Lewis, S.A.: Extracellular Modulation of Epithelial Permeability

One of the primary functions of an epithelium is to act as a barrier to the movement of substances between the lumen of the epithelium and the blood. Loss of epithelial barrier function due to cell death can lead to a loss of homeostasis and result in death of the organism. Proteins associated with eosinophils, certain bacteria and present in human semen have been demonstrated to be toxic to mammalian epithelial cells. The eosinophil proteins are major basic protein and eosinophil peroxidase, the bacterial protein is polymyxin B and the proteins found in semen are histones and protamine. A property shared by these proteins is a high density (15-80%) of positively charged (basic) amino acids. The effect of these proteins on the mammalian urinary bladder epithelium was studied using electrophysiological techniques and confocal microscopy. It was demonstrated that these proteins cause cell death by interacting and increase the ion permebility of the cell membrane. Specifically, we demonstrate that these proteins kill epithelial cells by making their cell membrane leaky to both cations and anions, resulting in cell swelling and ultimately cell lysis. Additional sites of protein interaction have been suggested from studies utilizing confocal microscopy. A model for epithelial cell death by these positively charged proteins will be discussed, and includes protein-membrane interaction, a voltage dependent step, a recycling of membrane receptors and sites for divalent cation modulation.