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PERSPECTIVES
Department of Physiology, Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, Alabama
ABSTRACT
Recent permeability studies comparing endothelial cell phenotypes derived from alveolar and extra-alveolar vessels have significant implications for interpreting the mechanisms of fluid homeostasis in the intact lung. These studies indicate that confluent monolayers of rat pulmonary microvascular endothelial cells had a hydraulic conductance (Lp) that was only 5% and a transendothelial flux rate for 72-kDa dextran only 9% of values determined for rat pulmonary artery endothelial cell monolayers. On the basis of previous studies partitioning the filtration coefficients between alveolar and extra-alveolar vascular segments in rat lungs and previous studies of lymph albumin fluxes and permeability, the contribution of the alveolar capillary segment to total albumin flux in lymph was estimated to be less than 10%. In addition, the Starling safety factors against the edema calculated for the alveolar capillaries are quite different from those estimated for whole lung. Estimates of the edema safety factor due to increased filtration across the alveolar capillary wall based on the low Lp indicate it is quantitatively the greatest safety factor, although it would be a minor safety factor for extra-alveolar vessels. Also, a markedly higher effective protein osmotic absorptive force for plasma proteins must occur in the capillaries relative to extra-alveolar vessels. The lower Lp for alveolar capillaries also has implications for the sequence of hydrostatic edema formation, and it also may have a role in preventing exercise-induced alveolar flooding.
capillary permeability; pulmonary edema; lymph flow
0.3 µm thick (28). Although this architecture facilitates diffusive gas exchange, these same features facilitate both diffusion of solutes and fluid exchange. In spite of this, the alveolar spaces remain dry over a wide range of pulmonary vascular pressures and blood flows.
Capillary filtration is determined by a balance of Starling forces.
Ernst Starling recognized that the major force operating to limit fluid filtration from the capillaries was the difference between the capillary hydrostatic pressure (Pc) and plasma colloid osmotic pressure (
p) (19). Subsequent studies have implicated the hydraulic conductivity (Lp), surface area (S), reflection coefficient (
), and interstitial oncotic (i) and hydrostatic pressures (Pi) such that transcapillary filtration rate (Jv) is determined by (24):
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In the pulmonary circulation, a low capillary hydrostatic pressure of 7 mmHg and a plasma colloid osmotic pressure of 28 mmHg provides a greater potential absorptive force than most systemic vascular beds (4). This pressure differential is partially offset by a high-baseline tissue protein concentration that reduces the effective transcapillary colloid osmotic absorptive pressure [(p – i)]. In dog lungs, baseline Pc averaged 11.1 cmH2O, whereas the plasma-lymph oncotic gradient (p – L) averaged 11.0 cmH2O (13). In spite of a 10-fold greater capillary surface area in lung compared with leg (3,600 vs. 300 cm2/g), the lung has a resting baseline lymph flow of 0.06 ml·min–1·100 g–1, which is approximately equivalent to resting lymph flow of the leg (12).
Lp of different lung vascular segments. Recent studies from our laboratory suggest that an additional feature of the lung capillaries, which limits fluid filtration, is the low Lp of the pulmonary microvascular endothelial cells (15). Lp values averaged 22-fold greater for rat pulmonary artery endothelial cells (RPAEC) (28.6 ± 5.6 x 10–7 cm·s–1·cmH2O–1) than rat pulmonary microvascular endothelial cells (RPMVEC) (1.30 ± 0.50 x 10–7 cm·s–1·cmH2O–1) in newly confluent monolayers. The baseline Lp values we observed for RPAEC monolayers are comparable to Lp values reported for cultured monolayers of porcine pulmonary artery endothelial cells (21.0 x 10–7 cm·s–1·cmH2O–1) (22), bovine aortic endothelial cells (11.4 ± 8.0 x 10–7 cm·s–1·cmH2O–1), and human umbilical vein endothelial cells (29.0 ± 8.5 x 10–7 cm·s–1·cmH2O–1) (10). In contrast, the RPMVEC Lp values were comparable to direct micropuncture measurements of Lp using the split-drop technique in dog lung venules of 2.9 ± 0.02 x 10–7 cm·s–1·cmH2O–1 (2) or that in rat lung venules of 4.4 x 10–7 cm·s–1·cmH2O–1, which decreased to 1.5 x 10–7 cm·s–1·cmH2O–1 after hypertonic challenge (18). Low microvascular Lp values were also calculated using estimated surface areas of lung vascular segments. We previously reported a segmental distribution of the filtration coefficient (Kf = LpS) in isolated rat lungs that was partitioned 18% arterial, 41% capillary, and 41% venous segments (16). By adjusting these segmental Kf values to segmental surface areas derived from vascular cast data, we estimated Lp values for arterial, venous, and microvascular segments of 6 x 10–8 cm·s–1·cmH2O–1, 1.3 x 10–7 cm·s–1·cmH2O–1, and 1.8 x 10–9 cm·s–1·cmH2O–1, respectively. Another Lp estimate for rat lungs can be derived from morphometric measurements of vascular surface area reported by Weibel (29), who reported an average capillary surface area of 0.41 m2 in lungs of 140-g rats. Using an estimate of lung weight (1.22 g) and filtration coefficient (0.1 ml·min–1·cmH2O–1·100 g–1) for this sized rat, a vascular surface area of 3,360 cm2/g lung weight and an average Lp of 4 x 10–9 cm·s–1·cmH2O–1 can be calculated from their data. However, the overestimation of capillary surface area in fluid-filled lungs using morphometry led to more than a twofold overestimate of pulmonary diffusion capacity (29). Therefore, these Lp estimates for the intact lungs may be an order of magnitude too low and indicate the need for further studies. The low Lp values for lung microvascular endothelial cells, their rapid growth rate, and predominance of E-cadherin also suggest an epithelial-like phenotype (8, 15).
Effect of phenotype differences on transcapillary and lymph protein fluxes.
The high protein concentration in pulmonary lymph and the relatively low reflection coefficients () of 0.62 for total protein and 0.5 for albumin derived from the maximal lymph protein washdown suggest a relatively leaky capillary bed (13). These values were calculated using:
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is the lymph/plasma partition coefficient at high lymph flows. However, the lack of lymphatic vessels below the level of terminal bronchioles and a low microvascular fluid conductance suggests that alveolar capillaries may contribute significantly less fluid and protein to pulmonary lymph than filtration through small extra-alveolar conduit vessels (24). This means that the permeability coefficients derived from lymph protein concentrations would be weighted by filtration across extra-alveolar conduit vessel endothelium. This is a reasonable assumption because Kelly et al. (7) observed an 11-fold greater flux of 72-kDa dextrans across RPAEC monolayers compared with RPMVEC monolayers. Since the 72-kDa dextran is close to albumin in size, a of 0.96 can be estimated for albumin across the alveolar capillary endothelium. The relative contributions of alveolar and extra-alveolar vessels to total convective albumin fluxes (Js) can then be calculated using:
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6% to total convective albumin flux in the lymph. A contribution of bronchial vascular filtration to lung lymph flow as high as 30% would result in even less of a contribution to lung lymph by microvascular protein clearance (27).
A low alveolar capillary Lp as an edema safety factor.
The classic tissue safety factors that adjust to maintain filtration homeostasis are an increased interstitial pressure, a decreased interstitial protein concentration, and an increased lymph flow (24, 26). The edema safety factor contributed by an increased lymph flow (Jv) is a function of the sum of the Starling hydrostatic and osmotic pressure gradients across the vascular wall (
Pdrop) and the fluid conductance for a given filtration pressure such that:
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Pdrop has been considered to be a minor safety factor in preventing edema formation as filtration increases when calculated using gravimetric estimates of Kfc but exceeds 20 mmHg when calculated using Kfc derived from a balance of Starling forces (23, 26). Using baseline values for lung lymph flow (0.06 ml·min–1·100 g–1) and gravimetric Kfc (0.1 ml·min–1·cmH2O–1·100 g–1), a 6.3-fold increase in filtration (lymph flow) would result in a safety factor of only 4.0 cmH2O (14, 16, 24, 26). Considering an Lp for alveolar capillaries, which is only 5% that for conduit vessels and partitioning the microvascular contribution to lymph flow in proportion to its Kf, a Pdrop safety factor across alveolar capillaries for a comparable increase in lymph flow would be 33 cmH2O!
The relative differences in between endothelial phenotypes would also minimize edema formation across alveolar vessels by increasing the safety factor due to oncotic absorptive force, because p would be 13 mmHg greater across alveolar capillaries than conduit vessels. Although a potential safety factor due to tissue protein washdown of 19.1 cmH2O was calculated at a 6.3-fold increase in lymph flow for dog lungs (13), recent experiments by Hu et al. (5) suggest that average tissue protein concentration may have only minimal effects on filtration because of significant plasma protein sieving across the glycocalyx before fluid entry into junctional pores (11). Since alveolar septal interstitial pressure is likely to increase only 1–2 cmH2O during edema formation (24), the safety factor offered by a low endothelial Lp for alveolar capillaries would far exceed the magnitude of the other tissue safety factors against hydrostatic edema formation.
Implications for hydrostatic pulmonary edema formation.
Hydrostatic pulmonary edema is characterized by early perivascular and peribronchial edema cuff formation that later progresses to alveolar flooding (21). Previous studies in zone I and embolized lungs indicate that filtration from extra-alveolar vessels moves directly into perivascular edema cuffs and lymphatics and comprises 2/3 of total filtration (1, 6, 9, 16) (Fig. 1). Capillary filtrate may also enter the interstitium of the blood-gas barrier and percolate down an interstitial pressure gradient to the perivascular/peribronchial edema cuffs (3, 24). However, the low hydraulic conductivity of the alveolar endothelial cells suggests that filtration from small extra-alveolar vessels directly into the perivascular spaces likely accounts for most of the early cuff formation. The possibility of retrograde alveolar flooding with fluid leaking from the interstitium surrounding terminal bronchioles also appears more likely (20).
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GRANTS
This work was supported by National Heart, Lung, and Blood Institute Grant P01-HL-66299.
FOOTNOTES
Address for reprint requests and other correspondence: J. C. Parker, Dept. of Physiology, College of Medicine, Univ. of South Alabama, 307 University Blvd., Mobile, AL 36688 (jparker{at}usouthal.edu)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
REFERENCES
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  T. Stevens, S. Phan, M. G. Frid, D. Alvarez, E. Herzog, and K. R. Stenmark Lung Vascular Cell Heterogeneity: Endothelium, Smooth Muscle, and Fibroblasts Proceedings of the ATS, September 15, 2008; 5(7): 783 - 791. [Abstract] [Full Text] [PDF]
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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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B. Troyanovsky, D. F. Alvarez, J. A. King, and K. L. Schaphorst Thrombin enhances the barrier function of rat microvascular endothelium in a PAR-1-dependent manner Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L266 - L275. [Abstract] [Full Text] [PDF]
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