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Center for Tobacco Regulatory Science and Lung Health

Project II

The Effects of Tobacco Exposure on the Airway Mucus/Mucin Integrity and Proteome: Determining the Tobacco Mucomarkers

Tobacco smoking and exposure is an important cause of respiratory tract morbidity and mortality worldwide. Mucus is one of the first points of contact with inhaled smoke and mucus acts as the first line of defense to inhaled biological and chemical substances. Mucus forms a major component of the lung’s innate immune system and is a complex network of mucins, antimicrobial peptides, enzymes and wide variety of scavenging proteins that detect, immobilize, destroy and/or remove a range of foreign bodies, toxins and pathological factors that would otherwise overwhelm our humoral immune system. Biomolecules in mucus are split into two distinct groups, the first group being globular type proteins of between 6 kDa to 200 kDa and the second being the mucins which are large, space-filling glycoconjugates of 200 kDa to 100 MDa, with most of this mass being carbohydrate in origin. Besides these biomolecules, mucus also contains secreted vesicles with innate immune properties. For example, we have previously shown that exosome-like-vesicles are one of the major innate immune players in the mucus barrier. Their cargo carries 100s of proteins as well as specifics sets of RNAs that may communicate with macrophages and other immune cells. Under normal conditions, the biophysical properties of mucus (i.e. its ability to be cleared from the lung) is mostly influenced by MUC5B and MUC5AC mucins. However, chronic smoke exposure leads to goblet cell metaplasia and mucus hypersecretion, as well as mucus dehydration. Furthermore, mucus from smokers and COPD subjects has an altered composition, and changes in the MUC5B/ MUC5AC ratio are observable, suggesting that its biophysical properties have been altered. Thus, the overarching aim of this project, using mucus from in vitro and in vivo models and from human subjects, is to look for novel biomarkers of tobacco exposure (mucomarkers) and to determine the effects of exposure to different tobacco products, including “low tar” and “flavored” cigarettes and little cigars and hookah, on the expression of potential mucomarkers to assess the relative toxicology of new and emerging tobacco products. We proposed flowing aims to achieve a more integrated view of mucus/mucin related biomarkers and thus more rational approaches against tobacco exposure to protect public health.

Support: P50 HL120100 (Tarran) sub # 8206 (Kesimer)