Kesimer Lab

The airway mucosal barrier

is the heart of a powerful innate immune system that maintains the underlying epithelial surface in the face of physical, chemical, and pathological erosion. There are two distinctive zones or layers to the barrier: One zone termed the peri-ciliary liquid layer (PCL) surrounds the microvilli and reaches to the top of the cilia, the other is the characteristic mucus layer above. The maintenance of these zones is proposed to be vital for effective lung function and in diseases such as Cystic Fibrosis and chronic bronchitis. Kesimer et al. Mucosal Immunology (2013) 6, 379–392
Nature MI cover March 2013

Schematic depiction of the mucosal surface of human airways showing a goblet cell (left) , cilia,and the periciliary layer, as well as the macromolecular organization of various tethered and gel forming mucins. For more detail, see Figure 8 in the paper by Kesimer et al. (page 379)
MI cover October 2016

Mucins are the major gel forming components of the mucus. The cover photograph is an atomic force microscope image of the organizational framework of the mucin ineractome. Glycosylated domains/chains of the mucins are shown in green. The brown areas represents protein regions of the framework, including mucin's naked protein domains, as well as small mucin-binding proteins. Large brown protein nodes in the framework indicate the presence of more than one, or larger, and/or more hydrophobic proteins on the nodes. Membrane tethered mucins are incorporated into mucin network and determine the biophysical properties of the mucus gel. For further information, see the article by Radicioni et al. on page 1442
Science translational Medicine Cover Article October 5, 2016

Not all individuals who have respiratory reactions to allergens progress to asthma. In this issue, Cho et al. found that although allergic asthmatics and allergic nonasthmatics both experienced inflammation after allergen challenge, asthmatics had more mucin and type 2 cytokines, and allergen-specific T cells sampled from the airspace had increased innate type 2 receptors. Using orientation-resolved optical coherence tomography, described by Adams et al., they demonstrated that allergic asthmatics also had increased airway smooth muscle mass. This technique allows for in vivo imaging of airway smooth muscle structure and function, which could shed light on the pathogenesis of many respiratory diseases.
Cover article, Science August 24, 2012

Mucus clearance is the primary defense mechanism that protects airways from inhaled infectious and toxic agents. In the current gel-on-liquid mucus clearance model, a mucus gel is propelled on top of a “watery” periciliary layer surrounding the cilia. However, this model fails to explain the formation of a distinct mucus layer in health or why mucus clearance fails in disease. We propose a gel-on-brush model in which the periciliary layer is occupied by membrane-spanning mucins and mucopolysaccharides densely tethered to the airway surface. This brush prevents mucus penetration into the periciliary space and causes mucus to form a distinct layer. The relative osmotic moduli of the mucus and periciliary brush layers explain both the stability of mucus clearance in health and its failure in airway disease
Airway mucin concentrations show promise as an important biomarker for chronic bronchitis, which is a key component of chronic obstructive pulmonary disease (COPD). Our study published Sept. 6 online in the New England Journal of Medicine, suggest that airway mucin concentrations, "describe a potential disease-causing, chronic-bronchitis pathway that is associated with sputum production and disease severity."

The Kesimer lab is located in the Marsico Lung Institute. The core of our research focuses on the basic mechanisms that constitute the major components of innate immunity in the lung.

The upper airway is protected by two complex interacting gel systems, one surrounding the cilia, and the other attached above.
These two complex layers are structured by large complex molecules called mucins. Mucins form a scaffold that supports some 200 globular proteins, most of which have known or suspected functions concerned with innate immunity. For instance, they recognize and interact with chemical, physical, and pathological irritants.
In an ideal situation, this system acts as an integrated whole; however, in diseases such as chronic bronchitis, asthma, cystic fibrosis, and many others, it fails. In cystic fibrosis, the source of the failure (a gene defect) is known, but we don’t know how this defect affects the local protective gels. Recent data from the Kesimer lab suggest that in cystic fibrosis, the gene defect affects the mucin biology. This compromises the structures’ protective functions and dramatically changes the resulting mucus biophysical properties.

After COVID-19 became a pandemic, we rapidly implemented our research tools and methodology to COVID-19 basic and translational research to understand the clinical trajectory, pathogenesis, and prognosis of the disease.

Past group photos