Kharge AB, Wu Y, Perlman CE. Surface tension in situ in flooded alveolus unaltered by albumin. J Appl Physiol 117: 440 -451, 2014. First published June 26, 2014 doi:10.1152/japplphysiol.00084.2014.-In the acute respiratory distress syndrome, plasma proteins in alveolar edema liquid are thought to inactivate lung surfactant and raise surface tension, T. However, plasma protein-surfactant interaction has been assessed only in vitro, during unphysiologically large surface area compression (%⌬A). Here, we investigate whether plasma proteins raise T in situ in the isolated rat lung under physiologic conditions. We flood alveoli with liquid that omits/includes plasma proteins. We ventilate the lung between transpulmonary pressures of 5 and 15 cmH2O to apply a near-maximal physiologic %⌬A, comparable to that of severe mechanical ventilation, or between 1 and 30 cmH2O, to apply a supraphysiologic %⌬A. We pause ventilation for 20 min and determine T at the meniscus that is present at the flooded alveolar mouth. We determine alveolar air pressure at the trachea, alveolar liquid phase pressure by servo-nulling pressure measurement, and meniscus radius by confocal microscopy, and we calculate T according to the Laplace relation. Over 60 ventilation cycles, application of maximal physiologic %⌬A to alveoli flooded with 4.6% albumin solution does not alter T; supraphysiologic %⌬A raise T, transiently, by 51 Ϯ 4%. In separate experiments, we find that addition of exogenous surfactant to the alveolar liquid can, with two cycles of maximal physiologic %⌬A, reduce T by 29 Ϯ 11% despite the presence of albumin. We interpret that supraphysiologic %⌬A likely collapses the interfacial surfactant monolayer, allowing albumin to raise T. With maximal physiologic %⌬A, the monolayer likely remains intact such that albumin, blocked from the interface, cannot interfere with native or exogenous surfactant activity. alveolar edema; albumin; plasma proteins; surfactant; surface tension IN THE ACUTE RESPIRATORY DISTRESS syndrome (ARDS), high alveolar-capillary barrier permeability results in pulmonary edema.1 The liquid that floods the alveolus contains plasma proteins that can inactivate lung surfactant by adsorbing faster than surfactant and, once present at the interface, blocking further surfactant adsorption (21,45,47,53). Plasma proteins have been shown in vitro to increase surface tension, T, in a dose-dependent fashion (18,41,42,45,53). Elevated surface tension may, in turn, underlie a decrease in lung compliance in ARDS (29) and thus contribute to the need for mechanical ventilation. Intratracheal delivery of exogenous surfactant has been tested in six randomized, controlled clinical trials as a therapy for ARDS, a means of reversing surfactant inactivation, but has failed to reduce mortality (5), which remains Ͼ35% (33).The evidence for increased surface tension in ARDS stems from the reduced surface activity of bronchoalveolar lavage fluid (BALF) from ARDS patients (14,18,19,32,34). This reduced surface activity is principally attri...

With proteinaceous-liquid flooding of discrete alveoli, a model of the edema pattern in the acute respiratory distress syndrome, lung inflation over expands aerated alveoli adjacent to flooded alveoli. Theoretical considerations suggest that the overexpansion may be proportional to surface tension, T. Yet recent evidence indicates proteinaceous edema liquid may not elevate T. Thus whether the overexpansion is injurious is not known. Here, working in the isolated, perfused rat lung, we quantify fluorescence movement from the vasculature to the alveolar liquid phase as a measure of overdistension injury to the alveolar-capillary barrier. We label the perfusate with fluorescence; micropuncture a surface alveolus and instill a controlled volume of nonfluorescent liquid to obtain a micropunctured-but-aerated region (control group) or a region with discrete alveolar flooding; image the region at a constant transpulmonary pressure of 5 cmH2O; apply five ventilation cycles with a positive end-expiratory pressure of 0-20 cmH2O and tidal volume of 6 or 12 ml/kg; return the lung to a constant transpulmonary pressure of 5 cmH2O; and image for an additional 10 min. In aerated areas, ventilation is not injurious. With discrete alveolar flooding, all ventilation protocols cause sustained injury. Greater positive end-expiratory pressure or tidal volume increases injury. Furthermore, we determine T and find injury increases with T. Inclusion of either plasma proteins or Survanta in the flooding liquid does not alter T or injury. Inclusion of 2.7-10% albumin and 1% Survanta together, however, lowers T and injury. Contrary to expectation, albumin inclusion in our model facilitates exogenous surfactant activity.

In the acute respiratory distress syndrome, alveolar flooding by proteinaceous edema liquid impairs gas exchange. Mechanical ventilation is used as a supportive therapy. In regions of the edematous lung, alveolar flooding is heterogeneous, and stress is concentrated in aerated alveoli. Ventilation exacerbates stress concentrations and injuriously overexpands aerated alveoli. Injury degree is proportional to surface tension, T. Lowering T directly lessens injury. Furthermore, as heterogeneous flooding causes the stress concentrations, promoting equitable liquid distribution between alveoli should, indirectly, lessen injury. We present a new theoretical analysis suggesting that liquid is trapped in discrete alveoli by a pressure barrier that is proportional to T. Experimentally, we identify two rhodamine dyes, sulforhodamine B and rhodamine WT, as surface active in albumin solution and investigate whether the dyes lessen ventilation injury. In the isolated rat lung, we micropuncture a surface alveolus, instill albumin solution, and obtain an area with heterogeneous alveolar flooding. We demonstrate that rhodamine dye addition lowers T, reduces ventilation-induced injury, and facilitates liquid escape from flooded alveoli. In vitro we show that rhodamine dye is directly surface active in albumin solution. We identify sulforhodamine B as a potential new therapeutic agent for the treatment of the acute respiratory distress syndrome.

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