The mucosal surface of multiple organ systems interfaces with the external environment. These interactions are geared towards harnessing beneficial components such as nutrients, oxygen, and resident microbes, while limiting exposure of underlying tissue to harmful substances including toxins and pathogenic organisms. A major structural feature of the mucosal surface is the layer of epithelial cells, which provides a physical barrier to external threats. It has become increasingly appreciated that this epithelial layer further serves a dynamic immunological role in that it manifests multiple mechanisms to assist in host defense against toxins, allergens, and pathogenic organism upon exposure and recognition.
Such processes include the production of anti-bacterial peptides, mucus, and modulators involved in orchestrating and recruiting innate and adaptive immune cells. These modulators include cytokines that inform the actions of immune cells, chemokines that direct the positioning of immune cells, and a plethora of lipid mediators with a range of functional capacity. With such an integral role in host defense, it is not surprising the array of diseases that have been characterized whereby breach of the mucosal barrier is considered to play a prominent role.
A major focus of our work is to understand processes that lead to mucosal barrier breach in the context of inflammation and disease within the lung and the digestive tract. Insults with the potential to compromise the mucosal barrier include microbial toxins that target or exploit the polarized mucosal epithelium or pathogens and their products that instigate inflammation resulting in recruitment of neutrophils that breach epithelial barriers and cause tissue damage.
Neutrophils serve an important role in innate immunity charged with eradicating dangerous pathogens. Owing to the non-specific nature of the neutrophil arsenal, neutrophil infiltration of the mucosa can be detrimental to host tissue if sufficient resolution is not achieved following neutrophil mobilization. Destructive neutrophilic breach of the mucosa can occur in the airway and the gut in response to pathogenic infection or as a result of autoimmune or auto-inflammatory disease.
Examples of such illness include cystic fibrosis, pneumonia, acute respiratory distress syndrome and chronic obstructive pulmonary disease in the lung, and inflammatory bowel disease and certain enteric infections in the gut. We have identified a neutrophil chemo-attractant that is critical to directing neutrophil breach of mucosal barriers. This molecule is an eicosanoid called hepoxilin A3, and it is produced by mucosal epithelial cells of both the lung and gut (figure B).
Efforts are under way to better understand the genes involved in the synthesis of hepoxilin A3 by epithelial cells and to develop strategies to interfere with hepoxilin A3 function. Such approaches may prove efficacious in combating overzealous inflammation marked by neutrophil breach of mucosal barriers progressing to severe tissue damage, which characterizes numerous ailments of the lung and digestive tract. Ultimately a more thorough understanding of the mucosal barrier and its vulnerabilities will serve to drive development of therapeutics aimed at mucosal barrier fortification in the face of a diverse array of threats.