Mucin Production during Prenatal and Postnatal Murine Lung Development

Abstract

Mucus is a protective gel that lines respiratory tract surfaces. To identify potential roles for secreted gel-forming mucins in lung development, we isolated murine lungs on embryonic days (E) 12.5-18.5, and postnatal days (PN) days 5, 14, and 28. We measured the mucin gene expression by quantitative RT-PCR, and localization by histochemical and immunohistochemical labeling. Alcian blue/periodic acid-Schiff-positive cells are present from E15.5 through PN28. Muc5b transcripts were abundant at all time points from E14.5 to PN28. By contrast, transcript levels of Muc5ac and Muc2 were approximately 300 and 85,000 times lower, respectively. These data are supported by immunohistochemical studies demonstrating the production and localization of Muc5ac and Muc5b protein. This study indicates that mucin production is prominent in developing murine lungs and that Muc5b is an early, abundant, and persistent marker of bronchial airway secretory cells, thereby implicating it as an intrinsic component of homeostatic mucosal defense in the lungs. At approximately 4 weeks of gestation in humans (embryonic days 9.0-9.5 in mice), tracheal and lung-bud formation initiates as a pocket of endoderm evaginates from the ventral floor of the embryonic foregut and invades the underlying mesoderm. The developing lungs undergo repeated branching steps, giving rise to the complex of tubes that form the conducting airways and alveolar saccules. During this process of branching and morphogenesis, the endoderm changes from an undifferentiated mass to a pseudostratified squamous layer, and then to a differentiated layer comprised of heterogeneous progenitor and mature cells (1).Mature respiratory epithelial cells possess many unique functions that can be attributed to their structural features or their secretory products. Structural features such as the long, apical projections of tracheobronchial ciliated cells and the thin sheet-like squamous morphologies of alveolar Type I cells are examples of obvious morphological traits that are specifically linked to cellular function (ciliary clearance and gas exchange, respectively). Secreted products also demarcate the functions of individual respiratory epithelial subtypes. The tracheobronchial epithelium produces secreted products, such as mucins, that serve defensive functions by preventing the accumulation of particles and pathogens in the distal lung (2-4), whereas Type II pneumocytes produce surfactant lipids that reduce surface tension and prevent alveolar collapse, thereby permitting effective gas exchange (5). Additional anatomically selective markers include the secretaglobin (Scgb) family, with members such as Scgb1a1 (or Clara cell secretory protein) in the airways, and surfactant proteins A, B, and C in the alveoli. The expression of many of these markers is low early during lung development, when the bronchial epithelium is poorly differentiated, and becomes more abundant as epithelial maturation occurs late in embryonic gestation and throughout postnatal life (6).The importance of muc...

MUC5AC interactions with integrin β4 enhances the migration of lung cancer cells through FAK signaling

“…40–42 MUC5AC is a secretory glycoprotein, which is normally expressed in the lung; but its expression is altered in lung cancer. 4,5,43–45 In the present study, we elucidate the role of MUC5AC in lung cancer cell growth and metastasis. Following MUC5AC knockdown in two lung adenocarcinoma cell lines, we observed significant reduction of growth.…”

“…Aberrant expression and accumulation of mucins has been associated with lung cancer, 1 inflammatory conditions 2 and other chronic diseases. 3–5 Mucins interact with various molecules and affect cell–cell interaction during cancer progression and metastasis. 6–8 MUC5AC is a high molecular weight secretory polymeric mucin, synthesized as a glycoprotein in a selective and cell-specific manner.…”

“…6–8 MUC5AC is a high molecular weight secretory polymeric mucin, synthesized as a glycoprotein in a selective and cell-specific manner. 5,9 Multiple cysteine-rich domains in both N- and C-terminal regions of MUC5AC are responsible for its disulfide-mediated polymerization, which is critical for gel-forming properties. 10 MUC5AC is expressed in the trachea and bronchi, but not in the bronchioles and smaller alveolar epithelial cells.…”

Control of lung defence by mucins and macrophages: ancient defence mechanisms with modern functions

“…These are reviewed extensively elsewhere (37–42). Lastly, endogenous factors include developmental (43–46) and epigenetic (47–49) regulatory mechanisms, which may play roles in the expression of mucins in cancers.…”

Younger patients with COME are more likely to have mucoid middle ear fluid containing mucin MUC5B

“…Finally, some have posited that MUC5AC is secreted earlier upon infectious/inflammatory stimuli, in a more robust fashion, relative to MUC5B which not only responds in a comparatively mutated fashion, but at much later time points after an initial infectious insult 17 . One can perhaps extrapolate that relative to the acute responder MUC5AC, MUC5B is more critical for long-term baseline homeostasis than MUC5AC, as has been postulated by others 18,19 . It is possible that those patients with MUC5AC in our study had experienced a more recent bacterial infection in the middle ear, and that this was the reason for the MUC5AC presence.…”