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Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 2005-2009
Plasminogen Deficiency Differentially Affects Recruitment of
Inflammatory Cell Populations in Mice
By
Victoria A. Ploplis,
Esther L. French,
Peter Carmeliet,
Desire Collen, and
Edward F. Plow
From the Joseph J. Jacobs Center for Thrombosis and Vascular Biology,
Department of Molecular Cardiology, Cleveland Clinic Foundation,
Cleveland, Ohio; and Flander's Interuniversity Institute for
Biotechnology, Leuven, Belgium.
 |
ABSTRACT |
It is widely held that the plasminogen (Plg) system plays a role in
inflammation through plasmin-mediated directional cell migration.
However, substantial evidence for its involvement in the inflammatory
response has been obtained from indirect studies and lacks firm
biological confirmation. To directly characterize plasminogen's
involvement in the inflammatory response, we used thioglycollate to
induce a peritoneal inflammatory reaction in Plg(+/+),
Plg(+/ ), and Plg(/) mice. At 6 hours
poststimulation, neutrophil recruitment into the peritoneum was maximal
and similar between Plg(+/+), Plg(+/), and
Plg(/) mice. In contrast, monocyte recruitment was
significantly diminished after 24 hours poststimulation in
Plg(/) mice relative to Plg(+/+) mice.
Lymphocyte recruitment also was blunted. Blood monocyte levels in these
mice indicated that diminished recruitment into the peritoneum was not
the result of a diminished source of cells in the circulation.
Macrophage phagocytic function was similar between Plg(+/+)
and Plg(/) mice. This study establishes a direct
involvement of plasminogen in monocyte recruitment during a
representative inflammatory response.
| |
INTRODUCTION |
THE PLASMINOGEN SYSTEM, because of
its ability to assemble on the surface of a number of cell types, has
been implicated in directional cell migration associated with
physiological responses, such as embryogenesis, development, and tissue
remodeling1-3 and a number of pathophysiological events
such as inflammation4 and tumor cell invasion.5
This role in cell migration depends on the capacity of plasmin to
either directly degrade a number of extracellular matrix proteins or to
activate other proteases with matrix degrading capabilities. In vitro
studies have identified urokinase (u-PA) and its receptor at the
leading migratory edges of monocytes and smooth muscle
cells.6,7 This complex can generate plasmin from cell-bound
plasminogen thereby inducing a front of proteolysis, which can
facilitate migration by degrading protein barriers or provisional
matrices composed of fibrin. In vitro stimulated murine peritoneal
macrophages produce and secrete a plasminogen activator, which has been
identified as u-PA.8 More recently, an in vivo study on rat
peritoneal macrophages indicated that procoagulant activity is
expressed very early after intraperitoneal stimulation with the
inflammatory agent, thioglycollate, followed by enhanced expression of
fibrinolytic activity.4 Additionally, components of the
plasminogen system may regulate the expression and/or activity
of cytokines involved in inflammatory processes. For example, u-PA
amplifies tumor necrosis factor- secretion by THP
monocytoid cells independent of plasmin.9 In addition,
plasmin has been shown to release macrophage derived interleukin-1
(IL-1)10 and to activate transforming growth
factor- .11
Despite these relationships, controversy still exists over the
involvement and importance of the plasminogen system in inflammation. For example, in a study assessing wound healing in
Plg(/) mice, keratinocyte migration was impaired,
but no effect on the inflammatory response at the wound site was
noted.12 However, it has been shown that u-PA is required
for a pulmonary inflammatory response to Cryptococcus
neoformans.13 u-PA deficiency resulted in inadequate inflammatory cell recruitment, uncontrolled infection, and death. Recently, it has been shown that fewer CD45-immunoreactive leukocytes are present in the media and neointima of Plg(/)
arteries relative to Plg(+/+) arteries during the early stages
of a response to vascular injury.14 To directly address the
role of plasminogen in the inflammatory response, this investigation
used a classic acute peritoneal inflammation model in Plg(+/+),
Plg(+/), and Plg(/) mice.
Inflammatory cell recruitment was differentially affected in
plasminogen-deficient mice.
| |
MATERIALS AND METHODS |
Mice.
Plg(/) mice were developed and characterized as
previously described.15 Mice were housed in microisolation
cages on a 12-hour day/night cycle and fed a regular chow diet.
Experimental mice were 10 to 12 weeks of age, of mixed gender, and
appeared healthy during the course of the experiments. All animal
experiments were performed in accordance with protocols approved by the
Institutional Animal Care and Research Advisory Committee.
Peritoneal inflammation model.
Plg(+/+), Plg(+/), and
Plg(/) mice (n = 8 to 13 per group) were injected
intraperitoneally with 0.5 mL of a 4% Brewer thioglycollate medium
solution (Difco Laboratories, Detroit, MI). At various timepoints after
stimulation the mice were sacrificed by isoflurane inhalation (Abbott
Laboratories, North Chicago, IL). The peritoneal cavity was then
exposed and the exudate collected by washing the cavity with sterile
saline using an 18-gauge catheter.
Cell counts and differentials.
Cell counts performed in triplicate on each peritoneal exudate sample
were quantitated using a hemacytometer. A total of 105
cells/exudate were subject to cytospin onto a glass slide and stained
with Wright stain (EM Science, Gibsstown, NJ). Cell differentials were
performed in duplicate, and values were expressed as mean ± standard error of the mean (SEM).
For blood leukocyte counts, samples were collected into EDTA
microtainer tubes (Becton Dickinson, Rutherford, NJ) via cardiac puncture. After thorough mixing, 20 µL of blood was added to the reservoir of a Unopette microcollection system for leukocyte
determination (Becton Dickinson). After allowing time for lysis of red
blood cells (10 minutes) the leukocytes were counted in duplicate using a hemacytometer. Blood differentials were performed by spreading 5 µL
of whole blood onto a glass slide and stained with Wright stain.
Differentials were performed in duplicate on 100 leukocytes per slide.
Histology of peritoneum.
Plg(+/+) and Plg(/) mice were
anesthetized 6, 24, 48, and 72 hours after thioglycollate stimulation
and then perfused with Histochoice (Amersco, Solon, OH). A
5-cm2 section of peritoneal cavity wall was removed,
examined for the presence of adhesions using a dissecting microscope,
and then paraffin embedded. Five-micrometer sections of cross sectional areas of the cavity wall were stained with hematoxylin/eosin. Four
fibrin identification sections were stained with phosphotungstic acid/hematoxylin (Rowley Biochemical Institute, Danvers, MA).
Electron microscopy of peritoneal macrophages.
Plg(+/+) and Plg(/) mice were
anesthetized 72 hours after thioglycollate stimulation and then
perfused with a fixative containing 1% paraformaldehyde, 1.25%
glutaraldehyde (Electron Microscopy Sciences, Fort Washington, PA) in
0.1 mol/L cacodylate buffer, pH 7.4. After perfusion, macrophages were
collected from peritoneal exudate and postfixed in cacodylate buffered
OsO4 followed by staining with 1% uranyl acetate. Samples
were then embedded in Spurr (Ernest F. Fullam Inc, Latham, NY) and
sections were obtained using an MT 6000-xl ultramicrotome (Research and
Manufacturing Company Inc, Tucson, AZ) and viewed with a JEOL 1200 EX
II transmission electron microscope (JEOL USA Inc, Peabody, MA) at
3,000 to 25,000 magnification.
Phagocytosis of zymosan particles.
Zymosan (Sigma, St Louis, MO) was sterilized by autoclaving for
45 minutes at 120°C in phosphate-buffered saline (PBS) containing 1 mmol/L calcium and magnesium (PBS+). After autoclaving, the
suspension was washed three times in PBS+ and stored at
4°C. Before use, the zymosan suspension was sonicated (water bath
apparatus) to disrupt residual clumps, washed three times with
PBS+, and resuspended (108 particles/mL) in
PBS+.
Peritoneal macrophages, obtained 72 hours after thioglycollate
stimulation, were adjusted to 2.5 × 105 cells/mL in
Hank's balanced saline solution (HBSS) containing 25 mg/mL bovine
serum albumin (BSA). A 0.5 mL aliquot of cell suspension was added to
Lab-Tek 4 chamber culture slides (Nunc Inc, Naperville, IL) that were
previously coated with gelatin. The cells were allowed to adhere for 30 minutes at 37°C. Nonadherent cells were removed by gentle washing
with HBSS containing 25 mg/mL BSA. A suspension of 12.5 × 106 zymosan particles in HBSS/BSA were added to the
adherent cells and incubated for 30 minutes at 37°C. Unbound
particles were removed with gentle washing with PBS. Slides were
stained with crystal violet (Sigma, St Louis, MO) for zymosan particle
visualization and Wright stain for cell identification.
Statistical analysis.
Results are expressed as the mean ± SEM. Significance of difference
was determined by a one-way ANOVA or an unpaired Student's t-test.16
| |
RESULTS |
Leukocyte recruitment after peritoneal stimulation with
thioglycollate.
An analysis of total leukocyte levels in the peritoneal exudate of
Plg(+/+), Plg(+/), and
Plg(/) mice was made at various timepoints after
thioglycollate induced inflammation (Fig
1). Peak leukocyte recruitment occurred at 6 hours in all three
genotypes. Peritoneal leukocyte levels diminished dramatically in
Plg(/) mice after 6 hours relative to
Plg(+/+) mice. The response in Plg(+/) mice was
intermediate to that observed in Plg(+/+) and Plg(/) mice and would appear to indicate a
plasminogen dose dependency on sustained leukocyte recruitment. To
further identify the inflammatory cells contributing to this response,
cell differentials were performed.
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| Fig 1.
Total peritoneal leukocytes 0 to 96 hours after
peritoneal stimulation with thioglycollate. (- -)
Plg(+/+), (- -) Plg(+/), and (- -)
Plg(/). Unstimulated peritoneum is represented as t = 0. Values represent mean ± SEM. For Plg(+/+),
Plg(+/), and Plg(/) mice P = .003 at 72 hours poststimulation determined by one-way ANOVA
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As documented by other investigators,17,18 neutrophil
recruitment occurs early during the inflammatory response
(Fig 2A). At 6 hours poststimulation, neutrophil levels
were maximal and similar between Plg(+/+),
Plg(+/), and Plg(/) mice
[24.07 ± 3.82 × 106 (n = 11) in
Plg(/) mice, 15.15 ± 2.33 × 106 (n = 12) in Plg(+/) mice,
and 19.09 ± 2.66 × 106 (n = 13) in
Plg(+/+) mice, P = not significant (NS)]. These levels diminished dramatically after 6 hours in all three genotypes.
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| Fig 2.
Cell differentials of peritoneal leukocytes 0 to 96 hours
after peritoneal stimulation with thioglycollate as determined by Wright stain. (A) Peritoneal neutrophils; (B) peritoneal macrophages; (--) Plg(+/+), (--) Plg(+/),
and (--) Plg(/). Unstimulated peritoneum is
represented as t = 0. Values represent mean ± SEM. Using one-way
ANOVA, P = NS for neutrophils at 6 hours poststimulation and
P < .001 for macrophages at 72 hours poststimulation for
Plg(+/+), Plg(+/), and Plg(/)
mice.
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Monocyte recruitment, which occurs later during the inflammatory
response,19,20 peaked at 72 hours poststimulation in
Plg(+/+) mice. This response was severely compromised in
Plg(/) mice [11.50 ± 1.48 × 106 (n = 11) in Plg(/) mice versus
25.94 ± 2.84 × 106 (n = 13) in Plg(+/+)
mice at 72 hours poststimulation, P < .001] (Fig 2B).
Moreover, plasminogen deficiency dramatically diminished sustained
monocyte recruitment: The level of macrophages appeared to plateau at
24 hours poststimulation in the plasminogen deficient mice whereas
recruitment continued to increase in the wild type mice. Interestingly,
levels in the Plg(+/) mice were intermediate (14.70 ± 2.05 × 106 at 72 hours poststimulation)
indicative of a gene dosage dependency consistent with intermediate
antigen levels present in plasma [35 ± 2 µg/mL (n = 3) for
Plg (+/) mice versus 84 ± 8 µg/mL (n = 4) for
Plg(+/+) mice].15 Additional studies using
fluorescent-labeled peritoneal macrophages injected intraperitoneally
into thioglycollate stimulated Plg(+/+) and
Plg(/) mice indicated that the observed difference in monocyte recruitment was not attributable to differences in recovery of macrophages in Plg(+/+) and
Plg(/) mice (data not shown).
However, a minor component of the inflammatory response in this model
sustained recruitment of lymphocytes also was compromised in
plasminogen-deficient mice: 1.06 ± 0.15 × 106 (n = 13) for Plg(+/+) mice versus 0.66 ± 0.11 × 106 (n = 11) for Plg(/) mice at 72 hours poststimulation P < .05.
Blood leukocyte levels after peritoneal thioglycollate
stimulation.
To determine if diminished levels of peritoneal macrophages are caused
by a diminished source of monocytes in circulation, cell differentials
were performed on blood collected from Plg(+/+), Plg(+/), and Plg(/) mice during
the inflammatory response. The early increase in circulating
neutrophils and monocytes is reflective of a response to the
inflammatory agent. This effect is seen most dramatically in the
neutrophil response (Fig 3A). The slightly increased neutrophil levels in the peritoneum of Plg(/) relative to Plg(+/+) mice, at 6 hours poststimulation, may be the result of increased levels of these
cells in circulation. However, the diminished response in monocyte
recruitment into the peritoneum cannot be explained by a diminished
source in circulation (Fig 3B). In addition, the enhanced levels of
monocytes in blood coincident with inflammation in
Plg(/) mice would suggest that accumulation of
monocytes in peripheral circulation is unaffected by plasminogen
deficiency.
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| Fig 3.
Blood cell differentials 0 to 96 hours after peritoneal
thioglycollate stimulation. (A) Blood neutrophils and (B) blood
monocytes from Plg(+/+) and Plg(/) mice.
(--) Plg(+/+) and (--)
Plg(/). Blood cell levels from unstimulated
mice are represented as t = 0. Values represent mean ± SEM.
Monocyte P < .05 at 2 and 24 hours poststimulation using
Student's t-test for Plg(+/+) and Plg(/) mice. Neutrophils P < .05 at all
timepoints poststimulation using Student's t-test for
Plg(+/+) and Plg(/) mice .
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Microscopy of peritoneum and macrophages.
During the inflammatory process in the peritoneum, the mesothelial
lining of the cavity transforms from a nonadhesive to an adhesive
surface.21,22 Eventually fibrinous adhesions are found to
accumulate on the mesothelial surface and are eventually resolved by
mesothelium-derived proteases.23 A lack of resolution of these adhesions could potentially affect migration of inflammatory cells. Analysis of peritoneal cavity lining of Plg(+/+) and
Plg(/) mice at the light microscopic level
indicated development of fibrinous adhesions associated with the
mesothelium as early as 6 hours poststimulation. These adhesions
appeared patchy and loosely associated with the cavity wall. Electron
microscopic analysis of recruited macrophages did not show fibrin on
the cell surface.
Macrophage phagocytic function.
Because macrophages were the most prominent cell type affected by
plasminogen deficiency during an inflammatory response, an analysis of
their function in Plg(+/+) and Plg(/)
mice was made. For this purpose, phagocytic potential was assessed
using zymosan particles. The percent of macrophages that ingested
zymosan [83.00 ± 1.25 (n = 3) for Plg(+/+) mice versus
82.67 ± 1.79 (n = 3) for Plg(/) mice] as
well as the number of particles per phagocytic cell [9.89 ± 0.21 (n = 3) for Plg(+/+) mice versus 10.65 ± 0.31 (n = 3) for
Plg(/) mice] were similar between the two
genotypes. This would indicate that a macrophage function, in this case
phagocytic potential, is not affected by plasminogen deficiency.
| |
DISCUSSION |
Proteases play a major role in the inflammatory response by
contributing to tissue injury and remodeling as well as regulating the
activation and function of inflammatory cells. The plasminogen system
has been implicated in playing a role in the inflammatory response by
virtue of the capacity of inflammatory cells to synthesize and assemble
components of the system on their surface.4,7,8,24 In
addition, the main components of the fibrinolytic system, plasminogen, plasminogen activators, and inhibitors have been identified in exudates
and extracts of inflamed tissues.25,26
To directly analyze plasminogen's involvement in the inflammatory
response this study used a classic acute inflammatory model. Plg(+/+), Plg(+/), and
Plg(/) mice were exposed to the inflammatory agent, thioglycollate, through intraperitoneal injection, and the
cellular response quantitated. Total leukocyte recruitment indicated
that the initial response was equivalent between the genotypes but a
sustained response was compromised in the absence of plasminogen.
An analysis of the specific cellular response indicated that the
kinetics of recruitment as well as the quantitative response of
neutrophils was equivalent between the different genotypes and occurred
early during inflammation.27 Prior studies have shown that
neutrophils are able to degrade subendothelial matrix via an
elastase-dependent process, and therefore, plasminogen may play a less
significant role in mechanisms involved in neutrophil recruitment
during an inflammatory response.27 The early but brief
neutrophil response during inflammation is consistent with other
studies.4 It is known that the lifespan of neutrophils in
tissues is short the result of emigration via the lymphatics or
apoptosis leading to phagocytosis by macrophages.28,29 At later timepoints after stimulation, the predominant recruited cell
types are monocytes that continue to migrate to the site and eventually
differentiate into long-lived macrophages.
An analysis of the monocyte response indicated that monocyte
recruitment is severely compromised in Plg(/)
mice and intermediate in Plg(+/) mice suggesting a gene
dosage dependency of the response. Macrophages are capable of
generating procoagulant and fibrinolytic activity and the coordinate
expression of these two activities may contribute to inflammatory and
healing processes by regulating fibrin turnover.4,30 In
addition, both plasmin and plasmin-derived fibrin(ogen) degradation
products have been identified as leukocyte chemoattractants, and
therefore, diminished levels of these chemoattractants may partly
explain impaired monocyte recruitment.31-33
During peritoneal inflammation the mesothelial cells that line the
interior cavity of the peritoneum become activated and fibrinolytic
activity is temporarily diminished resulting in deposition of fibrin
and collagen fibrils on the peritoneal surface. Eventually, the
plasminogen activating activity of the peritoneal mesothelium leads to
fibrinolysis and degradation of extracellular matrix protein. In vitro
studies assessing macrophage mediated extracellular matrix degradation
in u-PA (/) and t-PA (/) mice indicated a
dependence on Plg and, thus, would implicate Plg in cell migratory events associated with extracellular matrix degradation.34
In addition, the observed presence of patchy fibrin-like adhesions along the peritoneal cavity could potentially effect transmesothelial migration into the cavity.
Levels of macrophage colony forming cells after thioglycollate
stimulation are dependent on the presence of promonocyte bone marrow
cells and circulating monocytes.35 During an acute
inflammatory response in the peritoneal cavity both peritoneal
macrophages and monocytes in peripheral blood increase in
number.36 Therefore, an analysis of blood monocyte levels
was performed to determine whether diminished recruitment was
reflective of a diminished source in Plg(/) mice.
Circulating levels of monocytes were comparable between
Plg(+/+) and Plg(/) mice and even
slightly elevated in Plg(/) mice during the
timecourse of the study. In addition, the comparable kinetics of an
increase in circulating monocytes between Plg(+/+) and
Plg(/) mice after thioglycollate stimulation
would appear to suggest that emigration of monocytes from bone marrow
is not affected by plasminogen deficiency.
Plasminogen deficiency may result in diminished recruitment of
subpopulations of monocytes or lymphocytes. It has been shown that the
recruitment of CD4+ population of T lymphocytes is
specifically affected in u-PA-deficient mice during pulmonary
cryptococcus infection13; and, although lymphocytes
are not a prominent cell type in this peritoneum inflammatory model
migration of lymphocytes appear to be compromised in
Plg(/). An assessment of macrophage phagocytic function, a property developed early during differentiation, was made
between Plg(+/+) and Plg(/) mice and was
found to be comparable.
While the mechanisms of inflammatory cell recruitment may vary
depending on the specific tissue target site, as observed in the
P-Selectin/ICAM-1 double mutant mice,37 this study directly shows a role for plasminogen in an inflammatory response specifically in processes that regulate sustained leukocyte recruitment. Additional studies assessing the response to other peritoneal stimulants as well
as the inflammatory response to other sites are currently ongoing.
| |
FOOTNOTES |
Submitted February 20, 1997;
accepted October 30, 1997.
Supported by National Institutes of Health Grant No. HL17964 and Human
Frontiers of Science Grant No. RG 363/95M.
Address reprint requests to Victoria A. Ploplis, PhD, Joseph J. Jacobs
Center for Thrombosis and Vascular Biology, Cleveland Clinic
Foundation, 9500 Euclid Ave, Cleveland, OH 44195.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We thank Dr Meredith Bond, Dr Kandice Marchant, John Gabrovsek, and
Frankie Whaller for assistance in microscopy studies and Suzanne Turner
and Gene Lazuta for assistance in preparing this manuscript.
| |
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Abstract
Introduction
Abstract