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Monosodium urate monohydrate crystalinduced inflammation in vivoQuantitative histomorphometric analysis of cellular events.

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ARTHRITIS & RHEUMATISM
Vol. 46, No. 6, June 2002, pp 1643–1650
DOI 10.1002/art.10326
© 2002, American College of Rheumatology
Monosodium Urate Monohydrate Crystal–Induced
Inflammation In Vivo
Quantitative Histomorphometric Analysis of Cellular Events
C. Schiltz,1 F. Lioté,1 F. Prudhommeaux,1 A. Meunier,2 R. Champy,1 J. Callebert,3
and T. Bardin1
Objective. To quantify the inflammatory cell response in rat air pouch pseudosynovial membrane
during monosodium urate monohydrate (MSU) crystal–
induced inflammation.
Methods. In the rat air-pouch model, we used a
computer-assisted histomorphometric method to quantify cell distributions, based on cell linear densities, in
histologic sections of membranes from pouches injected
with MSU or saline. The volume, white blood cell (WBC)
count, and histamine content of the pouch exudates
were determined at several time points.
Results. Injection of 10 mg of MSU crystals into
the pouch produced an acute exudate. After peaking at
24 hours, the exudate volume and WBC count decreased
spontaneously over the next 3 days, simulating the
self-limited course of acute gout. Membrane thickness
followed a parallel course. Membrane polymorphonuclear cell (PMN) linear densities were closely correlated
with exudate WBC counts, suggesting PMN recruitment
from the subintimal synovial membrane. Both
monocyte/macrophage and mast cell linear densities
increased in the subintimal layer 2 hours after crystal
injection (P ⴝ 0.038 and P ⴝ 0.03, respectively, versus
controls), whereas PMN linear densities showed 2
peaks, one at 4 hours and the other 24 hours. The
exudate histamine content peaked 6 hours after crystal
injection, when mast cell linear densities were minimal
in the membranes, suggesting mast cell degranulation.
Conclusion. An increase in monocyte/macrophage
and mast cell densities in the membrane preceded the
PMN influx in the pouch membrane and exudate,
suggesting that mast cells may be involved in the early
phase of MSU crystal–induced inflammation, at least in
this rat model.
The pathogenesis of acute gout has been addressed in many studies. Synthetic monosodium urate
monohydrate (MSU) crystals have been injected into the
tissues or joints of various animals, including dogs (1),
rats (2), mice (3), and rabbits (4). These in vivo experiments have elucidated the kinetics of acute-phase proteins, cytokines, and polymorphonuclear cell (PMN) and
mononuclear cell (MNC) contents in exudates, showing
a peak in cell recruitment and demonstrating that the
acute phase was followed by self-limitation of the MSU
crystal–induced inflammation. In vitro studies have
shown that MSU crystals added to various cell cultures
(5) induced time- and dose-dependent cytokine secretion. Schumacher et al (1) and Gordon et al (6) have
reported evidence that acute gout is initiated by phagocytosis of free MSU crystals by the lining cells (type A
[macrophage-like] synovial cells). This event is currently
acknowledged to precede synovial inflammation per se
(7,8). However, little is known about the kinetics of the
cellular events within the synovial membrane.
Supported by grants from the Paris 7 University, the Association Rhumatisme et Travail, the Association pour la Recherche en
Pathologie Synoviale (ARPS), and the Fondation pour la Recherche
Médicale.
1
C. Schiltz, F. Lioté, MD, PhD, F. Prudhommeaux, PhD, R.
Champy, MD, T. Bardin, MD: Hôpital Lariboisière, Paris, France, and
Paris 7 University, Paris, France; 2A. Meunier, PhD: UPRES-A CNRS
1432, Paris, France; 3J. Callebert, PhD: Hôpital Lariboisière, Paris,
France.
Address correspondence and reprint requests to C. Schiltz,
Laboratoire de Radiologie Expérimentale et de Physiopathologie
Articulaire (JE2149), Centre Viggo Petersen, Hôpital Lariboisière, 2
rue Ambroise Paré, 75475 Paris Cedex 10, France. E-mail:
corinne.schiltz@lrb.ap-hop-paris.fr.
Submitted for publication June 7, 2001; accepted in revised
form February 21, 2002.
1643
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SCHILTZ ET AL
In addition to the initial role played by
macrophage-like lining cells, cell activation is believed to
trigger massive recruitment not only of PMNs, which are
recognized as the main inflammatory cells in acute gout,
but also of mast cells, MNCs, and endothelial cells
associated with acute neoangiogenesis. Few qualitative
pathologic studies of human or animal synovial tissues
have been reported (9,10), and we are not aware of
systematic quantitative studies of cellular changes over
time. Therefore, in the rat air-pouch model of the
synovial cavity, we used a quantitative histomorphometric method (11) to evaluate the inflammatory response
induced in the pouch pseudomembrane by MSU crystal
injection.
MATERIALS AND METHODS
Crystal preparation. Synthetic MSU crystals were
prepared as described previously (12). We added 1.68 gm of
uric acid (ICN Biomedicals, Aurora, OH) to a 0.01M NaOH
solution heated to 70°C. NaOH/HCl was added as required to
keep the pH between 7.1 and 7.2. The solution was stirred
slowly and continuously at room temperature. Twenty-four
hours later, the crystals were harvested by decanting the
supernatant; they were then washed, dried, dispensed into
individual vials (10 mg), and sterilized by autoclaving. The
needle shape and size of the crystals were checked by polarizing light microscopy. The absence of endotoxin contamination
was verified using a Limulus amebocyte cell lysate assay
(E-toxate kit; Sigma, St. Louis, MO). The sterile MSU crystals
were resuspended in 5 ml of sterile saline solution just before
injection into 6-day-old rat air pouches.
Rat air-pouch model. We used the rat air-pouch model
of the synovial cavity (13). All experiments were conducted
according to European ethical guidelines. Noninbred SpragueDawley rats weighing 130–150 gm at the time of the experiment (Centre d’Elevage R Janvier, Le Genest-St. Isle, France)
were used. Five rats were housed per cage, fed normal chow,
and maintained in accordance with current standards for the
confinement of laboratory animals. The experiments were
performed with the rats under anesthesia induced by intraperitoneal ketamine injection.
Twenty milliliters of sterile air was injected subcutaneously through a 0.25-␮m microfilter into the backs of the
animals to create a pseudosynovial cavity. A second air injection was given on day 3 to keep the pouch inflated. Six days
after the first air injection, 5 ml of sterile saline solution
(control group) or 10 mg of MSU crystals resuspended in
sterile saline solution (MSU group) was injected into the
pouch. Groups of 6–8 the animals were killed by cervical
dislocation under anesthesia at 1, 2, 4, 6, 24, and 48 hours after
the crystal or saline injections.
Collection and processing of samples. The exudates
and pseudosynovial membranes from the air pouches were
harvested. Exudates were collected using a catheter under
sterile conditions and were immediately cooled on ice before
processing. Exudate volumes were measured, and white blood
cell (WBC) counts were obtained using a standard hemocytometer. Differential WBC counts were determined after
cytospin centrifugation followed by May-Grünwald–Giemsa
staining. Histamine contents were measured using the radioenzymatic assay described by Haimart et al (14).
Pseudomembranes were dissected, fixed in 10% buffered formalin (pH 7.2–7.4), dehydrated in ethanol, and embedded in Paraplast. Random 5-␮m sections (20 per pouch)
were cut using a Minot-type microtome and routinely stained
with Masson’s trichrome or hematoxylin–eosin–saffron (HES).
These sections were used for the quantitative light microscopy
analysis. Other sections were stained with toluidine blue (pH
4.2) and used to identify and count mast cells (15).
For transmission electron microscopy (TEM), small
pieces of membrane were fixed in 2.5% glutaraldehyde solution, postfixed in 1% osmic acid solution, and, after gradual
dehydration in alcohol, embedded in SPURR resin (TABB,
Berkshire, UK). Ultrafine sections ⬃90-nm thick were examined under an EM300 microscope (Philips, Eindhoven, The
Netherlands).
Computer-assisted cell counting. To quantify changes
in pouch membranes, we used a method previously developed
by Christel and Meunier for determining cell distributions in
tissue encapsulating surgically implanted biomaterials (11).
Sections were observed at 400⫻ or 1,000⫻ magnification
under a BHT microscope (Olympus France, Rungis, France)
equipped with a drawing tube. The image of the histologic
section was digitized using the diode cursor of a graphic tablet
connected to a microcomputer, with the diode superimposed
on the histologic slide through the drawing tube. For each
optical field, membrane contours and vessels were digitized at
400⫻ magnification. The nuclei of each cell type (fibroblasts,
macrophages, PMNs, and mast cells) and the blood vessels
were digitized at 1,000⫻ magnification. During the digitization
process, the computer recorded the coordinates of the cell
nuclei with reference to the membrane’s inner contour (Figure
1). The procedure was repeated on at least 5 separate fields of
the membrane, and the data from these 5 fields were pooled.
The following parameters were calculated: 1) distance
parameters, including membrane thickness as well as the
median and quartile (25%, 75%) distances of each cell type
from the pouch lining; 2) linear densities, taking into account
the number of cells per millimeter of digitized membrane; and
3) cumulative counts of each cell type in 5-␮m sections with no
gap, from the lining to the subintimal layer. Because no
significant cell changes occurred between 0 ␮m and 20 ␮m
from the surface, this area was arbitrarily defined as the lining,
and the area from 20 ␮m to 80 ␮m, where the tissue was looser,
was defined as the subintima.
Statistical analysis. For normally distributed parameters, namely, membrane thickness, vessel numbers, and
WBC counts, as well as histamine concentrations, results were
expressed as the mean and SD. Between-group comparisons
were performed using one-way analysis of variance, and differences between means were determined using Student’s
t-test.
MSU CRYSTAL–INDUCED INFLAMMATION IN VIVO
1645
Figure 1. Parameters evaluated by histomorphometry. Membrane contours, vessels, and each cell
type were digitized using a histomorphometric apparatus with 400⫻ or 1,000⫻ magnification.
Membrane thickness and linear densities (LDs) of vessels and of each cell type (fibroblasts,
macrophages, polymorphonuclear cells, and mast cells) were computed per millimeter of digitized
membrane interface. Because LDs were not normally distributed (see graph in box), the
nonparametric Mann-Whitney test was used for statistical analysis. d ⫽ mean length of the
membrane border.
Linear densities of fibroblasts, macrophages, PMNs,
and mast cells were not normally distributed. For these parameters, results were calculated as the median ⫾ quartiles and
were compared using the nonparametric Mann-Whitney test.
Linear correlations were determined using the nonparametric
Spearman’s rank correlation test.
Validation of the quantitative and histomorphometric
method. Intraobserver and interobserver errors. Intraobserver
error was calculated by digitizing the same histologic section 5
times. Intraobserver error was 0.9% for membrane thickness,
5% for fibroblast densities, and 12% for macrophages. Interobserver differences determined by having two observers digitize the same 5 sections were not statistically significant for
any cell types (data not shown).
Staining and magnification. Cell counts were not significantly different with Masson’s trichrome or HES staining.
However, optical magnification significantly influenced the cell
counts (P ⬍ 0.01), with the most reliable results being achieved
at high magnification (1,000⫻). The various parameters were
representative of the slide only if at least 5 fields on the slide
were digitized; digitizing more than 5 fields did not modify the
findings.
Similarly, serial sections of air-pouch membrane were
cut, digitized, and examined. No significant differences were
found across the slides (data not shown). Consequently, for the
study, a single slide taken at random was digitized for each air
pouch.
RESULTS
Qualitative analysis of the pseudosynovial membrane not exposed to MSU crystals. The pouch membrane comprised 3 layers, as previously described (16).
The lining layer or intima, was well defined, with 1–3
layers of cells, including flattened fibroblasts and macrophages. Rare PMNs were scattered among these two cell
types. The subintimal layer was a looser tissue with an
abundance of cells, including fibroblasts, macrophages,
PMNs, lymphocytes, and mast cells, as well as many
small vessels and capillaries. A few MNC aggregates
were found around the vessels. Under the subintimal
layer, there was an areolar zone, with fewer cells and a
greater number of blood vessels.
Quantitative histomorphometry. Membrane
thickness increased transiently after MSU crystal injection. Compared with control membranes, the increase
was significant 6 hours after the injection (P ⫽ 0.004)
(Figure 2). Maximal thickness was achieved after 24
hours (P ⫽ 0.001 and P ⫽ 0.004 versus thickness after 6
hours and 48 hours, respectively). No difference in vessel
number, as determined by counting vessel and capillary
1646
SCHILTZ ET AL
seen 24 hours after crystal injection. Compared with
saline, MSU crystals significantly increased PMN linear
densities at 4 hours and 24 hours (P ⫽ 0.04 and P ⫽ 0.05,
respectively). PMN densities returned to values similar
to those in the controls at 48 hours. As with the
monocyte/macrophages, this transient increase in the
number of PMNs was seen in the subintima, but not in
Figure 2. Kinetics of air-pouch membrane thickness. Values are the
mean and SD. Comparison between the control group and the
monosodium urate monohydrate (MSU) crystal–induced inflammation group was performed by Student’s t-test.
sections, was found between injected and control
pouches (data not shown).
Kinetics of fibroblast, monocyte/macrophage,
PMN, and mast cell linear densities. Fibroblasts. Only
one significant difference was observed between the two
groups. This consisted of a significant decrease in median fibroblast linear densities 4 hours after crystal
injection (P ⫽ 0.03) (data not shown).
Monocyte/macrophages. Compared with control
tissues, MSU crystal injection resulted in a significant
increase in monocyte/macrophage linear densities as
early as 2 hours after crystal injection (P ⫽ 0.038)
(Figure 3A). Between 1 hour and 2 hours after crystal
injection, median monocyte/macrophage linear density
increased by 160%, from 48 cells/mm to 125 cells/mm, in
the MSU-injected animals. The monocyte/macrophage
linear density increase over time was not significant in
the lining (the most superficial 20 ␮m of depth), but was
highly significant in the subintima (20–80 ␮m from the
surface) in both the MSU and control groups (Figure
4A). Wide variations in monocyte/macrophage linear
densities over time were noted in the subintima of the
MSU-injected membranes, whereas the increase was
steadier in the control membranes. Importantly,
monocyte/macrophage linear densities remained high in
the subintima after 48 hours (110 cells/mm), although
inflammation in the pouch exudate had diminished by
then.
PMNs. In controls, median PMN linear densities
showed little change over time, remaining at very low
values (⬍5/mm after 24 hours). In the MSU crystal–
injected animals, 7–13 PMNs/mm were counted within
the membrane as early as 4 hours after crystal injection
(Figure 3B). A second PMN density peak (25/mm) was
Figure 3. Kinetics of monocyte/macrophage, polymorphonuclear cell
(PMN), and mast cell linear densities in the air-pouch membranes
after injection of monosodium urate monohydrate (MSU) crystals.
Values are the median. A, A significant increase in monocyte/
macrophage linear density was found after 2 hours in the MSU group
(P ⫽ 0.038 versus control group). B, Two peaks in PMN linear
densities were seen at 4 hours and 24 hours after crystal injection (P ⫽
0.04 and P ⫽ 0.05, respectively, versus control group). PMN linear
density remained ⬍5 cells/mm in the control group. C, Mast cell linear
densities peaked 2 hours after crystal injection (P ⫽ 0.03 versus control
group). No mast cells were detected by toluidine blue staining 6 hours
after crystal injection. A low mast cell linear density peak was observed
after 6 hours in the control membranes.
MSU CRYSTAL–INDUCED INFLAMMATION IN VIVO
1647
point (P ⫽ 0.03) (Figure 3C). Inflammatory membranes
contained 17–24 mast cells/mm within 2 hours after
crystal injection (Figure 3C). In contrast, 6 hours after
crystal injection, no mast cells were detected by toluidine
blue staining. The histamine content in pouch exudates
peaked 6 hours after crystal injection, when mast cell
linear densities assessed by toluidine blue staining were
minimal in the membrane (Figure 6), a finding consistent with early degranulation. In control membranes, a
significant, but lower, mast cell linear density peak was
achieved at 6 hours (P ⫽ 0.002) (Figure 3C).
As can be seen in Figure 3, comparison of mast
cell and PMN linear density kinetics in the crystalinjected pouches showed that the PMN peak was preceded by an early mast cell peak. A similar early
monocyte/macrophage increase was observed 2 hours
after crystal injection.
DISCUSSION
Figure 4. Kinetics of monocyte/macrophage, polymorphonuclear cell
(PMN), and mast cell counts within the membrane. Cumulative
numbers of A, monocyte/macrophages, B, PMNs, and C, mast cells
were determined in consecutive 5-mm segments from the lining to the
subintimal layer. The 20-␮m line was used as a cutoff in all cases
because significant cell changes occurred only below this line (20–80
␮m from the surface). MSU ⫽ monosodium urate monohydrate.
the lining (Figure 4B). Median PMN linear densities
were strongly correlated with contemporaneous exudate
WBC counts (r2 ⫽ 0.91, P ⫽ 2 ⫻ 10⫺6) (data not shown),
which decreased spontaneously after peaking at 24
hours.
Mast cells. Again, mast cells identified by toluidine blue staining (Figure 5A) and characteristic ultrastructure (Figure 5B) were found only in the subintima
(Figure 4C). Mast cell linear density peaked as early as
1–2 hours after crystal injection, whereas no mast cells
were detected in control membranes at this early time
We used a quantitative histomorphometric
method to determine the kinetics of cellular changes in
an experimental rat air-pouch model of acute MSU
crystal–induced inflammation. This acute inflammation
was characterized by an early and transient increase in
leukocyte linear densities within the membrane subintimal layer, the kinetics of which correlated with the PMN
influx (r2 ⫽ 0.91, P ⫽ 2 ⫻ 10⫺6) in pouch exudates.
Macrophage linear density increased significantly after 2
hours in the sublining around the vascular areas, and
macrophages were the most abundant inflammatory
cells in the membrane, a finding consistent with descriptions of the synovium in human gout (10). Interestingly,
we also observed mast cell infiltrates in the subintimal
layer; these developed at the same time as the monocyte/
macrophages and before the PMN recruitment to the
membrane. Determinations of histamine levels in pouch
exudates, specific toluidine blue staining, and TEM of
the pseudosynovial membrane confirmed that early mast
cell degranulation occurred. The increase in cell linear
density was observed only in the subintima, at levels
deeper than 20 ␮m from the surface. Inflammatory cell
recruitment from the bloodstream may occur in the
subintima, since this area contains constitutive vessels.
The absence of linear density changes in the lining
(within 20 ␮m of the surface) suggests cell migration
from the membrane through the cavity.
The histomorphometric technique we used was
developed to evaluate the biocompatibility of implants
in rodents (11). This time-consuming technique allowed
us to perform a comprehensive statistical analysis of
1648
Figure 5. Micrographs of a mast cell in a membrane. A, Toluidine
blue staining of a mast cell. B, Electron micrograph of a mast cell in a
membrane, sampled 2 hours after monosodium urate monohydrate
crystal injection. (Original magnification ⫻ 1,000 in A; ⫻ 11,700 in B.)
several parameters reflecting the distribution of various
cell populations over time. Thus, we were able to obtain
a detailed picture of normal and inflammatory
pseudomembranes. We did not take into account the
functional status of cells, which could be studied, for
example, by immunochemistry and in situ hybridization
for pro- and antiinflammatory cytokines.
Membrane thickness was significantly increased 6
hours after MSU injection compared with the membrane in control pouches. This rapid increase in thickness probably reflects an early increase in vascular
permeability, with egress of protein and water resulting
in membrane edema. The increase was contemporaneous with mastocyte degranulation, which releases various stored materials, among which only histamine was
measured in this study. This bioamine release might
have contributed to the observed variation in membrane
SCHILTZ ET AL
thickness through various transduction couplings (e.g.,
Na⫹/H⫹ exchange) (17).
There was no difference in the number of capillaries or venules between control and MSU-injected
membranes, although inflammation is believed to be
associated with neoangiogenesis. This intriguing observation may be ascribable to the fact that we investigated
neither vessel types nor endothelial cell activation. We
examined only the number of vessels, irrespective of
their diameter, type (arterioles, venules, or capillaries),
and location in or outside of the lining. A study in an
animal model of acute crystal-induced inflammation has
shown that intracutaneous MSU crystal injection activated capillary endothelial cells, as demonstrated by
E-selectin expression (18). Interestingly, colchicine
down-regulates E-selectin expression in vitro (19) and in
vivo (20), leading to reduced leukocyte migration in
inflamed tissues. The antiinflammatory effect of antiselectin antibodies in a model of acute peritoneal MSU
crystal inflammation in rodents further supports a role
for endothelial cell activation through selectin expression (21).
One interesting aspect of our experiment is that it
allowed us to compare changes over time in the numbers
of various inflammatory cell types in the membrane.
Importantly, the monocyte/macrophage peak occurred 2
hours after crystal injection, preceding the PMN peaks,
which occurred 4 hours and 24 hours after crystal
injection. Monocyte/macrophages are known to release
preformed and de novo–synthesized chemotaxins and
Figure 6. Kinetics of histamine levels in air-pouch exudates associated with mast cell linear density in the membranes. Mast cell linear
densities were expressed as medians. Histamine levels were measured
in supernatants. The histamine content in pouch exudates peaked 6
hours after monosodium urate monohydrate crystal injection, when
mast cell linear densities assessed by toluidine blue staining were
minimal in the membranes, suggesting an early degranulation.
MSU CRYSTAL–INDUCED INFLAMMATION IN VIVO
endothelial cell–activating factor (22) and may therefore
play a major role in PMN recruitment to the membrane
and pouch exudate. However, one limitation of our
study is that we did not determine the activation status of
membrane monocyte/macrophages; this needs to be
done to test the hypothesis of a role for monocyte/
macrophages.
As demonstrated for monocyte/macrophages,
changes in PMN numbers were more striking around the
vessels in the subintimal layer after crystal injection.
Together with the highly significant correlation between
PMN linear densities in the membrane and WBC counts
in the exudate, this suggests that PMNs were recruited
from the subintimal layer at the early phase and that
they migrated into the pouch cavity during the acute
phase. PMNs, which are the predominant cells found in
the synovial fluids of patients with acute gout, are
believed to play a pivotal role in MSU-induced inflammation (23). Their ability to phagocytose crystals, as well
as to release numerous mediators, including chemotactic
factors, indicates that PMNs contribute to amplifying
MSU crystal–induced inflammation.
Interestingly, we also found an early increase in
the number of mast cells in the subintimal layer of
MSU-injected pouch membrane, suggesting that recruitment of mast cells from the blood occurred during the
early phase of MSU crystal–induced inflammation. The
increase in mast cell linear density started before the
monocyte/macrophage and PMN peaks, supporting the
hypothesis that mast cells play a role in the early phase
of MSU-induced inflammation, which involves vascular
exudation and cell attraction.
Mast cells are present in small numbers in the
normal synovial membrane and in larger numbers in the
rheumatoid arthritis pannus (24–26). They have not
been observed in human synovium from joints with acute
gout, although specimens have not been obtained during
the very early stages of synovial inflammation. Mastocytes are known to generate and to release several
biologically active molecules following activation by IgEmediated stimuli, complement-derived anaphylatoxins,
lymphokines, and monokines (27). The numerous compounds released by mast cells include vasoactive amines,
which are potent exudation factors, and chemotactic
factors that promote PMN influx, such as the chemokine
epithelial neutrophil activating peptide 78 (22). Getting
et al (21) have reported that mast cell mediators may
contribute to the PMN influx generated by peritoneal
MSU crystal injection in mice. In this model, a role for
endogenous histamine and platelet-activating factor
(PAF) was supported by the inhibitory effect of PAF
1649
inhibitor and of an anti-H1 histamine receptor antagonist.
Taken together, these results demonstrate that
early infiltration of the pseudosynovial membrane by
monocyte/macrophages and activated mast cells precedes the PMN influx triggered by MSU crystal injection. Thus, synovial mast cells may be involved in the
early phase of gouty inflammation. Our study shows that
both exudates and membranes should be analyzed in
parallel to gain insight into cell kinetics during experimental gouty inflammation.
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urate, crystalinduced, inflammation, monosodium, histomorphometric, vivoquantitative, analysis, monohydrate, cellular, event
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