Did you know...the fluid extravasation which leads to pulmonary edema may occur across large vessels as well as capillaries?


Figure 1. Two sites of fluid accumulation. Increased capillary permeability leads to alveolar flooding (left panel). Increased artery and/or vein permeability leads to perivascular cuffing (right panel).

Due to the large surface area of the capillary network, all extra-vascular pulmonary fluid has traditionally been thought to result from pathological fluid movement across the capillary endothelium. In this model, fluid leaking from capillaries is drawn by negative interstitial pressure to the extra-alveolar interstitium, and moves into alveoli only when interstitial pressure reaches some critical value which forces fluid across the alveolar epithelium [1]. However, there is considerable evidence from animal models to suggest that extra-vascular pulmonary fluid may result from fluid flux across arteries or veins as well as capillaries. Rat pulmonary venules are more permeable than capillaries when edema is induced with alpha-naphthylthiourea [2]. Arteries have been shown to be the primary source of extra-vascular fluid in models of hypoxic pulmonary edema [3]. Under conditions of increased vascular pressure in excised or in situ dog lungs, fluid movement across extra-alveolar vessels accounts for approximately 60% of extravascular fluid accumulation [4, 5]. In rat and rabbit models of acute lung injury, 50 to 75% of vascular permeability occurs in extra-alveolar vessels [6, 7]. Treatment of isolated lungs with the plant alkaloid thapsigargin induces increased permeability in large pulmonary vessels, due to retraction of cell-cell borders [8].

Of course, fluid filling of alveoli does occur during fulminate pulmonary edema and likely has significant pathophysiologic effects. For this reason, research has focused on the mechanisms controlling the accumulation and removal of fluid in the alveolar airspace [9]. However, fluid accumulation outside the alveolar airspace has also been documented in both human pathology and in animal models. Extra-alveolar fluid accumulates in the interstitium surrounding large pulmonary vessels and is often termed ‘vascular cuffing’ (see Figure). Such fluid collections have been described in lungs of patients and animals with sepsis due to Pseudomonas aeruginosa [10]. Extra-alveolar fluid collections also likely occur in patients with edema due to heart failure [11], and are documented in numerous animal models of pulmonary edema [4, 12]. Researchers have suggested that such extra-alveolar fluid accumulation contributes to airway narrowing and increased resistance to airflow [13], increased airway closing pressure and functional residual capacity in post myocardial infarct patients [11], and increased pulmonary vascular resistance [14]. In summary, classic models of fluid movement within the lung suggest that pulmonary edema results when fluid crosses the capillary membrane. However, evidence that extra-alveolar vessels may be more permeable than capillaries under both normal and pathological conditions should lead us to question the ubiquitous application of this model. Future research into the pathophysiology of diseases like Acute Respiratory Distress Syndrome (ARDS) will require accurate descriptions of the sites along the arterial-capillary-venous axis where increases in permeability occur.



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8 Chetham, PM, Babal, P, Bridges, JP, Moore, TM, and Stevens, T. Segmental regulation of pulmonary vascular permeability by storeoperated Ca2+ entry. American Journal of Physiology. 1999;276:L41-50.

9 Matthay, MA, and Zimmerman, GA. Acute lung injury and the acute respiratory distress syndrome: Four decades of inquiry into pathogenesis and rational management. Am. J. Respir. Cell Mol. Biol. 2005;33: 319-27.

10 Teplitz, C. Pathogenesis of Pseudomonas vasculitis and septic legions. Archives of Pathology & Laboratory Medicine. 1965;80:297-307.

11 Hales, CA, and Kazemi, H. Small-airways function in myocardial infarction. New England Journal of Medicine. 1974;290:761-5.

12 Luchtel, DL, Embree, L, Guest, R, and Albert, RK. Extra-alveolar veins are contiguous with, and leak fluid into, periarterial cuffs in rabbit lungs. Journal of Applied Physiology. 1991;71:1606-13.

 13 Wagner, EM. Effects of edema on small airway narrowing. Journal of Applied Physiology. 1997;83:784-91.

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Endothelin and Endothelium & Epithelium and Epithelial Transport
Pathology and Pathophysiology
Vasoreactivity: Vasoconstriction and Vasodilatation

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PVRI Chronicle Vol 2: Issue 2 cover image

July 2015

PVRI Chronicle Vol 2: Issue 2

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