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Key Event Title
Chronic, Mucus hypersecretion
|Level of Biological Organization|
Key Event Components
|mucus secretion||lung goblet cell||increased|
Key Event Overview
AOPs Including This Key Event
Key Event Description
Mucus hypersecretion is a physiological response to inhalation exposures to pollutants or infectious agents. As such, it is typically of short duration and does not pose a major problem to normal lung function. Under chronic stress/exposure conditions, airway remodeling and mucus hypersecretion will cease being a physiological stress response aimed at eliminating the potential hazard and regaining the balance of a healthy airway epithelium, and chronic mucus hypersecretion will ensue. This is the case in many respiratory diseases that feature a chronic inflammatory micoenvironment such as chronic obstructive pulmonary disease and asthma (Evans et al., 2009; Allinson et al., 2016). Recent estimates of chronic mucus hypersecretion in the global population range from 3.5 to 27% (Kim et al. 2011; Martinez et al. 2014; Montes De Oca et al. 2012).
How It Is Measured or Detected
To our knowledge, there is no report regarding the assessment of chronic mucus hypersecretion in vitro. This is most likely related to the fact that many in vitro studies are of short duration, employing acute exposures to mucus-inducing stimuli. However, mucus hypersecretion is a feature of animal models of asthma (Shim et al., 2001; Singer et al., 2004; Song et al., 2016) and occurs in mice and rats following inhalation of e.g. acrolein and cigarette smoke (Deshmukh et al., 2008; Yang et al., 2012; Chen et al., 2013; Vlahos and Bozinovski, 2015; Liu et al., 2017). There appears to be no consensus as to the "chronicity" of mucus hypersecretion, and no standardized measure exists.
Clinically, coughing and sputum production for >3 months in at least two consecutive years is defined as (chronic) mucus hypersecretion (Vestbo, 2002). More recently, questionnaires such as the St George’s Respiratory Questionnaire (Hardin and Rennard, 2015), the COPD Assessment Test (CAT) (Stott-Miller et al., 2020) and the American Thoracic Society Questionnaire (Cassidy et al., 2015) have been employed to evaluate cough and sputum production, and hence mucus hypersecretion. At times, sputum volumes are recorded as measure of mucus production. Current clinical practice, however, does not include a quantitative measure of mucus hypersecretion.
Domain of Applicability
Mucus hypersecretion was described in mice and rats following ovalbumin challenge (Shim et al., 2001; Singer et al., 2004; Song et al., 2016) or exposure to acrolein and cigarette smoke (Deshmukh et al., 2008; Yang et al., 2012; Chen et al., 2013; Vlahos and Bozinovski, 2015; Liu et al., 2017). Chronic mucus hypersecretion is also frequently found in long-term smokers, COPD patients with chronic bronchitis and asthma patients (Danahay and Jackson, 2005).
Evidence for Perturbation by Stressor
Smokers had a higher mucus volume density than non-smokers (27.78 ± 10.24 μL/mm2 vs 3.42 ± 3.07 μL/mm2) (Kim et al., 2015).
A cross-sectional study in twins indicated that smoking was a risk factor for chronic mucus hypersecretion, and there was a dose-response relationship between daily tobacco consumption and prevalence of chronic mucus hypersecretion (Harmsen et al., 2010). A dose-response relationship between chronic mucus hypersecretion and pack-years of smoking was also observed in the Dutch LifeLines cohort study. This study additionally highlighted that exposure to environmental cigarette smoke ("seond-hand smoke") was also associated with the risk of chronic mucus hypersecretion (Dijkstra et al., 2014).
A statistically significant positive association was seen between prevalent chronic bronchitis, defined as chronic cough productive of phlegm for at least 3 months out of a year for a minimum of 2 consecutive years, and PM10 [estimated median exposure concentration: 2.16 μg/m3 (interquartile range: 5.8 μg/m3); odds ratio (OR) per IQR increase in PM10 = 1.07; 95% confidence interval (CI): 1.01, 1.13] and chronic phlegm (OR = 1.07; 95% CI: 1.02, 1.11) in the NIEHS Sister Study (Hooper et al., 2018).
The SAPALDIA study observed that an increase of 10 mg/m3 in PM10 levels was associated with an increase in the prevalence of chronic phlegm, and chronic cough or phlegm. Within the range of 10.1 to 33.4 mg/m3 PM10, the OR for an increase of 10 mg/m3 in the annual mean was 1.35 (CI: 1.11 to 1.65) for chronic phlegm among never-smokers and 1.27(CI: 1.08 to 1.50) for chronic cough or phlegm (Zemp et al., 1999).
Nonsmoking women cooking with wood stoves reported chronic phlegm more frequently than those cooking with gas stoves. The peak indoor concentration of particulate matter (PM10) often exceeded 2 mg/m3 (Regalado et al., 2006).
Nonsmokers who experienced several years of many days per year when PM10 exceeded 80 pg/m3 developed chronic productive cough and overall chronic bronchitis significantly more frequently than those not exposed to PM10 concentrations below this cut-off (Abbey et al., 1998).
At the individual level, self‐reported traffic intensity and home outdoor levels of NO2 (a surrogate of traffic exposure) were associated with frequency of chronic phlegm in females, independent of smoking (Sunyer et al., 2006).
Abbey, D.E., Nishino, N., and McDonnell, W.F. (1998). Development of chronic productive cough as associated with long-term ambient inhalable particulate pollutants (PM10) in nonsmoking adults: the AHSMOG study. Appl. Occup. Environ. Hyg. 13, 444-452.
Allinson, J.P., Hardy, R., Donaldson, G.C., Shaheen, S.O., Kuh, D., and Wedzicha, J.A. (2016). The presence of chronic mucus hypersecretion across adult life in relation to chronic obstructive pulmonary disease development. Am. J. Resp. Crit. Care Med. 193, 662-672.
Cassidy, R.N., Roberts, M.E., and Colby, S.M. (2015). Validation of a Respiratory Symptom Questionnaire in Adolescent Smokers. Tob. Regul. Sci. 1, 121-128.
Chen, P., Deng, Z., Wang, T., Chen, L., Li, J., Feng, Y., et al. (2013). The potential interaction of MARCKS-related peptide and diltiazem on acrolin-induced airway mucus hypersecretion in rats. Intl. Immunopharmacol. 17, 625-632.
Danahay, H., and Jackson, A.D. (2005). Epithelial mucus-hypersecretion and respiratory disease. Inflamm. Allergy Drug Targets 4, 651-664.
de Oca, M.M., Halbert, R.J., Lopez, M.V., Perez-Padilla, R., Tálamo, C., Moreno, D., et al. (2012). The chronic bronchitis phenotype in subjects with and without COPD: the PLATINO study. Eur. Respir. J. 40(1), 28-36.
Deshmukh, H.S., Shaver, C., Case, L.M., Dietsch, M., Wesselkamper, S.C., Hardie, W.D., Korfhagen, T.R., Corradi, M., Nadel, J.A., and Borchers, M.T. (2008). Acrolein-activated matrix metalloproteinase 9 contributes to persistent mucin production. Am. J. Resp. Cell Mol. Biol. 38, 446-454.
Martinez, C.H., Kim, V., Chen, Y., Kazerooni, E.A., Murray, S., Criner, G.J., et al. (2014). The clinical impact of non-obstructive chronic bronchitis in current and former smokers. Respir. Med. 108, 491-499.
Regalado, J., Pérez-Padilla, R., Sansores, R., Páramo Ramirez, J.I., Brauer, M., Paré, P., et al. (2006). The effect of biomass burning on respiratory symptoms and lung function in rural Mexican women. Am. J. Resp. Crit. Care Med. 174, 901-905.
Shim, J.J., Dabbagh, K., Ueki, I.F., Dao-Pick, T., Burgel, P.R., Takeyama, K., Tam, D.C.W., and Nadel, J.A. (2001). IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils. Am. J. Physiol. Lung Cell. Mol. Physiol. 280, L134-140.
Song, L., Tang, H., Liu, D., Song, J., Wu, Y., Qu, S., and Li, Y. (2016). The chronic and short-term effects of gefinitib on airway remodeling and inflammation in a mouse model of asthma. Cell. Physiol. Biochem. 38, 194-206.
Stott-Miller, M., Müllerová, H., Miller, B., Tabberer, M., El Baou, C., Keeley, T., et al. (2020). Defining Chronic Mucus Hypersecretion Using the CAT in the SPIROMICS Cohort. Int. J. Chron. Obstruct. Pulmon. Dis. 15, 2467.
Sunyer, J., Jarvis, D., Gotschi, T., Garcia-Esteban, R., Jacquemin, B., Aguilera, I., et al. (2006). Chronic bronchitis and urban air pollution in an international study. Occup. Environ. Med. 63, 836-843.
Vestbo, J. (2002). Epidemiological studies in mucus hypersecretion. Novartis Found. Symp. 248, 3-12; discussion: 12-19, 277-282.
Wang, H., Yang, T., Wang, T., Hao, N., Shen, Y., Wu, Y., et al. (2018). Phloretin attenuates mucus hypersecretion and airway inflammation induced by cigarette smoke. Intl. Immunopharmacol. 55, 112-119.