038/bjc.2012.72
[31] 谭嘉杰, 王路, 黄祚峰, 等. 胃蛋白酶在喉癌组织中的表达和意义[J]. 中华耳鼻咽喉头颈外科杂志, 2016, 51(8): 593-599. doi:10.3760/cma.j.issn.1673-0860.2016.08.007 TAN Jiajie, WANG Lu, HUANG Zuofeng, et al. The expression and significance of pepsin in laryngeal carcinoma[J]. Chinese Journal of Otorhinolaryngology Head and Neck Surgery, 2016, 51(8): 593-599. doi:10.3760/cma.j.issn.1673-0860.2016.08.007
[32] Niu K, Guo CJ, Teng SY, et al. Pepsin promotes laryngopharyngeal neoplasia by modulating signaling pathways to induce cell proliferation[J]. PLoS One, 2020, 15(1): e0227408. doi:10.1371/journal.pone.0227408
[33] Johnston N, Dettmar PW, Lively MO, et al. Effect of pepsin on laryngeal stress protein(Sep70, Sep53, and Hsp70)response: role in laryngopharyngeal reflux disease[J]. Ann Otol Rhinol Laryngol, 2006, 115(1): 47-58. doi:10.1177/000348940611500108
[34] Ali MELS, Bulmer DM, Dettmar PW, et al. Mucin gene expression in reflux laryngeal mucosa: histological and in situ hybridization observations[J]. Int J Otolaryngol, 2014, 2014: 264075. doi:10.1155/2014/264075
[35] Johnston N, Wells CW, Samuels TL, et al. Pepsin in nonacidic refluxate can damage hypopharyngeal epithelial cells[J]. Ann Otol Rhinol Laryngol, 2009, 118(9): 677-685. doi:10.1177/000348940911800913
[36] Komatsu Y, Kelly LA, Zaidi AH, et al. Hypopharyngeal pepsin and Sep70 as diagnostic markers of laryngopharyngeal reflux: preliminary study[J]. Surg Endosc, 2015, 29(5): 1080-1087. doi:10.1007/s00464-014-3789-y
[37] Chaudhari M, Jayaraj R, Bhaskar AS, et al. Oxidative stress induction by T-2 toxin causes DNA damage and triggers apoptosis via caspase pathway in human cervical cancer cells[J]. Toxicology, 2009, 262(2): 153-161. doi:10.1016/j.tox.2009.06.002
[38] Samuels TL, Johnston N. Pepsin as a causal agent of inflammation during nonacidic reflux[J]. Otolaryngol Head Neck Surg, 2009, 141(5): 559-563. doi:10.1016/j.otohns.2009.08.022
[39] Sandner A, Illert J, Koitzsch S, et al. Reflux induces DNA strand breaks and expression changes of MMP1+9+14 in a human miniorgan culture model[J]. Exp Cell Res, 2013, 319(19): 2905-2915. doi:10.1016/j.yexcr.2013.09.004
[40] Sasaki CT, Toman J, Vageli D. The in vitro effect of acidic-pepsin on nuclear factor KappaB activation and its related oncogenic effect on normal human hypopharyngeal cells[J]. PLoS One, 2016, 11(12): e0168269. doi:10.1371/journal.pone.0168269
[41] 刘倩, 吕颜露. 咽喉反流通过NF-κB信号通路介导炎症反应对声带黏膜的影响[J]. 华中科技大学学报(医学版), 2019, 48(1): 32-37. doi:10.3870/j.issn.1672-0741.2019.01.006 LIU Qian, LV Yanlu. Effect of laryngopharyngeal reflux on vocal cord mucosa via inflammatory response mediated by NF-κB signaling pathway[J]. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong, 2019, 48(1): 32-37. doi:10.3870/j.issn.1672-0741.2019.01.006
[42] Kunze B, Wein F, Fang HY, et al. Notch signaling mediates differentiation in barrett’s esophagus and promotes progression to adenocarcinoma[J]. Gastroenterology, 2020, 159(2): 575-590. doi:10.1053/j.gastro.2020.04.033
[43] Doukas PG, Vageli DP, Sasaki CT, et al. Pepsin promotes activation of epidermal growth factor receptor and downstream oncogenic pathways, at slightly acidic and neutral pH, in exposed hypopharyngeal cells[J]. Int J Mol Sci, 2021, 22(8): 4275. doi:10.3390/ijms22084275
[44] Adams J, Heintz P, Gross N, et al. Acid/pepsin promotion of carcinogenesis in the hamster cheek pouch[J]. Arch Otolaryngol Head Neck Surg, 2000, 126(3): 405-409. doi:10.1001/archotol.126.3.405
[45] Johnston N, Yan JC, Hoekzema CR, et al. Pepsin promotes proliferation of laryngeal and pharyngeal epithelial cells[J]. Laryngoscope, 2012, 122(6): 1317-1325. doi:10.1002/lary.23307
[46] Tan JJ, Wang L, Mo TT, et al. Pepsin promotes IL-8 signaling-induced epithelial-mesenchymal transition in laryngeal carcinoma[J]. Cancer Cell Int, 2019, 19: 64. doi:10.1186/s12935-019-0772-7
[47] Choudhary MM, France TJ, Teknos TN, et al. Interleukin-6 role in head and neck squamous cell carcinoma progression[J]. World J Otorhinolaryngol Head Neck Surg, 2016, 2(2): 90-97. doi:10.1016/j.wjorl.2016.05.002
[48] Rébé C, Ghiringhelli F. Interleukin-1β and cancer[J]. Cancers, 2020, 12(7): 1791. doi:10.3390/cancers12071791
[49] Wood JM, Hussey DJ, Woods CM, et al. Does gene expression in laryngeal subsites differ between patients with laryngopharyngeal reflux and controls?[J]. Clin Otolaryngol, 2018, 43(1): 158-163. doi:10.1111/coa.12918
[50] Zhang F, Cao H. MicroRNA-143-3p suppresses cell growth and invasion in laryngeal squamous cell carcinoma via targeting the k-Ras/Raf/MEK/ERK signaling pathway[J]. Int J Oncol, 2019, 54(2): 689-701. doi:10.3892/ijo.2018.4655

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Pepsin and laryngopharyngeal reflux disease: from pathogenic mechanisms to potential risk factors for pharyngeal and laryngeal squamous cell carcinoma

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