Interactions between ligands and receptors are central to communication between cells and tissues. Human airway epithelia constitutively produce both a ligand, the growth factor heregulin, and its receptors--erbB2, erbB3 and erbB4 (refs 1-3). Although heregulin binding initiates cellular proliferation and differentiation, airway epithelia have a low rate of cell division. This raises the question of how ligand-receptor interactions are controlled in epithelia. Here we show that in differentiated human airway epithelia, heregulin-alpha is present exclusively in the apical membrane and the overlying airway surface liquid, physically separated from erbB2-4, which segregate to the basolateral membrane. This physical arrangement creates a ligand-receptor pair poised for activation whenever epithelial integrity is disrupted. Indeed, immediately following a mechanical injury, heregulin-alpha activates erbB2 in cells at the edge of the wound, and this process hastens restoration of epithelial integrity. Likewise, when epithelial cells are not separated into apical and basolateral membranes ('polarized'), or when tight junctions between adjacent cells are opened, heregulin-alpha activates its receptor. This mechanism of ligand-receptor segregation on either side of epithelial tight junctions may be vital for rapid restoration of integrity following injury, and hence critical for survival. This model also suggests a mechanism for abnormal receptor activation in diseases with increased epithelial permeability.
Asthma is characterized by airway inflammation, smooth muscle hyperreactivity, and airway remodeling with excessive mucus production. The effect cytokines like interleukin (IL)-9 have on airway epithelia has been addressed using murine models of asthma, as well as transgenic and knockout mice. Though highly informative, differences exist between mouse and human airway epithelia, including cellular composition (e.g., Clara cells) and stem cell/plasticity capabilities. Therefore, to address cytokine effects on human airway epithelia, we have used a primary model system to ask whether IL-9 can alter cell fates of human airway epithelia. Here, we show that IL-9 has little effect on fully differentiated ciliated human airway epithelia. However, in the setting of airway injury repair, IL-9 results in goblet cell hyperplasia. A similar response was observed when the epithelium was exposed to IL-9 before it became fully differentiated. Moreover, exposure to IL-9 resulted in increased lysozyme and mucus production by the epithelia. Thus, a combination of IL-9 and mechanical injury can explain, in part, goblet cell hyperplasia that is evident in the lungs of individuals with asthma. These data suggest that interventions that limit airway epithelial damage, block IL-9, or modulate the repair process should result in decreased airway remodeling and prevent the chronic manifestations of this disease.
The prevalence and predictors of gonorrhea and chlamydia infection differ significantly between blacks and whites. Until these disparities are better understood, it will be difficult to establish screening criteria for gonorrhea.
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