Hypersecretion, Mucus

Mucus hypersecretion occurs in obstructive airway diseases such as COPD, asthma, and cystic fibrosis. Excessive mucus is produced and plugging of airways can occur in small airways, leading to breathing difficulty. Mucins are produced in response to irritants such as virus, bacteria and environmental particulates including cigarette smoke, stimulating coughing to assist clearance of mucus (Nadel, 2013).

In large airways, cough receptors and submucosal gland ducts are co-localized, assisting the clearance of mucus via coughing, and stimulation of vagal sensory nerves cause reflex smooth muscle contraction, contributing to airway narrowing. In small airways, early detection is limited since they do not contain cough receptors and airway resistance due to obstruction is not noticeably changed because there are many small airways (Nadel, 2013).

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

In vivo

Studies investigate mucus hypersecretion in animals in response to a stimulant for a number of weeks, measuring increased cellular rate of glycoprotein secretion after 6 weeks of sulfur dioxide exposure (Coles et al., 1979), increased number of mucous glycoproteins (140-535%) by AB-PAS staining after 4 weeks of ovalbumin exposure (Shore et al., 1995). Shorter term experiments with less dramatic increases in mucus increase are also described as mucus hypersecretion, for example 15% increase in mucus production shown by AB-PAS staining after three weeks of acrolein exposure (Liu et al., 2009).

Since there is no clear quantitative cutoff for mucus hypersecretion, studies sometimes use the term loosely equating mucus hypersecretion with an increase in mucus production compared to normal over a short time period. Measures include mucin released into tracheobronchial lavage fluid by a MUC5AC-specific ELISA after 72 hours OVA challenge (Singer et al., 2004) or increased Muc5ac RNA and protein expression after 4 days of LPS in rats (Ou et al., 2008).

Clinical

Mucus hypersecretion is detected by continuous phlegm production for a number of weeks in the absence of chest infection, assessed by either questioning the patient (routine procedure) or measuring sputum volume, which is performed less frequently. In the Copenhagen City Heart Study, chronic mucus hypersecretion was considered present when cough and sputum had lasted at least 3 months for more than 1 year (Vestbo et al., 1996).

Many studies in mouse, rat and human describe the occurrence of mucus hypersecretion due to various stimuli. Studies in humans define mucus hypersecretion functionally, while studies in rats and mice define mucus hypersecretion as an increase in mucus production with no clear quantitative cutoff for amount and duration.

1. Coles, S.J., Levine, L.R., and Reid, L. (1979). Hypersecretion of mucus glycoproteins in rat airways induced by tobacco smoke. Am. J. Pathol. 94, 459–471.

2. Hewson, C., Edbrooke, M., and Johnston, S. (2004). PMA induces the MUC5AC respiratory mucin in human bronchial epithelial cells, via PKC, EGF/TGF-alpha, Ras/Raf, MEK, ERK and Sp1-dependent mechanisms. J Mol Biol 344, 683–695.

3. Liu, D.-S., Wang, T., Han, S.-X., Dong, J.-J., Liao, Z.-L., He, G.-M., Chen, L., Chen, Y.-J., Xu, D., Hou, Y., et al. (2009). p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in mice exposed to acrolein fog. Int. Immunopharmacol. 9, 1228–1235.

4. Nadel, J. (2013). Mucous hypersecretion and relationship to cough. Pulm Pharmacol Ther 26, 510–513.

5. Ou, X.-M., Wang, B.-D., Wen, F.-Q., Feng, Y.-L., Huang, X.-Y., and Xiao, J. (2008). Simvastatin attenuates lipopolysaccharide-induced airway mucus hypersecretion in rats. Chin. Med. J. (Engl.) 121, 1680–1687.

6. Shore, S., Kobzik, L., Long, N., Skornik, W., Van Staden, C., Boulet, L., Rodger, I., and Pon, D. (1995). Increased airway responsiveness to inhaled methacholine in a rat model of chronic bronchitis. Am J Respir Crit Care Med 151, 1931–1938.

7. Singer, M., Martin, L.D., Vargaftig, B.B., Park, J., Gruber, A.D., Li, Y., and Adler, K.B. (2004). A MARCKS-related peptide blocks mucus hypersecretion in a mouse model of asthma. Nat. Med. 10, 193–196.

8. Vestbo, J., Prescott, E., and Lange, P. (1996). Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Copenhagen City Heart Study Group. Am J Respir Crit Care Med 153, 1530–1535.