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Mechanism of MUC5AC in Exacerbating Pulmonary Diseases Such as COPD and Asthma

Mucus is an important gel-like liquid protective layer, mainly composed of mucin that spreads throughout the respiratory tract. One of these mucins, MUC5B, is essential for the innate defense of the various things we inhale. But another mucin called MUC5AC usually increases disproportionately in reactions to cigarette smoke and allergens, thereby increasing health problems.
In a new study, researchers from the University of North Carolina School of Medicine discovered for the first time how MUC5AC appeared in the respiratory tract of people with lung diseases such as chronic obstructive pulmonary disease (COPD) and asthma. Thus disturbing their breathing. This finding suggests that MUC5AC may become a target for better treatments to dissolve the super viscous mucus that plays a role in the health problems of millions of lung disease patients. The relevant research results were published in the PNAS journal on September 28, 2021, with the title of the paper "Assembly and organization of the N-terminal region of mucin MUC5AC: Indications for structural and functional distinction from MUC5B".
The corresponding author of the paper, Dr. Mehmet Kesimer, said, “At present, it is almost impossible to prevent the progression of chronic obstructive airway disease; we need better treatments. MUC5AC seems to be critical to the stagnant, viscous mucus formation we see in lung diseases such as chronic bronchitis and asthma, and we believe it should be a target for drug development for a range of diseases. We may only notice it when there is too much mucus; for example, when we have a cold, excessive mucus seems to be a natural response to the virus. But for proper health, the mucus layer of the entire body is vital, and because of this, the mucus protein that makes mucus is also vital. "
The mucin composition of different surface mucus depends on the functional requirements of each surface (also called epithelium). For example, in the small intestine and colon where a variety of microorganisms are hidden, mucin MUC2 forms a "tight mucus layer", which provides a niche for the microorganisms and protects the underlying epithelial cells from bacterial invasion. In the stomach, MUC6 and MUC5AC together provide a barrier to protect epithelial cells from the harmful effects of high acidity. The oral cavity is the main entry point for food and microbes, protected by saliva, and its main gel-forming mucin is MUC5B.
In the entire respiratory system, MUC5B and MUC5AC are expressed in different modes, depending on the requirements of each part of this complex system. Specific glands under the mucosal layer secrete MUC5B, which has been shown to be essential for the innate defense of the lungs. At the same time, only surface cells secrete MUC5AC, mainly in the larger airways. However, in response to chronic stresses such as cigarette smoke and allergens, the small airways also begin to secrete MUC5AC. This is why MUC5AC is closely related to the initiation and progression of chronic mucus obstructive lung diseases including chronic bronchitis and COPD, as Kesimer and colleagues recently reported in the journal Lancet Respiratory Medicine. (Lancet Respiratory Medicine, 2021, doi:10.1016/S2213-2600(21)00079-5)
In the new study, Kesimer and his team describe several techniques they used to understand the different biochemical properties of the two mucous proteins, specifically how MUC5AC becomes more viscous and branches to form static mucous networks in chronic airway health conditions.
Kesimer said, "We think our findings show why MUC5AC is so closely related to lung disease, and why MUC5AC may be a'bad mucin' compared to MUC5B. Therefore, we believe that it should be regarded as a potential target of compounds that can help prevent the onset and progression of the disease and improve the lung function of patients with chronic respiratory diseases. "
Reference: Jerome Carpenter et al. Assembly and organization of the N-terminal region of mucin MUC5AC: Indications for structural and functional distinction from MUC5B. PNAS, 2021, doi:10.1073/pnas.2104490118.
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