Greater than 95% of infectious agents enter through exposed mucosal surfaces, such as therespiratory, gastrointestinal and genitourinary tracts. These include HIV, sexually transmitted diseases,numerous opportunistic infections, TB, many emerging and re-emerging infections, and biologicalwarfare/terrorist agents, such as anthrax, Yersinia pestis and small pox. Most mucosal surfaces are lined bya monolayer of polarized epithelial cells, which forms the principal barrier to entry by infectious agents. Inessence, the epithelial layer can be considered the most basic component of the innate mucosal immunesystem. Some pathogens cross the epithelial layer by disrupting it. Other pathogens exploit disruptions inthe monolayer, which can be caused by tissue injury secondary to inflammation, trauma, or may result fromcell death or division within the monolayer. To maintain their function as a barrier to infection, epithelialtissues have developed efficient wound healing mechanisms. Wound healing is central to mucosal defenseagainst infection. The epithelial barrier must be restored as quickly as possible, to minimize the opportunityfor entry of infectious agents. Some infectious agents, such as Pseudomonas aeruginosa, not only exploitpre-existing wounds, but also impede the wound healing process. We are studying epithelial wound healingby growing epithelial cells in 3 dimensional cultures of extracellular matrix, which causes the cells to moreclosely resemble in vivo conditions.
In Aim 1 we are using a system of human primary lung alveolar type IIcells, which form alveolar-like cysts, as a model to study response to acute lung injury/acute respiratorydistress syndrome.
In Aim 2, we are using a three-dimensional system of a well-differentiated human airwaycell line, which forms cysts and tubules lined by pseudostratified epithelium, as a model to study airwayresponse to injury.
In Aim 3 we are studying the roles of matrix metalloproteinases and sulfatases (enzymesthat remove 6-O-sulfate groups from heparan sulfate proteoglycans) in our three dimensional culturesystems. This work will be in collaboration with Projects 2, 3 and 4, and supported by Cores B and C.Most infectious agents enter through the layer of cells that lines internal organs, such as the lung.Injuries to this cell layer makes it much easier for pathogens to enter and we are studying how the cell layerheals itself.
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