Mucus hypersecretion in asthma: causes and effects

Abstract

Purpose of review-Airway mucus plugging has long been recognized as a principal cause of death in asthma. However, molecular mechanisms of mucin overproduction and secretion have not been understood until recently. These mechanisms are reviewed together with ongoing investigations relating them to lung pathophysiology.Recent findings-Of the five secreted gel-forming mucins in mammals, only MUC5AC and MUC5B are produced in significant quantities in intrapulmonary airways. MUC5B is the principal gel-forming mucin at baseline in small airways of humans and mice, and therefore likely performs most homeostatic clearance functions. MUC5AC is the principal gel-forming mucin upregulated in airway inflammation and is under negative control by forkhead box a2 and positive control by hypoxia inducible factor-1. Mucin secretion is regulated separately from production, principally by extracellular triphosphate nucleotides that bind P2Y 2 receptors on the lumenal surface of airway secretory cells, generating intracellular second messengers that activate the exocytic proteins, Munc13-2 and synaptotagmin-2.Summary-Markedly upregulated production of MUC5AC together with stimulated secretion leads to airflow obstruction in asthma. As MUC5B appears to mediate homeostatic functions, it may be possible to selectively inhibit MUC5AC production without impairing airway function. The precise roles of mucin hypersecretion in asthma symptoms such as dyspnea and cough and in physiologic phenomena such as airway hyperresponsiveness remain to be defined.

DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma

“…The process of mucus hypersecretion during allergic asthma involves a complex multistep process, including mucin gene induction, mucus packaging in storage granules, mucus secretion, and changes in extracellular mucus viscosity. Both EGFR and IL-13 are known to contribute to mucous cell metaplasia by promoting mucin gene induction (e.g., MUC5AC, CLCA1) through independent and still incompletely understood mechanisms (43,44). The present findings indicating a role for DUOX1 in induction of various genes associated with mucous cell metaplasia (Muc5ac, Clca1, Postn) are consistent with previous observations (22) and are in keeping with the presence of DUOX1 in the central airways and the observed enhanced central airway resistance in response to methacholine.…”

IL13 activates autophagy to regulate secretion in airway epithelial cells

“…21,22 However, less is known about the regulation of airway-specific secretory processes. In airway epithelial cells, MUC5AC secretion is considered an adaptive response to environmental stimuli such as respiratory viruses, 23 airway allergens, 24 and cigarette smoke. 25 We, and others, have demonstrated a requirement of autophagy for cell secretion of VWF (Von Willebrand factor) from endothelial cells, 26 lysozyme from intestinal Paneth cells, 27 and MUC2 from colonic goblet cells.…”

Gel-forming mucins form distinct morphologic structures in airways

“…In asthma and models of airway hyperreactivity, mucus contains increased levels of MUC5B and MUC5AC, airways exhibit goblet cell hyperplasia, and MUC5AC transcripts are increased whereas MUC5B transcripts are decreased (1,4,5,(11)(12)(13). Chronic obstructive pulmonary disease manifests increased mucin production (9,13).…”