The airway epithelium represents the first line of defense for the lungs against inhaled-pollutants and infectious agents. Injury to the airway epithelium occurs during mechanical ventilation and in inflammatory diseases such as asthma. Movement of air into and out of the lungs during respiration causes wide variations in the distension of airways, and the epithelial cells lining the airways are thus exposed to both circumferential wall strain depending upon changes in airway diameter and longitudinal elongation or compression depending upon the expansion of the lung volume. Although there has been much interest in the function of epithelium in response to injury and in the pathogenesis of asthma and other chronic obstructive diseases, there has not been an investigation of the role of mechanical strain on the function of airway epithelium. The central hypothesis of this proposal is that physiological levels of mechanical strain regulate the rate of wound closure and the synthesis of eicosanoids in airway epithelial cells by mechanisms involving reactive oxygen species. This hypothesis will be investigated by stretching both primary cultures of cat tracheal epithelial cells and human bronchial epithelial cells as well as lines of human bronchial epithelial cells grown on elastic membranes using a novel biaxial strain device. Preliminary results demonstrate that both cyclic mechanical elongation and compression delay wound closure by inhibiting cell spreading and migration. Furthermore, indomethacin inhibits and prostaglandin E2 (PGE2) enhances wound closure. Cyclic strain inhibits synthesis of PGE2, and other prostanoids by inactivating the enzyme cyclooxygenase (COX). Preliminary evidence also suggests that COX inactivation is oxidant-mediated.
In Specific Aim 1, the mechanisms by which cyclic stretch and compression inhibit wound closure in epithelial monolayers will be determined. Measurements of wound width, cell area, and internuclear distances will indicate cell spreading and migration at the wound edge.
In Specific Aim 2, the mechanisms by which cyclic strain regulates the metabolism of arachidonic acid to prostanoids will be determined. Western blots of COX-l and COX-2 protein expression and Northern blots of mRNA levels will be used to determine the adaptation response to cyclic strain.
In Specific Aim 3, the role of epithelial oxidant/antioxidant balance in the stretch-induced regulation of wound closure and COX inhibition will be examined. Investigation of the mechanisms underlying epithelial repair and injury during cyclic strain may lead to better strategies for the management of patients during mechanical ventilation.
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