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, IL-1
, and IL-6 on
interstitial fluid pressure in rat skin
Department of Physiology, University of Bergen, Bergen, Norway
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Interstitial
fluid pressure (Pif) decreases
in several experimental models of acute inflammation, enhancing edema
formation. The present study was designed to determine the effect of
tumor necrosis factor-
(TNF-), interleukin (IL)-6, and IL-1
as
well as lipopolysaccharides (LPS) on
Pif in a model of gram-negative sepsis. Pif was
measured in the paw skin of anesthetized rats (pentobarbital sodium, 50 mg/kg ip) using micropipettes (3-7 µm) and servo-controlled
counterpressure technique. Test substances were injected
intra-arterially (ia), intravenously (iv), or subdermally (sd). After
intra-arterial or intravenous administration, the test substances were
circulated for 1 min before circulatory arrest was induced with an
intravenous injection of KCl while the rats were under pentobarbital
anesthesia. Circulatory arrest was induced to avoid edema formation,
which would raise interstitial fluid volume to cause a more positive
Pif. Administration of 0.5 ml of
LPS (5 mg/ml ia) lowered
Pif significantly from control
values of 
0.2 ± 0.3 to 2.0 ± 0.3 mmHg
(P < 0.05) within 1 h. Corresponding values for TNF- (500 ng/ml iv) were 0.4 ± 0.2 to
2.3 ± 0.1 mmHg (P < 0.05). Administration of 5 µl (5 mg/ml sd) of LPS did not affect
Pif significantly
(P > 0.05), but TNF-, IL-1,
and IL-6 had a significant effect on
Pif when given subdermally.
IL-6 (50 ng/ml) caused a decrease in
Pif from control values of
1.2 ± 0.3 to 2.8 ± 0.5 mmHg
(P < 0.05) within 1 h. The
experiments demonstrate that LPS, TNF-, IL-1, and IL-6 induce
lowering of Pif when given
intravenously or intra-arterially, whereas only TNF-, IL-1, and
IL-6 induce lowering of Pif when
given subdermally. We therefore suggest that the lowering of
Pif in this experimental model of
sepsis is related to the release of and a local effect in skin of
TNF-, IL-1, and IL-6.
lipopolysaccharide; edema; sepsis; acute inflammation
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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SEPSIS, OR SEPTICEMIA, is an illness of which bacteria enter the bloodstream faster than they can be removed (3). Eschericia coli is by far the most common cause of gram-negative bacteremia, and the symptoms are related to release of lipopolysaccharide (LPS) from the cell wall. LPS is made up of three parts: first, a core region, lipid A, which is responsible for the main toxic effects; second, an oligosaccharide region linked to lipid A; and third, a polysaccharide chain responsible for antigen specificity (2). The systemic effects of intravenous administration of LPS are hypotension, peripheral vasodilation, edema formation, and in severe cases cardiovascular failure and death.
LPS initiates synthesis of several cytokines in inflammation associated
with septicemia. Inflammation is characterized in the microcirculation
by enhanced movement of fluid and leukocytes from the blood into the
extravascular tissues. The inflammatory response is associated with the
accumulation of fluid and plasma components in the affected tissue, and
edema develops when movement of fluid into the extracellular space
exceeds the drainage via the lymphatics. The increased vascular
permeability could be initiated in one of two ways. First, a
cell-derived increase may result from mast cells releasing histamine as
well as the other proinflammatory mediators stored in the mast cell
granules. Second, inflammatory events are associated with basophils,
platelets, endothelial cells, and monocytes/macrophages. It is well
known that LPS can induce production and release of vasoactive
substances such as platelet-activating factor (PAF), bradykinin, as
well as cytokines (8a). In the latter category, interleukins (IL) and
tumor necrosis factor- (TNF-) are the two prominent members. LPS
causes a strong increase in vascular permeability within 10 min after
intradermal injection (29).
An important factor explaining the rapid development of edema in acute
inflammation is that the interstitial fluid pressure (Pif) becomes more negative in
the initial stages of several inflammatory reactions (21). The
hydrostatic pressure in the extravascular and extracellular space is
one of the pressures participating in control of the transcapillary
fluid exchange. Under normal conditions, the
Pif in rat skin is 0.5 to
1 mmHg (32), and the role of
Pif is to maintain interstitial
volume and transcapillary fluid flux at normal levels (1). Contrary to
the normal role of Pif in the
control of interstitial volume, increased negativity of
Pif becomes a major driving force
for the rapidly forming edema in acute inflammation (18), including the
edema formation in the skin (5, 20) and trachea (12, 13). During
initial stages of the inflammatory reactions, loose connective tissues will therefore actively enhance transcapillary fluid flux and edema
formation in skin and airways, because an increased negativity of the
Pif from 1 to between
5 and 10 mmHg will provide an increased driving pressure
for fluid into the extravascular spaces (24) and will represent a major
increase in net capillary filtration pressure, which is normally
0.5-1 mmHg (1).
The present study investigates the role of
Pif during an experimental
sepsis/septicemia in rats. We specifically investigated the effect of
LPS, TNF-, IL-1, and IL-6 on the
Pif. The three latter are produced
by monocytes/macrophages after stimulation by LPS (6, 7, 18). Part of
the present data has been reported briefly elsewhere (17).
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal Model
The experiments were performed on female Wistar Møller rats (200-250 g) anesthetized with pentobarbital sodium (50 mg/kg ip). While under the anesthesia, the rats were kept under a heating light to maintain body temperature at 37.5-38.5°C. LPS was administered through a polyethylene (PE)-50 catheter in the right carotid artery, whereas TNF- and interleukins were administered through a PE-50 catheter in the right external jugular vein. Circulatory arrest of the
pentobarbital-anesthetized rats was induced by intracardiac injection
of 0.5 ml of saturated KCl, as part of the experimental protocol. Circulatory arrest was induced after
administration of the inflammatory agents to limit the increase in
transvascular fluid flux, which is associated with the inflammatory
reactions. The increased transcapillary fluid flux will raise
interstitial fluid volume and therefore
Pif in turn potentially causing an underestimation of a lowered Pif.
The procedures described in this article were approved by and performed in accordance with the regulations established by the Norwegian State Commission for Laboratory Animals.
Agents
Lipopolysaccharide from E. coli (serotype 0127:B8; Sigma Chemical, St. Louis, MO) was diluted in 0.9% NaCl containing 0.1% bovine serum albumin (Fraction V; Sigma Chemical) at pH 7.4. The concentration of LPS in the stock solution was 5 mg/ml. TNF- (R & D Systems, Abingdon, UK) was diluted in Ringer acetate
containing 0.1% bovine serum albumin to a final concentration of 1 mg/ml in the stock solution. It was stored at 20°C, and on
reconstitution it was diluted to 100 and 500 ng/ml. IL-1 and IL-6 (R
& D Systems) were diluted in Ringer acetate containing 0.1% bovine
serum albumin and were stored under 20°C at 1 mg/ml. On
reconstitution they were diluted with the Ringer solution to 20 ng/ml
for IL-1 and 20 and 50 ng/ml for IL-6.
Procedures
Pif was measured with a servo-controlled counterpressure system (31) connected to sharpened glass capillaries (1.0 mm OD and 0.58 mm ID, GCF100-15; Clark Electromedical Instruments, Pangbourne, UK). The pipettes were filled with 0.5 M NaCl colored with Evans blue (Merck, Darmstadt, Germany). This system allows measurement of Pif without adding or removing fluid from the tissue. The measurements were performed under visual guidance using a stereomicroscope (Wild M5, Leitz, Germany). The punctures were performed on the dorsal side of the hind paw, with the rat in the supine position. The paw was immobilized using surgical tape and without applying stretch or compression to the skin. The measurements were performed 0.2- to 0.5-mm below the skin surface using a micromanipulator (Leitz, Weitzlar, Germany). The subdermal injections of NaCl, LPS, IL-1, IL-6, and TNF- were performed with a 10-µl
syringe (Hamilton, Bonaduz, Switzerland) containing 5 µl of the test
substance. Five microliters were deposited subdermally on the dorsal
side of the paw. A circle with a diameter of 5 mm was marked on the skin of the paw and would outline a volume of 10 µl deposited under
the skin (20). The pressure recordings were performed on the outer edge
of this circle. A measurement was accepted when the following
requirements were fulfilled (31): 1)
there was no visible distortion of the skin;
2) the measured pressure did not
change when feedback gain was increased;
3) after fulfilment of
criteria 1 and
2, suction applied to the pump should
result in an increased electrical resistance in the pipette due to
fluid of lower tonicity entering the pipette; and
4) zero pressure was the same after
the measurement was completed.
Zero pressure was measured at the level of the puncture site in a cup
containing 0.9% NaCl. The pressures were recorded twice every 10 min
in 60 or 90 min. In rats receiving subdermal injections Pif was recorded for 60 min after
injection, whereas in rats receiving intra-arterial or intravenous
injection, Pif was recorded for 90 min. Pif was recorded
in 30-min periods after the intravenous or subdermal injections.
Control Pif was recorded before
injections, i.e., recording periods were 5 to 0 (control),
0-30, 31-60, and 61-90 min. The recorded pressures were
averaged in these time periods.
Experimental Protocol
Pif was measured in all animals before any injections were made. The injections were made with the substances diluted as described above. The LPS was administered subdermally and intra-arterially. The TNF-, IL-1, and IL-6 were
given intravenously and/or subdermally.
Series 1: Lipopolysaccharide. Controls received either 0.5 ml of 0.9% NaCl intra-arterially (n = 6) or 5 µl of 0.9% NaCl subdermally (n = 6). Lipopolysaccharide (LPS) was given intra-arterially in a dose of 2.5 mg (n = 6) or 0.25 mg (n = 6) in a volume of 0.5 ml or subdermally in a volume of 5 µl (5 mg/ml) (n = 6).
Series 2: TNF-.
Controls (n = 6) received 5 µl of
0.1% bovine serum albumin in Ringer acetate subdermally or 1 ml
intravenously (n = 14). Nine rats
received 5 µl of TNF- (100 ng/ml) subdermally, whereas three rats
received 100 ng in 1 ml intravenously, and six rats received 500 ng in
1 ml intravenously.
Series 3: IL-1.
Controls received 1 ml of 0.1% bovine serum albumin in Ringer acetate
intravenously (n = 14) or 5 µl of
0.1% bovine serum albumin subdermally
(n = 6). Six rats received 1 ml of
IL-1 (20 ng/ml) intravenously, whereas six other rats received 5 µl subdermally (20 ng/ml).
Series 4: IL-6. Control groups received either 1 ml of 0.1% bovine serum albumin in Ringer acetate intravenously (n = 14) or 5 µl of 0.1% bovine serum albumin subdermally (n = 6). IL-6 was given intravenously at 50 ng (n = 6) or 20 ng (n = 6) in 1 ml or 5 µl (50 ng/ml) subdermally (n = 6).
Statistical Methods
Data are presented as means ± SE. Statistical analysis was performed by (one- or two-way) analysis of variance (ANOVA) with repeated measures (RM-ANOVA) followed by Bonferroni tests. P < 0.05 was considered statistically significant.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Intra-arterial Or Intravenous Injections
Control. Control Pif averaged0.4 ± 0.1 mmHg (Fig. 1) before circulatory arrest had
been induced. An intravenous injection of 1 ml of albumin followed by
circulatory arrest did not change Pif
(P > 0.05) (Table
1 and Fig. 1).
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LPS. Intra-arterial administration of 2.5 mg lowered Pif significantly (P < 0.05) at 30 and 60 min compared with its own control (Table 1 and Fig. 1), whereas intra-arterial administration of 0.25 mg LPS did not change Pif (P > 0.05).
TNF-. One hundred
nanograms in 1 ml given intravenously lowered
Pif significantly to 2.3 ± 1.0 mmHg (Table 1) compared with its own control
(P < 0.05) but not when compared
with albumin (P > 0.05). At 500 ng/ml
Pif was lowered significantly
compared with both the control and albumin
(P < 0.05) (Table 1 and Fig. 1).
IL-1. Intravenous
administration of IL-1 lowered
Pif to 2.0 ± 0.5 mmHg
after 90 min (P < 0.05 compared with
own control and albumin) (Table 1).
IL-6. IL-6 injected intravenously at
50 and 20 ng/ml lowered Pif at 90 min to 2.1 ± 0.7 and 2.5 ± 1.0 mmHg, respectively (P < 0.05 compared with intravenous
albumin) (Fig. 1).
Subdermal Injections
Controls. Control Pif averaged0.5 ± 0.4 mmHg in rats receiving albumin (n = 6); 1.3 ± 0.3 mmHg for rats receiving TNF-, IL-1, or
IL-6 (n = 21) (Fig.
2); and 0.6 ± 0.3 mmHg
(n = 6) in the animals that received
LPS.
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LPS. Subdermal injections of 5 µl of LPS (5 mg/ml) did not change Pif significantly compared with that of the control (P > 0.05).
TNF-. TNF- lowered
Pif to 2.0 ± 0.6 mmHg
at 60 min (P < 0.05 compared with
those subdermally injected with albumin) (Fig. 2).
IL-1. Five microliters
injected subdermally lowered Pif
to 2.3 ± 0.2 mmHg after 60 min
(P < 0.05 compared with that of the control and P < 0.001 compared with
those given albumin) (Fig. 2).
IL-6. IL-6 lowered
Pif to 2.8 ± 0.5 mmHg
after 60 min (P < 0.05 compared with
those given albumin) (Fig. 2).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study focuses on the in vivo effect of LPS and the
cytokines TNF-, IL-1, and IL-6 on loose connective tissue and in
particular their effects on interstitial fluid pressure (Pif). LPS, TNF-, IL-1,
and IL-6 all induced a lowering of
Pif. However, a lowered
Pif after LPS administration was
observed only after intra-arterial injection.
During endotoxin shock there is an increased extravasation of plasma and macromolecules in most organs (30). However, it has not been clear whether the enhancement is due to increased permeability and/or increased capillary net filtration pressure (30). Edema will result when the capillary filtration exceeds lymph drainage (1). Increased capillary filtration is caused by either increased net capillary filtration pressure and/or increased capillary filtration coefficient (CFC).
Visible edema in skin requires at least doubling of interstitial fluid
volume (32). When edema appears in 5-10 min in acute inflammation,
interstitial fluid volume is doubled in the same time period, whereas
it normally takes 12 and 24 h to create this amount of capillary
filtrate and turn over interstitial fluid volume (1). When edema
appears in 5-10 min, capillary fluid filtration must therefore
have increased by about 100 times above normal. An increased negativity
of Pif has been demonstrated
concomitant with development of inflammatory edema formation in the
skin and trachea (5, 23). The minimal time required to double the interstitial fluid volume (IFV) is between 12 and 24 h if lymph flow is
arrested and the capillary filtration is unchanged. After an increased
capillary permeability alone, a doubling of IFV will require 4-8 h
because CFC has been found to increase by only two or three times above
normal even in severe acute inflammatory injuries like burn injury
(18). In burn injuries, a lowering of
Pif from 1 to 150
mmHg has been observed in the skin and is thought to be the major
driving force required to explain the increased transcapillary fluid
filtration (22). Furthermore, LPS and the investigated
cytokines induce vasodilation (28), which will increase capillary
hydrostatic pressure (Pc).
Subdermal injections of TNF-, IL-1, and IL-6 lowered
Pif significantly from 1.3
to between 2 and 3 mmHg at 30-60 min after
injection, whereas subdermal injections of LPS did not change Pif significantly. However, when
LPS was given intra-arterially it reduced
Pif to 2.0 mmHg, and this
observation is most likely explained if TNF- and the two
interleukins are responsible for the lowering of
Pif. The time required from
administration of LPS until a significant amount of cytokines has been
released in plasma to obtain a biological effect is reported to be
1-2 h (9). The present study therefore demonstrates that the
cytokines act via a local mechanism in the tissue because local
administration caused Pif to
decrease. However, the lack of effect of local injected LPS might have
two explanations. Either too little time is available for local
cytokine production or, alternatively, the number of cells that produce
cytokines after LPS stimulation are lacking or present to an extent
that is insufficient to produce the amount of TNF- or interleukins
to elicit an effect. The present design cannot determine which is the
correct alternative. However, we would favor the explanation that lack
of effect by LPS is due to the fact that 1-2 h is normally
required to elicit the full biological effect of LPS. In accordance
with this view, LPS is the slowest acting substance of those
investigated (Fig. 1 and Table 1).
One of the initial steps of the immune response to bacterial endotoxin
is the binding of LPS to the cell surface receptor CD14, expressed on
the surface of monocytes and macrophages (25). Binding of LPS to CD14
induces production of cytokines such as TNF-, IL-1, IL-6, and
IL-8 (26). TNF- plays a well-known role during the development of
multiple organ failure, in part, mediated by adhesion molecules on
endothelial cell (12). TNF-, IL-1, and IL-6 infused intravenously
all decreased Pif from control values around 0.5 mmHg to between 2 and 3 mmHg
within 30-90 min, which will raise the capillary filtration
pressure and favor edema formation. Because normal capillary filtration
pressure is 0.5-1 mmHg, the lowering of
Pif by 2-3 mmHg will raise
the net filtration pressure two to five times above control. One
explanation for the decreased Pif
could be enhanced lymphatic pumping via a direct action on the
lymphatics. A lowering of Pif by 2 mmHg would require a removal of interstitial fluid amounting to 30% of
the interstitial volume because interstitial compliance in rat skin is
14% per millimeter of Hg (31). This seems unlikely for several
reasons. First, the full effect has occurred in <60 min, implying
that lymph flow must have increased by 10-20 times above normal in
the same time period. This is a larger figure for the rise in lymph
flow normally reported in skin (1). Second, the effects of endotoxin
and IL-1 on lymphatic pumping are reported to be a decrease of the
lymph vessel's ability to pump fluid, and they will therefore
contribute to rather than limit edema formation associated with sepsis
(8, 12). Finally, if enhanced lymphatic pumping was the explanation for
the lowered Pif, our observations
require that 30% of IFV is removed (see above) (31). Because one-third
of the interstitial volume in the rat is located in the skin (19)
(i.e., 7 ml/100 g), this translocation of IFV would raise plasma volume
by two to three times its normal value based on skin only. An effect
parallel to that in skin in the remaining two-thirds of IFV would make
this explanation even more unlikely. Translocation of IFV directly into
the capillaries is unlikely from the same reasoning, and because
circulatory arrest does not alter
Pif, i.e., there are no major
fluid movements out of the interstitium by this procedure alone. Thus
by exclusion we favor the explanation that the cytokines affect the
Pif by perturbing the interstitial
1-integrin receptors, i.e., the
cellular receptors toward extracellular matrix components (11). These receptors consist of an - and a -unit and specificity is
determined from the specific - and -receptors that are assembled
(11). Currently near 20 functionally integrin receptors have been identified.
The suggestion that cytokines also induce the lowering of
Pif via integrin receptors are
based on experiments in which in vivo blockade of
1-integrin adhesion receptors
in the rat skin causes local edema formation concomitant with lowering
of Pif (22). The
1 family of integrins
encompasses adhesion receptors for collagen, laminin, and fibronectin.
These receptors also mediate contraction of fibroblast-mediated
collagen gels (23). IL-1 inhibited collagen gel contraction and at
later stages induces a visible degradation of the collagen gels,
presumably due to the generation of collagenase activity (27). TNF-
affects collagen gel contraction in a qualitatively similar way to
IL-1 (K. Rubin, personal communication). IL-1 is known to induce
the production of prostaglandins as well as collagenase;
PGE2 has been reported to inhibit
collagen gel contraction (27), and
PGE2 and
PGI2 lower the
Pif (4). The mechanisms are not
fully understood, but previous studies from our laboratory indicate
that perturbation of 1-integrin
function is involved (22).
Circulatory arrest is induced as part of the experimental protocol. With intact circulation, the fluid filtration to the tissues, which is part of the inflammatory process, will increase and thereby increase the Pif. It has been shown that circulatory arrest does not change Pif for up to 90 min compared with control (31). Circulatory arrest was used to arrest increased capillary extravasation following exposure of LPS and cytokines.
To summarize, the present study demonstrates that LPS, TNF-,
IL-1, and IL-6 induce increased negativity of
Pif when given intravenously or
intra-arterially, whereas only TNF-, IL-1, and IL-6 induce
increased negativity of Pif when
given subdermally.
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ACKNOWLEDGEMENTS |
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The present study was supported by the Norwegian Research Council and The Norwegian Heart Association.
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FOOTNOTES |
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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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: T Nedrebø, Dept. of Physiology, University of Bergen, Årstadveien 19, N-5009 Bergen, Norway.
Received 22 February 1999; accepted in final form 1 July 1999.
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ABSTRACT
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RESULTS
DISCUSSION
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, 0.1%,
n = 14), tumor necrosis factor-
, 500 ng/ml, n = 6),
interleukin-6 (IL-6, 
, 50 ng/ml, n = 6), and lipopolysaccharide (LPS, 
, 5 mg/ml,
n = 6) on interstitial fluid pressure.
Values are means ± SE. * P < 0.05 compared with control values.
