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EDITORIAL FOCUS
Columbia University, New York, New York
SINCE ITS INTRODUCTION in the classic paper by Gaar et al. (2), determination of the microvascular filtration coefficient, Kf, has become a popular approach for quantifying the lung microvascular barrier. The method entails establishing a sustained step increase of the left atrial pressure to induce steady gain of lung weight. The ratio of the rate of weight gain to the induced pressure increase gives Kf that is usually expressed in units normalized for the lung's wet weight. Since in intact lung, lymphatic removal blunts the pressure-induced weight gain (unpublished observations), the determination works best in the isolated perfused lung.
Although procedural simplicity underlies the appeal of the Kf method, some important assumptions must be considered. These are: 1) increased microvascular filtration causes the weight gain; 2) the surface area of filtration remains constant between different experimental conditions; 3) Starling forces are constant both during the weight increase, as well as in different conditions; and 4) barrier-sensitive endothelial signaling is not invoked during the weight transient.
Assumption 1 is potentially subject to the well-known interference from blood volume. In an excellent review of theoretical and practical considerations, Parker and Townsley (11) address potential errors of Kf interpretation attributable to the high vascular compliance of the lung. Thus the pressure step causes not only the intended increase of microvascular filtration, but also vascular dilatation that increases lung blood volume, thereby independently augmenting weight gain. The early phase of the volume effect occurs as a rapid weight gain within <1 min after the pressure step. More problematic is the subsequent slower weight gain, attributable to vascular stress relaxation that causes a gradual and progressive vascular dilatation. Since the weight gain effect of stress relaxation is similar to that of filtration, a dominant stress-relaxation effect could potentially cause overinterpretation of Kf. To caution against these blood volume-induced errors, Parker and Townsley recommend that first, the pressure step should be held in the 7–10 cmH2O range to ensure filtration dominance of weight gain. Second, weight gain analyses should be delayed >20 min into the transient to ensure completion of stress relaxation.
Assumption 2, namely that of constant surface area, is also problematic, since the pressure step might dilate previously collapsed vessels to different extents, thereby causing unpredictable increases in the filtration surface area. Miyahara et al. (10), in this issue, from the Parker laboratory point out that the lung vasculature should be held in a "recruited" state at baseline. This zone 3 condition (left atrial > alveolar pressure) ensures that all vessels are already distended before the pressure step; hence, increasing pressure is unlikely to further increase the filtration surface area. However, under conditions such as severe edema or hemorrhage that might cause vascular compression, responses may be different. Under such conditions, the imposed pressure step might be large enough to open vessels that were pathologically collapsed at baseline, thereby increasing filtration surface area during the weight gain transient and incorporating overinterpretation bias to the Kf estimate.
With regard to Starling forces, namely assumption 3, it is important to recognize that in the absence of edema, increasing vascular pressure compresses the interstitium, thereby increasing interstitial pressure (3, 8). The increased filtration increases interstitial fluid content (9), thereby also increasing interstitial pressure. Such increases of interstitial pressure might progressively decrease the vascular-interstitial pressure gradient during the period of weight gain. In edema, when interstitial liquid flow to the alveolar compartment relieves interstitial compression, interstitial pressure reaches a maximum (1) and therefore may be less subject to compressive increases. By these considerations, the same increase of vascular pressure might increase interstitial pressure more in the presence than in the absence of alveolar edema. Thus a potential problem arises in comparing Kf estimates between these conditions. In alveolar edema, weight gain might be attributable to a higher hydrostatic gradient than in the nonedematous condition, predisposing to a Kf overestimate.
Although proponents of the Kf method have assumed that endothelial cells are unresponsive to the pressure step (assumption 4), optical imaging studies indicate otherwise. According to these studies, pressure increase in the range recommended by Parker and Townsley (11) increases endothelial Ca2+ in lung microvessels (5–7). Such Ca2+ increases might be barrier deteriorating to the extent that they induce proinflammatory effects such as endothelial reactive oxygen species production and leukocyte recruitment (4). The extent to which these responses affect the rate of weight gain remains undetermined. Although the responses subside following return of pressure to baseline, a sustained pressure step could also prolong these signaling responses, thereby inducing nonspecific barrier effects that complicate Kf interpretation.
These considerations add to the cautions well voiced by Parker and Townsley (11) regarding interference from the effects of blood volume and filtration surface area in the interpretation of Kf. We point out that, in addition, non-steady state interstitial and endothelial signaling effects also require consideration. Thus the recommendation to distance the analysis from the early volume effect is well taken. However, at slight variance from the Parker and Townsley recommendations, we suggest that it might be prudent to apply a smaller pressure step (e.g., 3–5 cmH2O) and to analyze the transient in the first 10 min of the weight response, to reduce time-dependent effects of interstitial edema and endothelial signaling. Finally, the sources of error attributable to all of the factors considered above are together sufficient to warrant rejection of Kf differences that fail to markedly exceed control. For an interpretation of microvascular hyperpermeability, a twofold increase above baseline must be the least accepted Kf response. Furthermore, Kf data must be supported by other quantifications of lung fluid balance, such as, for example, those related to macromolecular transport and the extravascular lung water content. Given adequate consideration of nonspecific factors that affect the weight data, the Kf determination stands a robust assessment of lung microvascular barrier properties.
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  J. C. Parker and M. I. Townsley Physiological determinants of the pulmonary filtration coefficient Am J Physiol Lung Cell Mol Physiol, August 1, 2008; 295(2): L235 - L237. [Abstract] [Full Text] [PDF]
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 T. Miyahara, K. Hamanaka, D. S. Weber, M. Anghelescu, J. R. Frost, J. A. King, and J. C. Parker Cytosolic phospholipase A2 and arachidonic acid metabolites modulate ventilator-induced permeability increases in isolated mouse lungs J Appl Physiol, February 1, 2008; 104(2): 354 - 362. [Abstract] [Full Text] [PDF]
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