Laboratory research of cough reflex utilizes almost exclusively male guinea pigs - a practice that represents a significant obstacle in the successful translation of results into clinical practice. Chronic hypersensitivity cough syndrome affects mostly postmenopausal women and it represents significant decrease in patient's quality of life. No cause for such exaggerated cough can be found, therefore this condition cannot be treated appropriately. One of the reasons leading to the lack of relevant data about mechanisms responsible for hypersensitivity of cough related pathways is nowadays widely discussed gender bias, which is present in nearly all branches of biomedical research. Since gender differences in cough reflex physiology do exist in humans, it would be reasonable to study cough-related phenomena on both sexes of laboratory animals. In this study, we focused on detailed characterization of cough response of female guinea pigs to aerosols of commonly used tussive agents (capsaicin, distilled water, allyl isothiocyanate, cinnamaldehyde, citric acid). In pooled data from multiple challenges we found no statistical difference in number of cough and cough latency between sexes. Based on our results we conclude that the utilization of female guinea pigs model does not lead to messy data and can be used in basic cough research.

Department of Pathophysiology Jessenius Faculty of Medicine Comenius University in Bratislava Martin Slovak

Zobrazit více v PubMed

ARNOLD AP. The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues. Horm Behav. 2009;55:570–578. doi: 10.1016/j.yhbeh.2009.03.011. PubMed DOI PMC

ARTERO-MORALES M, GONZÁLEZ-RODRÍGUEZ S, FERRER-MONTIEL A. TRP channels as potential targets for sex-related differences in migraine pain. Front Mol Biosci. 2018;5:73. doi: 10.3389/fmolb.2018.00073. PubMed DOI PMC

BEERY AK, ZUCKER I. Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev. 2011;35:565–572. doi: 10.1016/j.neubiorev.2010.07.002. PubMed DOI PMC

BELVISI MG. Sensory nerves and airway inflammation: role of A delta and C-fibers. Pulm Pharmacol Ther. 2003;16:1–7. doi: 10.1016/S1094-5539(02)00180-3. PubMed DOI

BELVISI MG, BOLSER DC. Summary: animal models for cough. Pulm Pharmacol Ther. 2002;15:249–250. doi: 10.1006/pupt.2002.0349. PubMed DOI

BELVISI MG, BONVINI SJ, GRACE MS, CHING Y-M, DUBUIS E, ADCOCK JJ, BIRRELL MA. American Thoracic Society International Conference Abstracts. American Thoracic Society; 2013. Activation of airway sensory nerves: a key role for the TRPV4 channel. D19. What’s Going on? Mechanisms of Remodeling and Hyperresponsiveness; p. A5265.

BOLSER DC, POLIACEK I, JAKUS J, FULLER DD, DAVENPORT PW. Neurogenesis of cough, other airway defensive behaviors and breathing: A holarchical system? Respir Physiol Neurobiol. 2006;152:255–265. doi: 10.1016/j.resp.2006.01.008. PubMed DOI PMC

BROZMANOVA M, CALKOVSKY V, PLEVKOVA J, BARTOS V, PLANK L, TATAR M. Early and late allergic phase related cough response in sensitized guinea pigs with experimental allergic rhinitis. Physiol Res. 2006;55:577–584. PubMed

BROZMANOVA M, MAZUROVA L, RU F, TATAR M, KOLLARIK M. Comparison of TRPA1-versus TRPV1-mediated cough in guinea pigs. Eur J Pharmacol. 2012;689:211–218. doi: 10.1016/j.ejphar.2012.05.048. PubMed DOI PMC

BROZMANOVA M, MAZUROVA L, TATAR M, KOLLARIK M. Evaluation of the effect of GABA(B) agonists on the vagal nodose C-fibers in the esophagus. Physiol Res. 2013;62:285–295. PubMed

CAHILL L. Why sex matters for neuroscience. Nat Rev Neurosci. 2006;7:477–484. doi: 10.1038/nrn1909. PubMed DOI

CANNING BJ. The cough reflex in animals: relevance to human cough research. Lung. 2008;186(Suppl 1):S23–S28. doi: 10.1007/s00408-007-9054-6. PubMed DOI PMC

CANNING BJ, MORI N. Encoding of the cough reflex in anesthetized guinea pigs. Am J Physiol Regul Integr Comp Physiol. 2011;300:R369–R377. doi: 10.1152/ajpregu.00044.2010. PubMed DOI PMC

CHEN Z, CHEN H, CHEN F, GU D, SUN L, ZHANG W, FAN L, LIN Y, DONG R, LAI K. Vagotomy decreases the neuronal activities of medulla oblongata and alleviates neurogenic inflammation of airways induced by repeated intra-esophageal instillation of HCl in guinea pigs. Physiol Res. 2017;66:1021–1028. doi: 10.33549/physiolres.933574. PubMed DOI

DEMOULIN-ALEXIKOVA S, PLEVKOVA J, MAZUROVA L, ZATKO T, ALEXIK M, HANACEK J, TATAR M. Impact of air pollution on age and gender related increase in cough reflex sensitivity of healthy children in Slovakia. Front Physiol. 2016;7:54. doi: 10.3389/fphys.2016.00054. PubMed DOI PMC

DICPINIGAITIS PV, RAUF K. The influence of gender on cough reflex sensitivity. Chest. 1998;113:1319–1321. doi: 10.1378/chest.113.5.1319. PubMed DOI

EBIHARA T, SEKIZAWA K, OHRUI T, NAKAZAWA H, SASAKI H. Angiotensin-converting enzyme inhibitor and danazol increase sensitivity of cough reflex in female guinea pigs. Am J Respir Crit Care Med. 1996;153:812–819. doi: 10.1164/ajrccm.153.2.8564137. PubMed DOI

ESCAMILLA R, ROCHE N. Cough hypersensitivity syndrome: towards a new approach to chronic cough. Eur Respir J. 2014;44:1103–1106. doi: 10.1183/09031936.00150614. PubMed DOI

FORSBERG K, KARLSSON JA, THEODORSSON E, LUNDBERG JM, PERSSON CG. Cough and bronchoconstriction mediated by capsaicin-sensitive sensory neurons in the guinea-pig. Pulm Pharmacol. 1988;1:33–39. doi: 10.1016/0952-0600(88)90008-7. PubMed DOI

GOY RW, McEWEN BS and Neurosciences Research Program. Sexual differentiation of the brain: based on a work session of the Neurosciences Research Program. MIT Press; Cambridge, Mass: 1980.

HENDRICH J, ALVAREZ P, JOSEPH EK, FERRARI LF, CHEN X, LEVINE JD. In vivo and in vitro comparison of female and male nociceptors. J Pain. 2012;13:1224–1231. doi: 10.1016/j.jpain.2012.09.009. PubMed DOI PMC

HOTHORN T, BRETZ F, WESTFALL P. Simultaneous inference in general parametric models. Biom J. 2008;50:346–363. doi: 10.1002/bimj.200810425. PubMed DOI

ITO N, SHIOYA T, WATANABE A, SANO M, SASAKI M, MIURA M. Mechanism of the antitussive effect of azelastine in guinea pigs. Arzneimittelforschung. 2002;52:441–447. doi: 10.1055/s-0031-1299912. PubMed DOI

JI Z, WANG Z, CHEN Z, JIN H, CHEN C, CHAI S, LV H, YANG L, HU Y, DONG R, LAI K. Melatonin attenuates chronic cough mediated by oxidative stress via transient receptor potential melastatin-2 in guinea pigs exposed to particulate matter 2.5. Physiol Res. 2018;67:293–305. doi: 10.33549/physiolres.933654. PubMed DOI

KASTELIK JA, THOMPSON RH, AZIZ I, OJOO JC, REDINGTON AE, MORICE AH. Sex-related differences in cough reflex sensitivity in patients with chronic cough. Am J Respir Crit Care Med. 2002;166:961–964. doi: 10.1164/rccm.2109061. PubMed DOI

KAVALCIKOVA-BOGDANOVA N, KOVACIKOVA L, BUDAY T, BIRINGER K, SIVAKOVA J, CALKOVSKY V, ANTOSOVA M, PLEVKOVA J. Sensitivity of airway cough-related afferents is influenced by female sex hormones. Respir Physiol Neurobiol. 2018;257:12–17. doi: 10.1016/j.resp.2018.01.006. PubMed DOI

KORPAS J, TOMORI Z. Cough and Other Respiratory Reflexes. Karger; Basel: 1979.

KUBA T, WU H-BK, NAZARIAN A, FESTA ED, BARR GA, JENAB S, INTURRISI CE, QUINONES-JENAB V. Estradiol and progesterone differentially regulate formalin-induced nociception in ovariectomized female rats. Horm Behav. 2006;49:441–449. doi: 10.1016/j.yhbeh.2005.09.007. PubMed DOI

MAZZONE SB, McGOVERN AE, YANG S-K, WOO A, PHIPPS S, ANDO A, LEECH J, FARRELL MJ. Sensorimotor circuitry involved in the higher brain control of coughing. Cough. 2013;9:7. doi: 10.1186/1745-9974-9-7. PubMed DOI PMC

MORICE AH. Chronic cough hypersensitivity syndrome. Cough. 2013;9:14. doi: 10.1186/1745-9974-9-14. PubMed DOI PMC

MORICE AH, JAKES AD, FARUQI S, BIRRING SS, McGARVEY L, CANNING B, SMITH JA, PARKER SM, CHUNG KF, LAI K, PAVORD ID, van den BERG J, SONG W-J, MILLQVIST E, FARRELL MJ, MAZZONE SB, DICPINIGAITIS P CHRONIC COUGH REGISTRY. A worldwide survey of chronic cough: a manifestation of enhanced somatosensory response. Eur Respir J. 2014;44:1149–1155. doi: 10.1183/09031936.00217813. PubMed DOI

PECOVA R, JAVORKOVA N, KUDLICKA J, TATAR M. Tussigenic agents in the measurement of cough reflex sensitivity. J Physiol Pharmacol. 2007;58(Suppl 5):531–538. PubMed

PENG H-Y, HUANG P-C, LIAO J-M, TUNG K-C, LEE S-D, CHENG C-L, SHYU J-C, LAI C-Y, CHEN G-D, LIN T-B. Estrous cycle variation of TRPV1-mediated cross-organ sensitization between uterus and NMDA-dependent pelvic-urethra reflex activity. Am J Physiol Endocrinol Metab. 2008;295:E559–568. doi: 10.1152/ajpendo.90289.2008. PubMed DOI

PINHEIRO J, BATES D, DEBROY S, SARKAR D R CORE TEAM. NLME: Linear and nonlinear mixed effects models. R package version 3.1–137. 2018

PLEVKOVA J, BUDAY T, KAVALCIKOVA BOGDANOVA N, KOVACIKOVA L, RUZINAK R. Role of gender in basic cough research. Respir Physiol Neurobiol. 2017;245:53–56. doi: 10.1016/j.resp.2016.12.006. PubMed DOI

R CORE TEAM. R: A language and environment for statistical computing. R Foundation for Statistical Computing; Vienna, Austria: 2018. https://www.r-project.org/

ROORDA RJ, GERRITSEN J, VAN AALDEREN WM, SCHOUTEN JP, VELTMAN JC, WEISS ST, KNOL K. Risk factors for the persistence of respiratory symptoms in childhood asthma. Am Rev Respir Dis. 1993;148:1490–1495. doi: 10.1164/ajrccm/148.6_Pt_1.1490. PubMed DOI

SHANSKY RM. Are hormones a “female problem” for animal research? Science. 2019;364:825–826. doi: 10.1126/science.aaw7570. PubMed DOI

SONG W-J, CHANG Y-S, FARUQI S, KIM J-Y, KANG M-G, KIM S, JO E-J, KIM M-H, PLEVKOVA J, PARK H-W, CHO S-H, MORICE AH. The global epidemiology of chronic cough in adults: a systematic review and meta-analysis. Eur Respir J. 2015;45:1479–1481. doi: 10.1183/09031936.00218714. PubMed DOI

VARECHOVA S, PLEVKOVA J, HANACEK J, TATAR M. Role of gender and pubertal stage on cough sensitivity in childhood and adolescence. J Physiol Pharmacol. 2008;59(Suppl 6):719–726. PubMed

VODO S, ARCELLI D, FIORENZANI P, MERIGGIOLA MC, BUTKEVICH I, DI CANIO C, MIKHAILENKO V, ALOISI AM. Gonadal ERα/β, AR and TRPV1 gene expression: Modulation by pain and morphine treatment in male and female rats. Physiol Behav. 2013;110–111:80–86. doi: 10.1016/j.physbeh.2012.12.014. PubMed DOI

Methods of Cough Assessment and Objectivization

Various aspects of sex and gender bias in biomedical research

Legacy of Prof. Juraj Korpáš: International Impact of Slovak School of Experimental Respirology