J Physiol 589.

12 (2011) pp 2945–2953 2945

SYMPOSIUM REVIEW

Pathophysiology of tissue fluid accumulation

in inflammation
Helge Wiig
Department of Biomedicine, University of Bergen, Norway

Abstract The potential role of extravascular factors for the local as well as systemic response to
an inflammatory stimulus is addressed here in light of recent data from the trachea, serving
as a surrogate for lower airways, and spleen, because of its role in the immune response
and fluid volume regulation. From analysis of interstitial fluid from trachea it is apparent
that the colloid osmotic pressure is high relative to plasma, suggesting a significant buffering
The Journal of Physiology

capacity against oedema formation, and also that there is a significant local production of
proinflammatory mediators to a systemic inflammatory stimulus. Inflammatory stimuli may
furthermore result in a rapid reduction in interstitial fluid pressure, thus leading to increased
filtration and oedema formation. Knowledge regarding the fluid phase within the spleen micro-
environment can be gathered via analysis of drained lymph. During a septic response induced by
lipopolysaccharide injection, the spleen contributes significantly to the production of pro- and
anti-inflammatory cytokines, and may induce protracted inflammation because of a dominant
role in IL-6 production. Significant amounts of immune cells exit via lymph, and acquire specific
activation signatures having been exposed to the spleen microenvironment. Although often
overlooked, extravascular or interstitial factors may therefore contribute significantly to the
inflammatory process and thus the ensuing oedema associated with inflammation.

(Received 26 January 2011; accepted after revision 4 April 2011; first published online 11 April 2011)
Corresponding author H. Wiig: Department of Biomedicine, Jonas Lies vei 91, N-5009 Bergen, Norway.
Email: helge.wiig@biomed.uib.no

Introduction central role in fluid filtration. Here I will briefly discuss

Increased microvascular fluid filtration may result in
tissue fluid accumulation and oedema, and can be the
result of increased endothelial permeability, alteration
of the so-called Starling forces determining fluid
filtration, or impaired lymph drainage (Levick & Michel,
2010). Oedema can affect organ function, and be life
threatening if occurring in the airways and brain. An
important instigator of increased endothelial permeability
is inflammation, and tissue swelling (‘tumour’) is one
of the hallmarks of inflammation. Traditionally, when
discussing the pathogenesis of inflammatory oedema, the
focus has been on the endothelial barrier because of its
This report was presented at The Journal of Physiology Symposium on
Physiology, pharmacology and pathology of tissue fluid exchange, which
took place at the 31st International Symposium on Intensive Care and
Emergency Medicine, Brussels, Belgium on 22 March 2011. It was
commissioned by the Editorial Board and reflects the views of the author.
determinants of transcapillary fluid exchange and review
recent data on the pathophysiology of inflammatory
oedema focusing on the extravascular compartment,
Helge Wiig completed his doctorate at
the University of Bergen, Norway, working
with Professors Knut Aukland and Rolf
K. Reed on questions related to inter-
stitial fluid pressure, primarily in skin
and muscle. Following his doctorate he
worked on the effect of the extracellular
matrix on the distribution of extracellular
proteins in the interstitial fluid (exclusion)
and oedema-preventing mechanisms. He
is now Professor at the Department of Biomedicine, University of
Bergen, focusing on interstitial fluid pressure, interstitial fluid and
lymph, i.e. the tissue microenvironment, in normal and pathological
conditions.


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2946 H. Wiig J Physiol 589.12

notably the interstitial fluid, and the local production
of signalling substances that influence the inflammatory
process. I will put special emphasis on two organs that
may be of particular interest in critically ill patients – the
trachea, serving as a surrogate for lower airways, and the
spleen, because of its role in the immune system and fluid
volume regulation – and on animal studies of systemic
inflammation using septicaemia as a model. Collectively
these studies show that the interstitium has an important
role in the pathophysiology of an inflammatory oedema.
Determinants of transcapillary fluid exchange
To assist in our analysis we need a quantitative framework,
and owe much of this framework to the fundamental
work by Starling more than a century ago (Starling,
1896). He proposed that the capillaries are semipermeable
membranes, and that transcapillary fluid movement is
determined by the imbalance between colloid osmotic
and hydrostatic forces. Subsequent experiments discussed
in Levick & Michel (2010) established the following
expression:
J v =L p A[(P c −P if )−σ(COPc −COPif )]
also known as the Starling equation, where J v is the net
capillary filtration, Lp is the hydraulic permeability of the
capillaries, A is the surface area available for filtration
and σ is the capillary reflection coefficient (see Fig. 1).
(P c – P if ) is the hydrostatic pressure difference between
plasma in the capillaries (c) and interstitial fluid (if), and
(COPc – COPif ) represents the corresponding difference
in colloid osmotic pressures. These hydrostatic and colloid
osmotic pressures are commonly referred to as Starling
forces, and I will mainly address the interstitial fluid or
the ‘inaccessible tissue factors’ in fluid volume regulation
(Aukland & Nicolaysen, 1981). During control conditions
the lymph flow will be equal to J v , and thereby the tissue
hydration is kept constant, whereas during inflammation
the various parameters will change as schematized in Fig. 1
and fluid will accumulate.
When discussing the Starling forces we should consider
recent data questioning the importance of COPif for fluid
exchange. According to Levick & Michel (2010), COPif
may be considered as the colloid osmotic pressure in
‘global’ interstitial fluid, whereas the pressure relevant
for fluid exchange is the pressure immediately distal
to the filtration barrier, which because of continuous
fluid filtration and dilution of proteins is significantly
lower. That such gradients exist was first suggested and
shown for fenestrated capillaries (Levick, 1994) and later
in non-fenestrated continuous mesenteric capillaries in
frogs (Hu et al. 2000) and rats (Adamson et al. 2004).
Such gradients are, however, filtration dependent, and

Figure 1. Overview of the transcapillary–interstitial fluid exchange system in control situation and
during inflammation
Left (Control): the transcapillary hydrostatic (P) and colloid osmotic pressure (COP) determining capillary fluid
flux. Subscripts ‘c’ and ‘if ’ denote capillary and interstitial fluid, respectively. Lp A and σ are capillary hydraulic
conductivity and capillary reflection coefficient, respectively. The capillary net filtration pressure (P) is normally
0.5–1 mmHg and results in a net fluid filtration (Jv ) that is removed by lymph flow. Collagen and glycosaminoglycans
including hyaluronan are abundant structural components of loose connective tissues. Right: presumed changes
in pressures and filtration parameters during inflammation. Modified from Wiig et al. (2003b).


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J Physiol 589.12 Interstitial fluid accumulation 2947

are most pronounced during increased filtration. In the
normal, steady-state situation, these gradients may be
small (Reed & Rubin, 2010), as also suggested by modelling
showing that the effective COP (i.e. for filtration) is
∼80% of the global COPif (Adamson et al. 2004). It is
accordingly of importance to determine COPif for normal
fluid filtration and to discuss this factor when considering
oedema-preventive mechanisms.
Access to the ‘inaccessible’ tissue factors in trachea
In order to quantify one of the interstitial Starling forces,
namely COPif , as well as the tissue fluid concentration
of signalling substances, it is imperative to have the
appropriate methodologies that provide native inter-
stitial fluid. Since interstitial fluid may not be readily
available in normally hydrated tissue, various techniques
have been developed for fluid isolation, as reviewed by
Aukland & Reed (1993) and recently by Wiig et al. (2010).
Prenodal lymph may be considered to represent inter-
stitial fluid (Aukland & Reed, 1993), but its use is mostly
limited to larger experimental animals. In an attempt
to address questions in relation to mechanisms behind
fluid extravasation in the airways from an ‘interstitial’
perspective, we recently demonstrated that a modified
version of a centrifugation method developed for isolation
of interstitial fluid from tumours and skin (Wiig et al.
2003a) could be used for interstitial fluid isolation in rat
trachea (Semaeva et al. 2008). Evidently, the study of the
trachea is of interest per se, but may also be considered as
a surrogate for lower airways.
To our knowledge there were no previous data on inter-
stitial fluid in normal trachea, and we were surprised
to find a COPif in the control situation 85% of that
in plasma (Semaeva et al. 2008), significantly higher
than the corresponding ratio for afferent lung lymph
in larger animals of ∼0.7 (Parker et al. 1981; Grimbert
et al. 1988; McClure & Weidner, 1988) and skin and
muscle of ∼0.6 (Wiig et al. 1988, 1991). Several specific
features of the trachea microcirculation may contribute
to a high COPif in the control situation. The trachea is
richly vascularized (Widdicombe, 1993, 1996), implying
that there is a significant area for exchange, thus allowing
for diffusion of proteins across the capillaries. Although
recent data suggest the possibility of lymphatic fluid and
protein exchange (Scallan & Huxley, 2010), the protein
concentration in afferent (prenodal) lymph and thereby
interstitial fluid is strongly dependent on net capillary
filtration (Taylor & Granger, 1984). It is thus possible that
a low net filtration will add to the increased diffusion to
create a high protein concentration in the trachea inter-
stitial fluid. Surprisingly, the interstitial fluid-to-plasma

Figure 2. Cytokines in interstitial fluid,

serum and bronchoalveolar lavage
Concentration of cytokines (IL-1β, IL-6, IL-10,
TNF-α) in trachea interstitial fluid (filled
squares), serum (filled triangles) and
bronchoalveolar lavage (BAL) (filled circles)
samples in experimental endotoxaemia induced
by I.V. injection of lipopolysaccharide
(3.0 mg kg−1 ). The experiment ended 180 min
after LPS administration. Controls (n = 10)
received vehicle alone and were kept for
180 min. Serum (n = 10), trachea interstitial
fluid (n = 5) and BAL samples (n = 5) from
control animals exhibited low or undetectable
levels of cytokines. Except for IL-10 in BAL, LPS
resulted in significant increases in all cytokines
in serum, interstitial fluid and BAL fluid.
ANOVA, ∗ : P < 0.05 compared with
experimental serum, §: P < 0.05 compared
with experimental BAL. Values are
mean ± SEM. Reproduced from Semaeva et al.
(2008) with permission, American Physiological
Society.


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2948
COP ratio was not decreased during volume overload.
Fluid overload will increase the net filtration and in several
other tissues has been shown to reduce lymph (and inter-
stitial fluid)-to-plasma protein concentration ratio (Taylor
& Granger, 1984). An increased filtration notwithstanding,
the large surface area will also contribute to protein
exchange by diffusion in this situation. Moreover, the
extensive lymphatic network in the trachea (Baluk et al.
2005) will probably contribute to removal of filtered fluid
and proteins and thus sustain the high relative COPif
during increased filtration.
Even though the importance of COPif has been
questioned as discussed above, this parameter is still
one of the predictors of the oedema-preventing capacity
of a tissue (Aukland & Reed, 1993). In rat skin and
muscle, a reduction in COPif can counteract an increase
in net filtration pressure of 8–10 mmHg (Fadnes, 1976;
Reed, 1981). Even if we do not know at what COPif
oedema develops in trachea, the observed high COPif
only 3 mmHg lower than plasma in the control situation
suggests that the interstitium in trachea is capable of
compensating for a significantly higher increase in net
filtration pressure than in skin and skeletal muscle. This
assumption is supported by the dramatic reduction during
H. Wiig J Physiol 589.12
induced hypervolaemia, and COPif may thus contribute
significantly to oedema prevention in situations with
increased filtration and thus be vitally important.
Interstitial fluid is furthermore an important element
of the tissue microenvironment, and access to such
fluid may reveal production of biologically important
substances and paracrine signalling occurring in the
tissue. By analysis of trachea interstitial fluid we were
able to demonstrate substantial local production of
pro- and anti-inflammatory mediators after exposure to
lipopolysaccharide (LPS) (Semaeva et al. 2008). This was
achieved by comparing interstitial levels of cytokines to
those of plasma since any solute transported across the
microvasculature from plasma will be present in a lower
concentration in interstitial fluid (and lymph, see below)
than in plasma (Curry, 2005). Local interstitial production
was most pronounced for the proinflammatory cyto-
kine IL-1β, which exceeded its concentration in serum
16-fold (Fig. 2). This observation was supported by
immunohistochemistry showing a dramatic increase in
IL-1β-producing cells in the trachea interstitium after
LPS stimulation (Fig. 3). Of note, increased IL-1β staining
was also observed for epithelial cells (Fig. 3), suggesting
that these cells together with macrophages, monocytes
Figure 3. Effect of LPS on IL-1β production in rat
trachea
Photomicrographs of sagittal tracheal sections double
stained with IL-1β (red) and ED1 (green – nuclei are
counterstained with blue). There is almost no staining
for IL-1β in the control rat (A). A few tissue
macrophages reside in the lamina propria (C) and the
tissue architecture appears normal (A, C and E).
Exposure to lipopolysaccharide (LPS) induced flattening
of the epithelial cells and increased staining for IL-1β in
the lamina propria and submucosa (B and F), as well as
increased infiltration with ED1+ cells in the same areas
(D and F). Open arrows indicate ED1+ cells producing
IL-1β (B and D). Furthermore, chondrocytes in the
tracheal cartilage were positively stained for IL-1β after
LPS exposure (filled arrows, B) indicating that they may
have contributed to the local production of IL-1β. lu:
lumen; ep: epithelial cells; sub: submucosa; hc: hyaline
cartilage. Reproduced from Semaeva et al. (2008 ) with
permission, American Physiological Society.

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J Physiol 589.12 Interstitial fluid accumulation 2949

and neutrophils contribute to the interstitial production

of mediators (Maus et al. 2002; Poynter et al. 2003;
Cheng et al. 2007). The response to these locally released
mediators may be complex and dependent on the species,
but a common denominator is that they are commonly
associated with vasodilatation, thickening of the mucosa,
increased capillary permeability with exudate and oedema
as a final result (Widdicombe, 1993, 1996; Daffonchio
et al. 2002). Interestingly, in spite of high levels of
proinflammatory mediators in septic animals, there was
no tracheal oedema in our experiments (Semaeva et al.
2008). Similar results were observed in skeletal muscle
(Borge et al. 2009). A likely explanation for these findings
is that LPS resulted in reduced capillary pressure and
blood flow as observed in the dental pulp (Bletsa et al.
2006). Even if the cytokine release increased the capillary
permeability, increased permeability alone is insufficient
to cause oedema unless capillary pressure is elevated
(Gabel et al. 1984).

Contribution of P if in acute inflammatory oedema

generation in trachea
When discussing the role of extravascular factors for
acute inflammatory oedema generation in trachea, the
importance of another factor, P if , has been emerging
during the last decades. In a series of studies, recently
reviewed in Reed & Rubin (2010), Reed and collaborators
have shown that lowering of P if is part of the
pathological process of tissue swelling in acute oedema.
Thus, after dextran-induced anaphylaxis in rats, P if in
trachea fell by 7.8 mmHg, thus markedly increasing
the net filtration pressure (Koller & Reed, 1992) and
thereby contributing to the oedema generation. Similar
results have been found after inflammation induced
by mast cell degranulation (Koller et al. 1993) and
neurogenic inflammation following stimulation of the Figure 4. Spleen lymph flow and colloid osmotic pressure in
vagal nerve (Woie et al. 1993), suggesting that this experimental endotoxaemia
is a general mechanism for oedema generation in A, spleen lymph flow after experimental endotoxaemia induced by
I.V. injection of lipopolysaccharide (3.0 mg kg−1 ) (open circles)
trachea. Interestingly, this effect can be counteracted by
(n = 6). Experiment ended 180 min after LPS administration.
α-trinositol, an agent suggested to act on β1-integrins Controls (n = 5) (filled circles) received vehicle alone and were kept
that are cellular adhesion receptors towards extracellular for 180 min. Values are means ± SEM. ANOVA, ∗ : P < 0.05
matrix components (Koller et al. 1997). Based on a compared with beginning of experiment, §: P < 0.05 when
series of subsequent experiments, Reed and co-workers compared with respective values in control animals. B, colloid
(Reed & Rubin, 2010) have suggested that under osmotic pressure in plasma (circles) and spleen lymph (triangles) in
control situation (n = 5) (filled symbols) and in experimental
normal conditions fibroblasts, via their collagen-binding endotoxaemia induced by I.V. injection of lipopolysaccharide
β1 -integrins, maintain a cellular tension on the collagen (3.0 mg kg−1 ) (open symbols) (n = 5). Values are means ± SEM.
and microfibril network limiting the tissue’s inherent ANOVA, ∗ : P < 0.05 compared with corresponding plasma
ability to swell. The lowering of P if is proposed to arise colloid osmotic pressure, §: P < 0.05 when compared with
from release of this tension during inflammation, allowing lymph control value, #: P < 0.05 when compared with plasma
control value. Reproduced from Semaeva et al. (2010) with
for expansion of glycosaminoglycans in the extracellular permission. Copyright 2010. The American Association of
matrix and thereby uptake of fluid and oedema formation Immunologists, Inc.
(Liden et al. 2006).


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2950 H. Wiig J Physiol 589.12

The spleen microenvironment in LPS-inflammation lymph, preferably prenodal, deriving from the spleen
should reflect the interstitial fluid phase (Aukland &
Above we have discussed frequently overlooked
Reed, 1993). We recently sampled lymph (postnodal)
extravascular factors that are contributing to and counter-
from the spleen of rats to provide information from the
acting the development of oedema in the airways during
spleen microenvironment on circulatory regulation and
an inflammatory response. Another organ of importance
immune function in systemic inflammation induced by
for an inflammatory process and where little is known
lipopolysaccharide (LPS) (Semaeva et al. 2010). Although
about the role of the microenvironment in this setting
it is known that postnodal lymph may be influenced by its
is the spleen. This organ plays important roles in fluid
passage through the lymph node (Adair et al. 1982; Young,
volume regulation as well as in immune responses and
1999), we argued that such alteration was modest in our
haematopoiesis (Mebius & Kraal, 2005). While there is
case (Semaeva et al. 2010).
no known method for spleen interstitial fluid isolation,

Figure 5. Concentration of cytokines in serum and lymph during endotoxaemia

Concentration of the proinflammatory cytokines IL-1β (A), IL-6 (B) and TNF-α (C) and the anti-inflammatory
cytokine IL-10 (D) in serum (filled circles) and spleen lymph (open circles) samples in experimental endotoxaemia
induced by I.V. injection of lipopolysaccharide (3.0 mg kg−1 ) (n = 5). The experiment ended 180 min after LPS
administration. Controls (n = 5) received vehicle alone and were kept for 180 min. Serum and spleen lymph
samples from control animals exhibited low or undetectable levels of cytokines and data are not shown. ANOVA,
∗ : P < 0.05 compared with experimental serum. Values are mean ± SEM. Reproduced from Semaeva et al. (2010)

with permission. Copyright 2010. The American Association of Immunologists, Inc.


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J Physiol 589.12 Interstitial fluid accumulation 2951

The spleen has a very high blood flow (Chen & and that STAT3 and CREB were important mediators
Kaufman, 1996), and a significant arterio-venous volume in the cellular signalling occurring in this condition
difference, suggesting that there is a substantial net (Semaeva et al. 2010). Collectively, these experiments
filtration out of the blood into the lymphatic system gave new information on the spleen’s role in a systemic
(Chen & Kaufman, 1996; Deng & Kaufman, 1996), an
effect that is increased by LPS (Andrew et al. 2000).
Our observation that LPS had a significant effect on
lymph flow as well as vascular sieving properties, and
resulted in an 8-fold increase in lymph flow (Fig. 4A)
might therefore be expected. Although the spleen is known
to have discontinuous capillaries, we could demonstrate
that there was a small, but significant, sieving mostly for
molecules exceeding the size of albumin. Such sieving was
even maintained after LPS, known to increase vascular
permeability (e.g. Lundblad et al. 2004), as evident from
a maintained gradient in COP between plasma and inter-
stitium (i.e. lymph) after LPS treatment (Fig. 4B). Another
implication of these findings is that the influence of plasma
and interstitial fluid COP in fluid filtration (and oedema
prevention, cf. above) is small in the spleen.
Having access to the spleen fluid microenvironment, i.e.
the fluid bathing the cells residing in the lymph drainage
area, we could assess mediators released from these cells
during endotoxaemia by relating the lymph concentration
to that of plasma (see above). We could show that there
was local production of the proinflammatory cytokines
IL-6 and TNF-α and the anti-inflammatory cytokine
IL-10 after LPS exposure (Fig. 5), and that the spleen may
provide the systemic circulation with cytokines that can
modify the inflammatory response (Semaeva et al. 2010).
The important role of the spleen for the cytokine response
was further emphasized by experiments in splenectomized
animals, showing a markedly higher IL-6 and a moderately
higher TNF-α response in rats with intact spleen (Fig. 6).
Interestingly, IL-6 appears to be a mediator that is released
‘distally’ to the ‘proximal’ cytokines IL-1β and TNF-α and
may downregulate proximal cytokines, thereby limiting
the inflammatory reaction (Blackwell & Christman, 1996).
Moreover, IL-6 seems to predict the level of cytokine
cascade activation and subsequent organ dysfunction
and death in sepsis (Blackwell & Christman, 1996). The
severely blunted IL-6 response to LPS after splenectomy
shows in a quantitative way the importance of the spleen in
the modulation of the inflammatory response that may be
of vital importance and predict survival. This reaction may
also be part of the explanation for the overwhelming sepsis Figure 6. Concentration of proinflammatory cytokines after
splenectomy
occurring in asplenic/hyposplenic individuals (Hansen &
Concentration of the proinflammatory cytokines IL-6 (A) and TNF-α
Singer, 2001; Poynter et al. 2003; Cheng et al. 2007). (B) in serum of control animals with intact spleen receiving vehicle
Apart from the vascular responses and secretion of alone (filled circles) (n = 5) and splenectomized (open circles) (n = 5)
signalling substances to the lymph we could demonstrate rats in experimental endotoxaemia induced by I.V. injection of
that significant amounts of lymphocytes exit the spleen via lipopolysaccharide (3.0 mg kg−1 ). The experiment ended 180 min
after LPS administration. Intact animals received vehicle alone and
the draining lymphatics, and that endotoxaemia resulted
were kept for 180 min. ANOVA, ∗ : P < 0.05 compared with serum
in increased T-cell and reduced B-cell efflux. We could from splenectomized rats. Values are mean ± SEM. Reproduced
furthermore show that exposure of lymphocytes to the from Semaeva et al. (2010) with permission. Copyright 2010. The
spleen microenvironment affected their signalling status American Association of Immunologists, Inc.


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2952 H. Wiig
inflammatory response that may influence therapeutic
strategy in asplenic patients.
Summary and perspectives
The data discussed here on extracellular factors
contributing to an inflammatory reaction and tissue
fluid accumulation in trachea and spleen may have
clinical implications. In trachea as well as other
organs, septicaemia induces a significant production of
proinflammatory mediators that do not induce local
oedema unless the capillary pressure is elevated, suggesting
that a volume overload in this situation may result
in oedema of the airways and should be taken into
consideration during fluid therapy of this category of
patients. The rapid increase in filtration pressure caused by
an inflammation-induced reduction in trachea interstitial
fluid pressure will contribute to acute oedema formation,
but this effect can be counteracted by α-trinositol (Koller
et al. 1997). Supporting this suggestion, Reed and
co-workers recently proposed a molecular mechanism
opposing interstitially induced oedema, showing that
tendencies to oedema formation can be counteracted via
an effect on platelet-derived growth factor (PDGF)-BB
through stimulating the activity of the αvβ3-integrin
(Liden et al. 2006). These data indicate that the
contribution to oedema-generation originating in the
interstitium can be targeted therapeutically. As for trachea,
analysis of spleen lymph shows that there is a significant
local production of signalling substances that contributes
to the local inflammatory response. Signalling substances
produced in the spleen and cells that have been exposed
to the spleen interstitium give important new information
on cell modifications occurring in the splenic lymphatic
bed in these conditions and thereby how the spleen
contributes to the systemic inflammatory response. This
knowledge may be particularly important in under-
standing the pathophysiology of overwhelming sepsis
(Hansen & Singer, 2001) that may occur in patients
missing the spleen or spleen function.
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