Ventilator-induced lung injury represents a significant increase clinical complication for which effective therapy is lacking. This form of lung injury was initially thought to result from frank alveolar-capillary rupture that caused permeability edema. However, we have recently shown that moderate ventilatory-induced lung injury is due to stretch activated cation charmers in endothelial cells, which promote gadolinium-sensitive calcium entry sufficient increases in endothelial cell cytosolic calcium produce macrovascular and not microvascular permeability. To date, putative molecular candidates encoding stretch activated cation channels have not been identified in mammalian cells. However, the Saccharomyces cerevisiae ,ID1 gene product was recently shown to encode a stretch activated cation channel when expressed in mammalian cells. Moreover, the channel encoded by MIDI exhibited biophysical properties resembling those of endogenous human umbilical vein endothelial cell stretch activated cation channels. Therefore, we Hypothesize that stretch activated cation channel-induced calcium entry, through a MID1-like channel, is sufficient to initiate the vascular permeability response to mechanical stress in pulmonary arterial and venous endothelial cells but not in microvascular endothelial cells.
Specific Aims test the related Hypotheses that: [1] Stretch activated cation channels in pulmonary arterial and venous endothelial cells have electrophysiological properties similar to those of the MID1 gene product but have a greater cation conductance or mean open frequency that do stretch activated cation channels in pulmonary microvascular endothelium; [2} Pulmonary arterial and venous endothelial cell monolayers exhibit gadolinium sensitive pressure and strain-induced increases in permeability which are presented in microvascular endothelial cell monolayers exhibit gadolinium sensitive pressure and strain-induced increases in permeability which are prevented in microvascular endothelial cell monolayers by an increased intracellular cAMP; and [3] Strain-induced segmental filtration coefficients in extra- alveolar vessels have a greater sensitivity to wall stress, oxidant enhancement and gadolinium than do microvascular vessels in intact lungs. Completion of this work will be important to further our understanding of mechanisms that underlie ventilation-induced lung injury (e.g. barotrauma and volutrauma) important for ventilatory management in patients with inflammatory lung diseases.
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