© 2000 American Heart Association, Inc.
UltraRapid Communications |
Mechanisms for Regulation of Fluid Shear Stress Response in Circulating Leukocytes
From the Department of Bioengineering and Whitaker Institute for Biomedical Engineering (S.F., T.Y., G.W.S.S.) and Division of Cellular and Molecular Medicine (D.N.P.), University of California San Diego, La Jolla, Calif. S.F. is currently affiliated with Department of Neurosurgery, Maizuru Municipal Hospital, Kyoto, Japan. T.Y. is currently affiliated with Cardiovascular Division, Omiya Medical Center, Jichi Medical School, Saitama, Japan.
Correspondence to Dr Geert W. Schmid-Schönbein, Department of Bioengineering and the Whitaker Institute for Biomedical Engineering, University of California San Diego, La Jolla, CA 92093-0412. E-mail gwss{at}bioeng.ucsd.edu
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Abstract—We have shown that leukocytes retract their pseudopods and detach from substrates after exposure to physiological fluid shear stresses (
1.5 dyn/cm2). In inflammation, however, pseudopod
projection during spreading and firm adhesion on
endothelium is observed even in microvessels with
normal blood flow and fluid shear stresses. Thus, we examined
mechanisms that may serve to regulate the shear stress response of
circulating leukocytes. In the presence of inflammatory mediators
(platelet-activating factor [PAF] f-met-leu-phe), a subgroup of
cells ceases to respond to shear stress. cGMP analogs and nitric oxide
(NO) donors enhance the shear stress response and reverse the
inhibitory effect of inflammatory mediators on the shear
stress response, whereas depletion of cGMP leads to cessation of the
shear stress response even in unstimulated leukocytes. The ability of
cGMP to enhance the shear stress response is not associated with CD18
expression, because cGMP has no effect on CD18 expression in response
to shear stress. The shear stress response of leukocytes in
endothelial nitric oxide synthase (-/-) mice, in
which NO level in blood is decreased, is attenuated compared with that
in wild-type mice. In rat mesentery venules stimulated by PAF under
normal blood flow, a cGMP analog diminishes pseudopod projection of
leukocytes, whereas inhibition of NO leads to enhanced pseudopod
projection and spreading. The evidence suggests that inflammatory
mediators suppress the shear stress response of leukocytes leading to
spreading even under normal physiological shear
stress, whereas cGMP may serve to maintain shear stress response even
in inflammation. The full text of this article is available at
http://www.circresaha.org.
Key Words: leukocyte • microcirculation • shear stress • nitric oxide • cGMP
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Introduction |
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There is now evidence that all cells in the circulation respond to physiological shear stress, including endothelial cells,1 erythrocytes,2 platelets,3 and leukocytes.4 Human leukocytes (neutrophils, monocytes, and lymphocytes) respond to fluid shear stress by retraction of pseudopods (lamellipodia, filopodia, and other forms) and membrane detachment.4 The shear stress response of leukocytes serves as the key mechanism to maintain circulatory leukocytes in a spherical shape without pseudopod formation. In the presence of pseudopods, leukocytes become trapped in capillaries with high probability.5 Pseudopod retraction is a requirement for normal passage of circulating leukocytes through the microcirculation.
In inflammation, however, pseudopod projection (change of the cell shape from a spherical shape) of adherent leukocytes is a requirement for migration across the endothelium into the tissue. The adhesion is readily observed even in venules that have essentially normal blood flow.6 Thus, there may exist a fundamental regulating mechanism for the leukocyte shear stress response in inflammation. Using in vitro experiments on human, rat, and mouse leukocytes and in vivo observations in the rat mesentery, we provide evidence in the present study that inflammatory mediators suppress pseudopod retraction by fluid shear stress, and that the shear stress response of leukocyte plays an inhibitory role in inflammation, which is enhanced by nitric oxide (NO) via cGMP.
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Materials and Methods |
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The study protocol was reviewed and approved by the University of California San Diego Human and Animal Subject Committee.
In Vitro Experiments Using Human Blood
After red cell sedimentation, the supernatant of leukocytes
collected from volunteers was resuspended in Plasma-Lyte (Baxter
Health Care) with 2.5 mmol/L Ca2+. The cell
suspension (100 µL) was deposited into a chamber on an inverted
microscope (Leitz). Micropipettes of 4 to 6 µm in diameter were
connected to a reservoir with hydrodynamic pressure adjustment and were
positioned above a neutrophil on the glass so that fluid flow could be
applied over the cell surface. The magnitude of the fluid stress on the
cell surface was numerically computed.4 The maximum length
across the cell and pseudopod, L, was measured and normalized by the
diameter of the cell, L0, without pseudopod
length (see Figure 1
). The cell suspension 2 hours after the
blood collection was also placed on a glass without shear stress for 30
minutes, and L in 100 cells of each group was measured.
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In Vitro Studies in a Cone-and-Plate Shear Field
Because procedures for isolation of living leukocytes
significantly affect the shear stress response (data not shown),
unseparated whole blood was used. Methylene blue, 8-bromoguanosine
3':5'-cyclic monophosphate (8-Br-cGMP), or 0.9% saline as control were
applied to each group 30 minutes after the blood collection from Wistar
rats and endothelial nitric oxide synthase (eNOS)
(-/-) and wild-type mice (C57BL/6J-NOS3tmlune,
Jackson Laboratory, Bar Harbor, Maine).7 The whole blood
(0.3 mL) was sheared in a cone-and-plate device8 at a
level of 5.0 dyn/cm2 for 10 minutes and fixed
with 2% glutaraldehyde. To measure CD18 expression,
the cells were fixed in 0.4% paraformaldehyde.
Unsheared control samples were also fixed at the same time in the same
way. The number of leukocytes with pseudopods stained by 0.02% crystal
violet was counted by light microscopy. To determine CD18 membrane
expression, FITC-labeled monoclonal antibody against rat CD18
(Pha-rMingen) or rat IgG isotype (PharMingen) was applied to each
blood group for 30 minutes. Red cells were removed by FACS Lysing
Solution (Becton Dickinson). CD18 expression was measured with a flow
cytometer (Becton Dickinson FACS analyzer).
NO Metabolites Measurement in Mice Blood
After centrifugation of mouse blood, NO
metabolites (nitrite/nitrate) in serum were measured using an NO
analyzer (ENO-20; Eicom Corp).9
In Vivo Observation of Pseudopod Formation
The mesenteric microcirculation was visualized with an
intravital microscope (Leitz). To reduce the shear stress in
microvessels to near zero, postcapillary venules were occluded for 3
minutes with a micropipette mounted on a micromanipulator. The
pseudopod formation was observed during flow occlusion and after flow
restoration for 2 minutes. Except for controls, the superfusion
contained 10-8 mol/L platelet-activating
factor (PAF). For measurement of the shear rate in venules, 0.1 mL of
erythrocytes from donor rats labeled by fluorescent dye PKH-26
(Zynaxis Cell Science)10 was intravenously
injected. The velocities of 50 labeled erythrocytes in each venule were
measured using an intravital fluorescence microscope with a SIT
camera (Dage-MTI). The shear rate on the endothelium in
each venule was estimated as 4xmean velocity/internal radius of the
vessel.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
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Results |
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In Vitro Observations on Adherent Leukocytes
Application of shear stresses (
1.5
dyn/cm2) on adherent leukocytes on a glass
surface caused instant pseudopod retraction irrespective of the
particular shape of the pseudopod (Figures 1A
through 1D and
2A). No pseudopod projection occurred
during shear stress application. L/L0 of sheared
leukocytes was significantly lower compared with nonsheared cells
during shear stress application (Figure 2A). This response was
observed in all fresh human leukocytes (50 of 50 tested cells).
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) and FMLP (
) on the neutrophil
response to shear stress. n=20 in each group. Responding leukocytes are
defined as the cells in which >20% reduction of L/L0 is
observed during shear stress. D, Pseudopod retraction velocity in
response to shear stress with
Inflammatory Stimulators and the Shear Stress Response of Adherent
Neutrophils In Vitro
The inflammatory stimulators PAF and
formyl-methionyl-leucyl-phenylalanine (FMLP) suppressed the shear
stress response of neutrophils in a dose-dependent manner (Figures 2B and 2C). Cells that showed a reduced response to fluid shear
stress tended to spread out on the substrate and exhibited reduced
migration.
cGMP and the Shear Stress Response of Adherent Neutrophils In
Vitro
The soluble guanylate cyclase inhibitor
methylene blue served to completely block the shear stress response
(Figures 2B and 2C) and also led to enhanced spreading of the
cells (Figures 1E through 1H). In contrast, pseudopod retraction
velocity was enhanced by the cGMP analog 8-Br-cGMP, at 1.5
dyn/cm2 (Figure 2D). The soluble
guanylate cyclase blocker LY83583 (100 µmol/L) also
inhibited the shear stress response at 1.5
dyn/cm2 (results not shown). In the absence of
fluid shear stress and without any inflammatory stimulator, 8-Br-cGMP
had no effect on the average cell length projected on a glass
surface, whereas the average length of the cells treated with PAF was
reduced by 8-Br-cGMP (Table 1).
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Effect of cGMP and NO Donors on the Shear Stress Response of
Stimulated Leukocytes In Vitro
In the presence of PAF, L/L0 of leukocytes
treated with 8-Br-cGMP was significantly lower during fluid shear
application (Figure 2B). The suppression of the fluid stress
response by PAF and FMLP could be attenuated in a dose-dependent manner
by the cGMP analogs 8-Br-cGMP and dibutyryl cGMP (Figure 3). The NO donors
S-nitroso-acetyl penicillamine (SNAP) and
3-morpholinosydnonimine (SIN-1) also enhanced the response to shear
stress of neutrophils stimulated by PAF or FMLP. Superoxide dismutase
(SOD) by itself did not enhance the shear stress response. The effect
of NO donors on the fluid stress response was, however, mildly enhanced
by SOD. NOS inhibitors, such as
NG-methyl-L-arginine
(L-MNA; 1 mmol/L) and
NG-nitro-L-arginine
methyl ester (L-NAME; 1 mmol/L), did not affect the shear stress
response in vitro in both the absence (data not shown) and presence of
PAF or FMLP (Figure 3).
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) or FMLP (
). n=10
to 20 in each group. Responding leukocytes are defined as the cells in
which >20% reduction of L/L0 is observed during shear
stress application. *P<0.05 vs control.
cGMP and Shear Stress Response of Suspended Leukocytes In
Vitro
Because the experimental observations on single cells depend on
their adhesion to a substrate, we introduced a technique that permits
the study of leukocytes in free suspension under well-controlled shear
stresses. In line with the experiments on adherent cells, the number of
leukocytes with pseudopod formation without treatment was significantly
decreased by application of shear stress (5.0
dyn/cm2) with the cone-and-plate shear device
(Figure 4A). 8-Br-cGMP enhanced pseudopod
retraction of circulating cells in response to shear stress, whereas
methylene blue significantly suppressed the response (Figure 4A).
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,
100 µmol/L 8-Br-cGMP;
In contrast, at a shear stress of 5 dyn/cm2, neither
8-Br-cGMP nor methylene blue had any significant effect on the
expression of CD18 of leukocytes (Figure 4B), although cGMP had
a tendency to reduce CD18 expression in the absence of shear stress,
and methylene blue tended to increase CD18 expression (Figure 4B). Shear stress served to reduce the CD18 expression with or
without cGMP present (Figure 4B).
Shear Stress Response of Leukocytes in eNOS Knockout Mouse
Although the number of leukocytes with pseudopod formation in both
eNOS (-/-) and wild-type mice was decreased by application of shear
stress (5.0 dyn/cm2) with the cone-and-plate
shear device, leukocytes of eNOS (-/-) mice responded less to shear
stress compared with wild types (Figure 4C). Plasma NO
metabolite levels in eNOS knockout mice were significantly lower than
in wild types (Table 2).
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Shear Stress Response In Vivo
Nonstimulated leukocytes projected pseudopods during vessel
obstruction in every direction. During obstruction, 5 of 8 adhered
leukocytes on the vessel wall projected pseudopods; 3 of 8 did not.
Adherent leukocytes retracted their pseudopods immediately after
restoration of fluid stress and were washed away in the bloodstream
once they reached an almost spherical shape (L/L0
1) (Figures 5A through 5C).
Nonadherent leukocytes were washed away in the bloodstream immediately
after flow restoration.
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In contrast, in the presence of 10-8 mol/L
PAF without shear stress, the majority of pseudopods were projected
over the endothelial cells, fewer pseudopods were
pointing into the vessel lumen, and all leukocytes (8 of 8 cells)
adhered to and crawled on the vessel wall during flow obstruction.
Pseudopod retraction in response to fluid stress could be suppressed by
application of PAF, which caused firm leukocyte adhesion (3 of 8). A
combination of NOS inhibition by L-MNA (2.5 mg/kg) with PAF application
led to diminished pseudopod retraction compared with the levels with
PAF without L-MNA after flow restoration and, consequently, to an
increased count of adherent (3 of 8) as well as migrating (3 of 8)
leukocytes (Figures 5D through 5F). 8-Br-cGMP (0.45 mg/kg)
diminished the ability of PAF to suppress the shear stress response in
terms of pseudopod projection and reversed the ability of L-MNA to
further block the shear stress response. In both PAF with 8-Br-cGMP and
PAF with L-MNA and 8-Br-cGMP groups, all leukocytes retracted their
pseudopods and were washed away in the bloodstream within 15 seconds
after flow restoration. L-Arginine (300 mg/kg) also
reversed the effect of L-MNA on the shear stress reaction in the
presence of PAF. There are no significant differences in microvessel
wall shear rates between groups (669.0±162.8 1/sec).
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Discussion |
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The present study provides evidence that the response of leukocytes to shear stress, in terms of pseudopod retraction, is suppressed at elevated concentrations of inflammatory mediators. In contrast, the shear stress response is enhanced by the cGMP analogs, whereas the blockers of soluble guanylate cyclase inhibit the response (Figures 2B
, 2C, 2D, 3, and 4A). cGMP
may be one of the requirements for leukocyte pseudopod retraction in
response to shear stress.
Although pseudopods on circulating leukocytes play an important
role during trapping in capillaries,5 they are essential
for migration and phagocytosis. After stimulation with inflammatory
mediators, the number of leukocytes that retract their pseudopods after
exposure to fluid shear stress is reduced in a dose-dependent manner
(Figures 2B and 2C). Moreover, the suppression of the fluid
stress response by inflammatory stimulators can be attenuated in a
dose-dependent manner by cGMP analogs (Figures 2B and 3).
The evidence thus suggests that cGMP and inflammatory stimulators have
the opposite effect of each other on the shear stress response and on
pseudopod formation during inflammation. In the presence of fluid shear
stress, cGMP increases the sensitivity of leukocytes to shear stress
and promotes pseudopod retraction, whereas inflammatory stimulators
attenuate the shear stress response by shifting from pseudopod
retraction to pseudopod projection. In inflammation, both cGMP and
inflammatory stimulators may regulate the shear stress response of
neutrophils. The balance between these two mechanisms may serve to
control pseudopod formation and cell spreading and migration.
Pseudopod projection and adhesion are closely associated with
expression of adhesion molecules.11 There is a possibility
that cGMP indirectly enhances pseudopod retraction in response to shear
stress via an effect on adhesion molecules. Among several adhesion
molecules, firm adhesion of neutrophils during migration on substrates
is mainly dependent on CD18.11 Therefore, we tested the
CD18 expression and the influence of cGMP on the shear stress response.
Although the CD18 expression on circulating neutrophils is
downregulated by shear stress, cGMP has no effect on the expression
after shear application (Figure 4B). Thus, the ability of cGMP
to regulate the pseudopod retraction in response to shear stress may be
independent of CD18 expression. Interestingly, in the absence of shear
stress, 8-Br-cGMP has no effect on pseudopod formation of nonstimulated
leukocytes, whereas the cGMP analog suppresses CD18 expression (Table 1, Figures 4A and 4B). In contrast, in the presence of
shear stress, 8-Br-cGMP enhances the pseudopod retraction but not the
downregulation of CD18 by fluid stress (Figures 4A and 4B). We
demonstrated that fluid shear stress regulates both pseudopod formation
and CD18 expression in leukocytes. Shear stress may play a role in
inflammation via the regulation of CD18 expression as well as pseudopod
retraction. Additional studies about changes in expression and
localization of CD18 in adherent leukocytes in response to shear stress
are needed.
One of the main mechanisms to increase intracellular cGMP levels
in leukocytes is by NO.12 In addition to cGMP analogs, the
NO donors SNAP and SIN-1 enhanced the neutrophil response to shear
stress in the presence of PAF and FMLP (Figure 3). Although NO
also acts as a scavenger of superoxide,13 the enhancement
of the shear stress response by NO donors may be attributed to an
increase in cGMP in neutrophils rather than the scavenging of
superoxide, given that SOD by itself did not enhance the response to
shear stress. The effect of NO donors on the fluid stress response is,
however, mildly enhanced by SOD (Figure 3), probably due to the
ability of SOD to scavenge superoxide derived from neutrophils and
thereby increase NO levels.
Because NO is mainly produced by endothelial
cells in the circulation,12 the
endothelial cell may serve as a regulator for the shear
stress response of leukocytes. To determine whether
endothelium-derived NO regulates the shear stress
response, we examined leukocytes of eNOS (-/-) mice,7 in
which endothelial cells no longer produce NO
synthesized by eNOS, with lower levels of NO in the blood (Table 2). Compared with leukocytes in wild-type mice, the cells in
eNOS (-/-) mice exhibited a reduced response to shear stress (Figure 4C). The evidence suggests that
endothelium-derived NO enhances the shear stress
response of leukocytes in the circulation.
To clarify mechanisms of the shear stress response controlled by
cGMP, NO, and inflammatory stimulators in vivo, we also examined
pseudopod formation by leukocytes in rat mesentery venules after
reduction and restoration of physiological shear
stresses. Nonstimulated leukocytes projected pseudopods during
vessel obstruction but retracted them immediately after restoration of
fluid stress. After retraction of the pseudopods, the leukocytes were
washed away from the endothelium by the bloodstream
(Figures 5A through 5C). Pseudopod retraction in response to
fluid stress could be suppressed by application of PAF. NOS inhibition
by L-MNA strongly enhanced the ability of PAF to attenuate the shear
stress response of leukocytes (Figures 5D through 5F). In the
presence of an inflammatory stimulator, leukocytes may need higher
levels of cGMP to maintain the shear stress response than under normal
conditions. Inhibition of NOS, therefore, may cause an imbalance
between cGMP and inflammatory stimulators in controlling pseudopod
formation under normal shear stresses. This hypothesis is further
supported by experiments that show that 8-Br-cGMP not only diminished
the ability of PAF to suppress the shear stress response in vivo but
also reversed the ability of L-MNA to block the fluid shear stress
response. Because L-arginine also reversed the blockade of
the shear stress reaction by L-MNA, L-MNA may influence the shear
stress response by inhibition of NO production. The release of
NO can be enhanced by the induction of NOS in
neutrophils.14 Yet, the shear stress response may require
mainly endothelium-derived NO, because in the absence
of endothelial cells, NOS inhibitors (L-MNA
and L-NAME) did not affect the shear stress response in vitro both with
and without inflammatory stimulators (Figure 4B). In eNOS
(-/-) mice, the shear stress response of leukocytes was reduced even
in the absence of the endothelium in vitro (Figure 4C), because eNOS (-/-) mice may have lower levels of cGMP in
leukocytes due to lower NO production in the circulation.
These in vitro and in vivo data suggest that NO may regulate the leukocyte-pseudopod formation in response to shear stress in the circulation via cGMP. The enhancement of the shear stress response by NO is likely to suppress pseudopod projection and spreading of leukocytes on microvascular endothelium and consequently the level of the inflammatory reaction. Therefore, the regulation of the shear stress response by NO may be one of the key factors to modulate leukocyte-endothelial cell interactions, although NO may have multiple additional effects on leukocyte-endothelial cell interactions.13 15 16 The effect of NO on pseudopod formation and spreading in the absence of flow is still uncertain. NO was reported to induce monocyte and granulocyte rounding on a substrate via a morphine receptor.17 NO reduced F-actin formation in neutrophils,18 19 whereas cGMP increases it.19 One report showed that NO had no direct effect on PAF-dependent neutrophil adhesion in vitro in the absence of shear stress,20 whereas others reported that NO attenuated neutrophil and monocyte adhesion.18 19 21 In the present study, we would like to emphasize the effect of cGMP in the presence of blood flow because the presence of fluid shear stress is the normal condition for peripheral leukocytes, and inflammation frequently occurs under conditions of blood flow, unless vessels are occluded. Endothelial cells that produce NO may raise cGMP in attached leukocytes and maintain their shear stress response by suppression of pseudopod projection. In contrast, endothelial cells that produce lower levels of NO are more likely to permit spreading and attachment of leukocytes in the presence of normal fluid stresses. It is of interest to note that endothelial cells increase NO production in response to shear stress,1 leading in turn to an enhancement of the shear stress response of leukocytes. These observations may be important for the understanding of attachment and spreading of leukocytes on vascular endothelium, lymphocyte recirculation, inflammation, and immunoprotection.
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Acknowledgments |
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This work was supported by US National Institutes of Health Grants HL 10881 and 43026 and National Science Foundation Grant IBN-95–12778. We thank the late Dr Benjamin W. Zweifach and Dr Shunichi Usami, Department of Bioengineering, University of California, San Diego, Yoshihiko Uemura, Department of Neurosurgery, Maizuru Municipal Hospital, for valuable advice, Dr John Frangos, Department of Bioengineering, University of California, San Diego, for the use of the cone-and-plate shear device, and Augustus P. Lestick for editorial assistance.
Received December 6, 1999; accepted December 6, 1999.
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