Rises in cytosolic calcium are sufficient to initiate the retraction of endothelial cell borders and to increase macromolecular permeability. Although endothelial cell biologists have recognized the importance of shifts in cytosolic calcium for several decades, only recently have we gained a rudimentary understanding of the membrane calcium channels that change cell shape. Members of the transient receptor potential family (TRP) are chief among the molecular candidates for permeability-coupled calcium channels. Activation of calcium entry through store-operated calcium entry channels, most notably TRPC1 and TRPC4, increases lung endothelial cell permeability, as does activation of calcium entry through the TRPV4 channel. However, TRPC1 and TRPC4 channels appear to influence the lung extraalveolar endothelial barrier most prominently, whereas TRPV4 channels appear to influence the lung capillary endothelial barrier most prominently. Thus, phenotypic heterogeneity in ion channel expression and function exists within the lung endothelium, along the arterial-capillary-venous axis, and is coupled to discrete control of endothelial barrier function.

Objective-Lung inflammation causes perivascular fluid cuffs to form around extra-alveolar blood vessels; however, the physiologic consequences of such cuffs remain poorly understood. Herein, we tested the hypothesis that perivascular fluid cuffs, without concomitant alveolar edema, are sufficient to decrease lung compliance.Design-Prospective, randomized, controlled study. Setting-Research laboratory. Subjects-One hundred twenty male CD40 rats.Interventions-To test this hypothesis, the plant alkaloid thapsigargin was used to activate store-operated calcium entry and increase cytosolic calcium in endothelium. Thapsigargin was infused into a central venous catheter of intact, sedated, and mechanically ventilated rats.Measurements-Static and dynamic lung mechanics and hemodynamics were measured continuously.Main Results-Thapsigargin produced perivascular fluid cuffs along extra-alveolar vessels but did not cause alveolar flooding or blood gas abnormalities. Lung compliance dose-dependently decreased after thapsigargin infusion, attributable to an increase in tissue resistance that was attributed to increased tissue damping and tissue elastance. Airway resistance was not changed. Neither central venous pressure nor left ventricular end diastolic pressure was altered by thapsigargin. Heart rate did not change, although thapsigargin decreased pressure over time sufficient to reduce cardiac output by 50%. Infusion of the type 4 phosphodiesterase inhibitor, rolipram, prevented thapsigargin from inducing perivascular cuffs and decreasing lung compliance. Rolipram also normalized pressure over time and corrected the deficit in cardiac output.Conclusions-Our findings resolve for the first time that perivascular cuff formation negatively impacts mechanical coupling between the bronchovascular bundle and the lung parenchyma, decreasing lung compliance without impacting central venous pressure. Keywordspermeability; endothelium; thapsigargin; store-operated calcium entry; acute respiratory distress syndromeThe authors have not disclosed any potential conflicts of interest. The pulmonary endothelium normally serves as a tightly regulated barrier between blood and interstitium. However, endothelial barrier function is compromised in the blood vessels of critically ill patients with acute lung injury or acute respiratory distress syndrome (ARDS). Endothelial cell barrier disruption causes fluid accumulation in the lung parenchyma, which ultimately leads to inefficient gas exchange and decreased alveolar ventilation, and also in perivascular spaces surrounding extra-alveolar arteries and veins (1). Traditional thinking advocates that capillary endothelial cell barrier disruption increases interstitial fluid accumulation that is pulled by negative interstitial pressure into perivascular spaces of larger vessels as a safety mechanism that limits alveolar flooding. However, recent acute lung injury and pulmonary edema animal models indicate that extra-alveolar vessels exhibit greater permeability responses than do capillarie...

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Ki-67 index of >10% is a sensitive indicator of malignant behavior and mortality. Future advances in management of pNETs will require development of staging guidelines with higher predictive value. Inclusion of Ki-67 labeling >10% as an indicator of aggressive disease may contribute to such improvements.