{"id":4261,"date":"2014-06-06T13:10:00","date_gmt":"2014-06-06T17:10:00","guid":{"rendered":"https:\/\/www.med.unc.edu\/biochem\/increased-mucins-pinned-to-worsening-cystic-fibrosis-symptoms\/"},"modified":"2018-08-01T10:33:24","modified_gmt":"2018-08-01T14:33:24","slug":"increased-mucins-pinned-to-worsening-cystic-fibrosis-symptoms","status":"publish","type":"post","link":"https:\/\/www.med.unc.edu\/biochem\/news\/increased-mucins-pinned-to-worsening-cystic-fibrosis-symptoms\/","title":{"rendered":"Increased mucins pinned to worsening cystic fibrosis symptoms"},"content":{"rendered":"
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The discovery from UNC School of Medicine researchers overturns a controversial research study and offers a path for creating and testing CF treatments<\/p>\n

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UNC School of Medicine researchers have provided the first quantitative evidence that mucins \u2013 the protein framework of mucus \u2013 are significantly increased in cystic fibrosis patients and play a major role in failing lung function.<\/p>\n

The research, published today in the <\/span>Journal of Clinical Investigation<\/i>, shows that a three-fold increase of mucins dramatically increases the water-draining power of the mucus layer. This hinders mucus clearance in the CF lung, resulting in infection, inflammation, and ultimately lung failure.<\/p>\n

\u201cOur finding suggests that diluting the concentration of mucins in CF mucus is a key to better treatments,\u201d said Mehmet Kesimer, PhD, associate professor of pathology and laboratory medicine and co-senior author of the <\/span>JCI<\/i> <\/span>paper.<\/p>\n

Ashley Henderson, MD, assistant professor of medicine and co-first author of the <\/span>JCI<\/i> <\/span>paper, added, \u201cWe think this study shows why nebulized hypertonic saline [sterile salty water] improves the hydration of the CF airway, improves the patient\u2019s mucus clearance and, in so doing, increases lung function.\u201d<\/p>\n

The UNC study also casts further doubt on a controversial 2004 study that disputed the theory that mucins play a major role in CF.<\/p>\n

This work, a collaboration of 13 UNC scientists, is part of an extensive UNC lung research program based in the new Marsico Lung Institute, which is led by Richard Boucher, MD, co-senior author of the <\/span>JCI<\/i> paper<\/a>.<\/p>\n

\u201cThis paper points to a therapeutic strategy to rectify this problem of mucus clearance and provides signposts, or biomarkers, to guide development of novel therapies,\u201d said Boucher, the James C. Moeser Eminent Distinguished Professor of Medicine. Also, by measuring mucin concentration in patient mucus, doctors could learn whether therapies are working and to what degree.<\/p>\n

Scientists and doctors have known for a long time that failing to clear mucus is the major reason why CF patients face chronic lung infection and inflammation. But the mechanisms of this failure have not been well understood.<\/p>\n

Normally, when we breathe, the mucosal layer of our lungs trap the contaminants \u2013 dust, pollutants, bacteria \u2013 naturally found in air. Then, epithelial cells with hair-like cilia brush the mucus up and out of our lungs. In people with cystic fibrosis, though, this process doesn\u2019t work as well because they lack a properly functioning CFTR gene. They continually battle infections and must work hard to clear mucus from their lungs.<\/p>\n

This is where mucins come into play. Mucins give mucus its gel-like thickness and elasticity. \u201cWithout mucins, mucus would have the viscosity of blood,\u201d Kesimer said. \u201cThe vast majority of mucus is water, but 30 to 35 percent of the remaining solid material is made up of mucins. They form a network of bonds that serves as a framework.\u201d<\/p>\n

This is why Kesimer and his UNC mentor, the late John Sheehan, PhD, Distinguished Professor of Biochemistry and Biophysics, suspected that something must happen to mucins in the CF lung. They and others knew that CF mucus is typically drier than normal mucus.<\/p>\n

Back in 2004, however, other researchers used a standard immunologic analysis to show that mucins were <\/span>decreased<\/i> <\/span>in CF secretions. They suspected DNA was the main culprit that caused problems in CF mucus. Sheehan and Kesimer were skeptical, as was Henderson, a clinician who saw CF patients and had been a research fellow in Sheehan\u2019s lab. They set out to conduct various novel experiments to physically measure the amount of mucins in CF secretions and normal mucus.<\/p>\n

In one experiment, they used a technique called size exclusion chromatography: in a column, they added custom-made beads that had small pores. Smaller proteins could enter the pores while mucins could not. Through this separation, Kesimer and Henderson\u2019s team isolated the mucins and simultaneously measured their concentration using a refractometer.<\/p>\n

By using sputum samples from CF patients, the researchers found that CF mucus contained three times as many mucins than did normal samples. They also conducted experiments to show that mucin overabundance led to a six-fold increase of the pressure between the mucus layer and the ciliated layer.<\/p>\n

This finding affirms the CF disease model that <\/span>UNC researchers published<\/a> <\/span>in the journal <\/span>Science <\/span><\/i>in 2012. In essence, in a CF patient, the increased osmotic pressure of the concentrated mucus layer crushes the ciliated cells so that mucus is not cleared. The lung becomes a breeding ground for bacteria. This leads to more mucins, more mucus, inflammation, and subsequently lung failure.<\/p>\n

Moreover, Kesimer\u2019s team showed precisely why the 2004 research was flawed. Those researchers used a classic antibody based immunologic technique called a western blot, which measures the expression of a given protein \u2013 in this case mucins \u2013 based on an antibody response to that protein.<\/p>\n

But, as Kesimer pointed out, antibodies must latch onto proteins at specific sites on the proteins\u2019 surfaces. When Kesimer conducted the western blot, he got the same result as the 2004 researchers. But then he used a technique called mass spectrometry to find that CF secretions are full of proteases \u2013 enzymes that break down molecules. The mass spectrometry showed that the proteases degraded the mucins, essentially \u201cerasing\u201d many of the sites where antibodies could bind without disrupting the structural integrity of mucins.<\/p>\n

\u201cFor that reason, we saw less antibody response using the western blot,\u201d Kesimer said. And so it <\/span>looked<\/i> <\/span>as if there were fewer mucins. \u201cBut by using more accurate methods, we clearly saw the increase of mucins. In fact, we\u2019ve analyzed many samples of sputum from patients with other chronic pulmonary diseases and we saw the increase in mucins in them, as well.\u201d<\/p>\n

Camille Ehre, PhD, a research associate at the UNC CF Research Center\/ Marsico Lung Institute, is co-first author of the paper. Other authors of the paper, all of whom conducted this research while at UNC, include Brian Button, PhD, Lubna Abdullah, PhD, Li-Heng Cai, PhD, Margaret Leigh, PhD, Genevieve DeMaria, PhD, Hiro Matsui, PhD, Scott Donaldson, PhD, C. William Davis, PhD, and John Sheehan, PhD.<\/i><\/p>\n

The National Institutes of Health and the Cystic Fibrosis Foundation funded this research.<\/i><\/p>\n


Link to video https:\/\/www.youtube.com\/watch?v=UxmCoPBPp6U<\/a>
<\/i><\/p>\n<\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"

<\/p>\n

The discovery from UNC School of Medicine researchers overturns a controversial research study and offers a path for creating and testing CF treatments<\/p>\n","protected":false},"author":37803,"featured_media":4262,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"layout":"","cellInformation":"","apiCallInformation":"","footnotes":"","_links_to":"","_links_to_target":""},"categories":[2],"tags":[22,20,4],"class_list":["post-4261","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-news","tag-news_alum","tag-news_2014","tag-recent-news","odd"],"acf":[],"yoast_head":"\nIncreased mucins pinned to worsening cystic fibrosis symptoms | Biochemistry and Biophysics<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" 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