CFTR, Mucins, and Mucus Obstruction in Cystic Fibrosis

Abstract

Mucus has long been recognized to reside on the moist, external and internal surfaces of the body. In the early 1930s, for instance, long before he became famous for the codiscovery of penicillin, Howard Florey wrote extensively on mucus secretion in the intestine and airways, as well as on the functions of mucus (Florey 1930; Goldsworthy and Florey 1930; Florey et al. 1932)⁵; his observations strike a surprisingly contemporary chord! The concept of mucus as a barrier against harsh environments or pathogens, however, is a more recent concept that was described first for the stomach (Forte and Forte 1970) and the cervix (Enhorning et al. 1970) in 1970. Since that time, our appreciation of this barrier function offered by mucus has been refined and generalized (Cone 2009) and is presently being appreciated at the molecular level (Pickles 2004; Linden et al. 2008). Also more recently appreciated is the role that the breakdown of the mucus barrier plays in inflammatory diseases (Rhodes 1989; Knowles and Boucher 2002; Johansson et al. 2010). Studies of the genetic disease cystic fibrosis (CF) have been central to much of our current understanding of the function of the mucus barrier in health and its dysfunction in disease, especially with respect to chronic infection and inflammation of the airways in the lungs of CF patients.

Mucus on most epithelial surfaces, such as airways and ocular surfaces, resides as a single layer of polymeric mucin gel (Hollingsworth and Swanson 2004), a few tens of micrometers thick, overlying the epithelial glycocalyx, which includes a class of mucins tethered to the apical plasma membrane (Hattrup and Gendler 2008; Govindarajan and Gipson 2010). In the stomach and colon, however, there are two layers of mucus, one that is adherent, forms from mucins released by goblet cells, and is impermeable to bacteria. The second is more luminal and non-adherent, forms from the enzymatic processing of mucins that are continuously released into the adherent layer, and harbors bacteria (Allen et al. 1984; Taylor et al. 2004; Johansson et al. 2011). Under normal conditions, the mucus barrier on epithelia functions as part of the innate immune system; however, under conditions of inflammation, mucus production is accelerated as part of the body’s response to infection or other insults, and the resulting hyperproduction can be deleterious to the health of the patient. This phenomenon of mucus hyperproduction and mucus plugging in the airways is especially true for CF patients, as we consider below.

^{MUC19 mucin glycoprotein is expressed in saliva from rats, horses, pigs, and cows, but was not detected in human saliva (}Rousseau et al. 2008).

^{Muc5b is expressed in Clara cells of wild-type (WT) mouse airways under control conditions, and during development and in mucus metaplasia (}Zhu et al. 2008; Roy et al. 2011). Muc5ac is expressed during mucus metaplasia (Zuhdi Alimam et al. 2000; Zhu et al. 2008); however, the human MUC gene products expressed in healthy and inflamed human small airways (bronchioles) remain to be identified.

^{MUC5B appears to be expressed in lacrimal glands but was not detected in tears (}Spurr-Michaud et al. 2007).

ACKNOWLEDGMENTS

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