MECHANISM OF PAF INDUCED LUNG INJURY

提出的研究旨在检查血小板活化因子

The proposed studies are designed to examine the platelet activating factor (PAF) as a mediator of lung injury and as a causative factor in the adult respiratory distress syndrome (ARDS). We intend to study the responses to PAF challenge in the awake animal with a chronic lung lymph fistula and left atrial balloon, the isolated lung preparation and the cultured endothelial cell monolayer (CEM). Our hypothesis is that PAF per se is injurious to the lung endothelium as well as lung epithelium and causes severe lung mechanical and gas exchange alterations. In the total PAF pathobiology certain facets may be mediated or modulated by 1) activated platelets and/or leukocytes singularly or synergistically; 2) by products of the cyclo- and lipo-oxygenase pathway or arachidonic acid metabolism. In vivo and in vitro experiments will be used to study our objectives. The injurious effect of PAF on the endothelium should be expressed as alterations in transvascular fluid and protein fluxes and will be assessed by 1) measurement of lymph flow, lymph and plasma protein concentrations, the protein reflection coefficient and extravascular lung water content in intact animals; 2) measurement of the capillary filtration coefficient in isolated rabbit lungs; and 3) measurement of 125I albumin transport in cultured endothelial cell monolayers. Epithelial damage as part of the PAF induced lung injury will be assessed in the awake animal by measuring clearance changes of aerosolized technicium 99m DTPA. Lung mechanical changes will be determined by measuring static and dynamic compliance in intact animals with simultaneous recordings of tracheal and intrapleural pressure. Functional residual capacity will be determined with the nitrogen washout method. Arterial and mixed venous blood will be monitored and alveolar dead space and shunt fraction calculated. Both in vivo and in vitro models will be utilized, each offering distinct advantages and therefore are complimentary to each other. The in vivo preparations are very suitable for identifying and quantifying the role of cells (platelets and leukocytes) and their interactions in determining the magnitude of the PAF injury as well as for determining the role and source of other secondary factors (products of AA metabolism). The intact sheep with lymph cannula will allow for determination of the role of PAF and its possible mediators in the acute lung injury and the efficacy of PAF inhibitory substances to modulate this response.