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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In animal models of endotoxemia, sepsis is associated with the accumulation of leukocytes and altered microvascular perfusion. In order to test the hypothesis that bacterial sepsis upregulates leukocyte-endothelial adhesion, we used intravital microscopy to examine the flow behavior of leukocytes in the postcapillary venules (PCV) of rats made septic by cecal ligation and perforation (CLP). Animals were randomized to CLP or sham study groups and studied 6 h, 24 h, or 48 h later. In postcapillary venules of the extensor digitorum longus muscle, we found that: (1) over the course of the study, leukocyte adhesion and extravasation increased in both experimental groups (analysis of variance [ANOVA], significant time effect: adhesion, p < 0.001; extravasation, p < 0.05); (2) leukocyte adhesion was decreased by CLP treatment (ANOVA, sepsis effect, p = 0.05), particularly after 24 to 48 h of sepsis (ANOVA, sepsis × time interaction, p < 0.05); and (3) the reduction in leukocyte adhesion in CLP animals was associated with a decrease in leukocyte extravasation (ANOVA, sepsis effect, p < 0.01). After correction for the reduction in systemic leukocyte count associated with CLP, the effect of sepsis on leukocyte adhesion and extravasation no longer reached statistical significance. These findings suggest that chronic (6 to 48 h) bacterial sepsis does not upregulate leukocyte adhesion in a manner similar to that seen in models of acute endotoxemia. These data suggest that the increased microcirculatory flow heterogeneity seen in this and other models of bacterial sepsis may not be explained by leukocyte entrapment in postcapillary venules.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The release of reactive oxygen species and hydrolytic enzymes by leukocytes plays an important role in the host defense against bacterial infection (1). In a number of inflammatory conditions, such as ischemia-reperfusion, thermal injury, and trauma, neutrophil-derived bactericidal defenses may cause significant microcirculatory injury (2). Proposed mechanisms for microvascular dysfunction include: (1) leukocyte-mediated endothelial injury, or (2) microvascular obstruction secondary to leukocyte accumulation within capillaries or postcapillary venules (PCV) (3).
In animals infused with endotoxin, leukocytes are activated
and accumulate within the tissues and microcirculation of organs such as the lung (4) and liver (5). In acute models of sepsis such as these, leukocytes cause tissue and microvascular injury (4, 5). Supporting the view that leukocyte accumulation in this context is receptor-mediated, these changes can be
blocked by the administration of monoclonal antibodies (i.e.,
anti-CD18 and anti-CD11b) that inhibit leukocyte adhesion to
postcapillary venular endothelial cells (6, 7). These data raise the
possibility that leukocyte entrapment in PCVs may account
for the increased heterogeneity of microcirculatory flow that
is characteristic of bacterial sepsis (8). To our knowledge,
no studies have examined venular leukocyte flow behavior in
a chronic model of polymicrobial sepsis
a model that closely
replicates human sepsis.
The objective of the present study was to investigate leukocyte flow behavior in a model of chronic polymicrobial sepsis, thereby to test the hypothesis that cecal ligation and perforation (CLP) would lead to increased leukocyte adhesion and
extravasation within PCVs of organs not directly affected by the
septic processan observation relevant to our understanding
of the microcirculatory dysfunction associated with bacterial
sepsis. We used intravital microscopy to study the flow behavior of leukocytes in PCVs of the extensor digitorum longus
muscle of rats made septic by CLP. In this study, the effect of
bacterial peritonitis was to reduce, rather than increase, leukocyte adhesion and extravasation in PCVs. To our knowledge, this is the first study to provide direct in vivo data describing leukocyte flow behavior in remote organs in bacterial
sepsis. These data suggest that the increase in leukocyte adhesion and extravasation seen in models of acute endotoxemia (11) may not reflect those seen in chronic bacterial sepsis. Our findings suggest that sepsis-induced microcirculatory dysfunction in skeletal muscle (11, 14) may not be explained by
leukocyte accumulation in venules of the microcirculatory unit.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal Preparation
Eighty-nine male Sprague-Dawley rats (weight 354 ± 5 g) were studied. After anesthesia with halothane, internal carotid (PE 50; Intramedic, Franklin Lakes, NJ) and external jugular lines (0.25 mm Silastic tubing; Dow Corning, Milland, MI) were inserted under sterile conditions for the monitoring of flood pressure and the infusion of saline. The tubing was tunneled subcutaneously to the back of the neck, where it was attached to a swivel device. Animals were then randomized to either sham or CLP groups. Sham animals (n = 37) had insertion of lines only, whereas in the CLP group (n = 47) a laparotomy was performed and a ligature placed around the cecum immediately distal to the ileocecal valve. The cecum was then punctured twice with an 18-gauge needle and depressed to ensure patency of the holes (8). In both groups, following recovery from anesthesia, fluid infusion (normal saline) was commenced at 300 to 400 ml/kg/d, and infusions of heparin (400 U/kg/d) and fentanyl (400 µg/kg/d) were started. Water and laboratory chow were available ad libitum. The animal protocol was reviewed and approved by the University of Western Ontario Committee on Animal Care.
Leukocyte-Endothelial Cell Interaction
Fifty-five animals were studied on the intravital microscope at either 6 h (sham = 8; CLP = 8), 24 h (sham = 9; CLP = 11), or 48 h (sham = 6; CLP = 8) after entry into the study. To determine baseline values, a group of naive animals was also included (n = 5). Before preparation of the extensor digitorum longus muscle (EDL) for microscopy, arterial blood was drawn to measure the hemoglobin, white cell count, platelet count, and lactate. At the appropriate times after entry into the study, the rats wee reanesthetized with halothane (0.8 to 1.5%, FIO2 = 0.3) and the EDL was exposed and mobilized on its intact vascular pedicle, as previously described (17). During preparation, the muscle was kept moist with normal saline, which was warmed to 32 to 35° C (17). The animal was then placed on the stage of an inverted intravital microscope (Fluovert FU; Ernst Leitz, Wetzlaar, Germany) in the right lateral position. The EDL muscle was reflected into a saline bath on the microscope stage and positioned at its in situ length. A coverslip was placed gently on top of the EDL such that the muscle remained in contact with the bottom of the bath. The preparation was then left undisturbed for a period of 30 min to allow recovery from the effects of surgery. During the experiment, body and muscle temperature were maintained at 37° C and 32° C, respectively, with overhead heating lamps.
The EDL preparation was observed through an inverted intravital microscope using ×32 objective lens (Leitz Wetzlaar L32/0.40), providing a magnification of ×1,000 at the video monitor. All visible PCVs (from three to six in each muscle) were recorded on videotape using a CCD camera (C2400; Hamamatsu, Hamamatsu City, Japan) attached to a videocassette recorder (VCR) (PS-S4380-K; Panasonic, Japan). Each field was recorded for a period of 180 s.
Tapes were analyzed by a single observer in a blinded fashion. Leukocyte interactions with endothelial cells were measured as: (1) rolling, if they made contact with any section of the venular wall within the measurement area; (2) stuck, if they remained in contact with the venular endothelium for a period of more than 30 s; and, (3) extravasated, if the cell body was completely extraluminal. The number of stuck, rolling, or extravasated leukocytes in each 3-min recording period was counted and expressed as the number of interactions per 1,000 µm2 of venule per min.
Measurement of Leukocyte Velocity
In a separate experiment, rats (sham, n = 4; CLP, n = 10) were studied under a fluorescence intravital microscope (Diaphot 300, filter set B-2A; Nikon Corp., Japan) 24 h after entry into the study (n = 14). Thirty minutes prior to the study, leukocytes were labeled with the fluorochrome 5(6) -carboxyfluorescein diacetate succinimidyl ester (CFDASE; Molecular Probes Inc., Eugene, OR). CFDASE was dissolved in dimethylsulfoxide (0.25 ml) immediately prior to the experiment, diluted in 1.5 ml of sterile water, and injected into the external jugular vein over a period of 3 min (3 mg/kg) (18). The EDL muscle was prepared as described earlier. Three to six randomly selected images of the microcirculation were obtained from each animal with a ×10 objective lens (Nikon L10/0.25). Each field was recorded for approximately 20 s. This duration was selected to avoid quenching of CFDASE-labeled leukocytes that may have been stuck within the capillary network.
Tapes were analyzed by a single observer in a blinded fashion. The passage of fluorescently labeled leukocytes through segments of the capillary network was analyzed using frame-by-frame playback from a VCR. Velocities were then calculated in the following microcirculatory segments: the distal arteriole, proximal capillary, midcapillary, and distal capillary just proximal to the PCV.
Neutrophil Expression of CD11b
CD11b expression was measured in a separate group of animals (n = 20). Blood specimens, used to measure CD11b expression, were collected from the animals either before CLP (n = 10) or sham (n = 10) treatment and then at 1 h, 2 h, 3 h, 6 h, and 24 h, or at 3 h, 24 h, and 48 h after entry into the study. In addition, arterial blood was drawn to measure the hemoglobin, white cell count, platelet count, and lactate at 6 h, 24 h, and 48 h following entry into the study. Neutrophil CD11b expression was measured with a flow cytometer (EPICS XL-MCL; Coulter Electronics, Hialeah, FL) and a phycoerythrin-conjugated monoclonal antibody against the rat CD11b complex (Serotec, Oxford, UK).
Statistical Analysis
Values are expressed as mean ± SEM. Statistical significance was assessed at the p < 0.05 level using analysis of variance (ANOVA) or an unpaired t test as indicated. Data were analyzed with SAS statistical software (Version 6.11; SAS Institute Inc., Cary, NC), and ANOVA was done with the PROC GLM (generalized linear model) procedure. When multiple measures were made in the same animal (i.e., multiple capillaries or venules were studied in the same animal) appropriate nesting was incorporated into the statistical model. Because the distribution of the parameters of leukocyte endothelial interaction examined in this study were of log-normal distribution, these data were log-transformed with the result that the assumptions of normality necessary to perform a parametric analysis were fulfilled. The data were subsequently "back-transformed" (mean and SE) before presentation in the text or figures. As the use of a log transform excluded data points at which the number of interactions was zero, a chi-square test was performed to determine whether the frequency of venules with zero leukocyte interactions differed between sepsis and sham-treated groups. This was not the case for the variables examined in this study (i.e., the number of rolling, stuck, or extravasated leukocytes).
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Model
Twenty-four hours after laparotomy, all CLP animals demonstrated reduced activity, piloerection, and exudation around the eyes and nose. In contrast, sham-treated animals demonstrated full recovery from anesthesia and surgery and had no detectable sign of disease. Generalized peritonitis was confirmed at postmortem in the CLP animals, whereas the sham-treated animals showed no signs of peritoneal inflammation. Blood cultures were taken at 24 h (n = 10) and 48 h (n = 6) after entry into the study from 16 of the rats in which serial changes in CD11b expression were measured. Cultures were negative in all sham-treated animals (n = 6) and were positive in 60% of CLP rats (n = 10). The organisms reported included enterococci (20%), gram-negative rods (40%), coliforms (40%), streptococci (20%), and Proteus sp. (10%). Table 1 shows physiologic and biochemical data obtained from wakeful animals studied 24 to 48 h after entry into the study.
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Systemic Hematologic Parameters
CD11b expression (mean channel fluorescence [MCF]) rose to maximum levels within 6 h in both the sham-treated and CLP groups (sham-treated, 17.5 ± 4.4 MCF; CLP, 14.7 ± 1.82 MCF). However, unlike the sham group, CD11b expression in the CLP group remained constant, resulting in significantly increased CD11b expression at 24 h and 48 h after entry into the study (p < 0.01 and p < 0.05, respectively) as compared with sham-treated animals (Figure 1). Associated changes in the systemic leukocyte count, hemoglobin, and platelet count are shown in Figure 2.
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p < 0.05, *p < 0.01).
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Leukocyte Occurrence in PCVs
The number of rolling leukocytes seen in PCVs was increased in sham-treated animals at 24 h (p < 0.05, Figure 3A). Leukocyte adhesion increased with time in both sham and CLP treatment groups (ANOVA, time effect, p < 0.001; Figure 3B), although the effect of time on leukocyte adhesion was less in the CLP-treated group (significant sepsis × time interaction, p < 0.05). Similarly, leukocyte extravasation increased with time in both CLP and sham-treated groups (ANOVA, time effect, p < 0.05; Figure 3C). The effect of bacterial sepsis (i.e., CLP) was to reduce leukocyte adhesion (ANOVA, significant sepsis effect, p = 0.05; Figure 3B) and extravasation (ANOVA, significant sepsis effect, p < 0.01; Figure 3C). Baseline values for leukocyte behavior were studied in a group of naive animals (n = 5). These data are presented in Figure 3. No difference was seen between the naive animals' values and the sham-treated animals' 6 h, 24 h, and 48 h values for leukocyte rolling, sticking, and extravasation (Dunnett's two-tailed t test). Leukocyte adhesion at 24 h was reduced to CLP animals as compared with naive controls (Dunnett's two-tailed t test, p < 0.05).
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Figure 4 shows leukocyte flow behavior expressed as a proportion of the systemic leukocyte count. Using these derived values, we observed that leukocyte adhesion increased significantly over time (ANOVA, significant time effect, p < 0.001; Figure 4B), as did extravasation (ANOVA, significant time effect, p < 0.05; Figure 4C). However, with this analysis, there was no demonstrable effect of CLP on either leukocyte adhesion or extravasation (Figure 4B and C).
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Leukocyte Velocity within the Capillary Network
Leukocyte velocity was measured within each segment of the
microcirculatory unit 24 h after either sham or CLP treatment
(Figure 5). A significant reduction in leukocyte velocity was
seen as fluorescently labeled cells passed from the arteriole to
the distal capillary (ANOVA, significant site effect, p < 0.01;
Figure 5). Although there was no effect of sepsis on absolute
leukocyte velocity (ANOVA, no sepsis effect; Figure 5), the
change in velocity between the segments of the microcirculatory unit (site-specific deceleration) was greater in sham- than
in CLP-treated animals (ANOVA, significant group × site interaction, p < 0.05; Figure 5). There was no difference in the
mean velocity of leukocytes between the two groups of animals (sham: 775 µm/s [95% CI: 711 to 839 µm/s]; CLP: 842 µm/s
[95% CI: 727 to 957 µm/s]). On the basis of these data we would
have detected a 10% change in mean velocity with a probability of 81% (
= 0.05).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study is unique in providing direct in vivo data about leukocyte flow behavior in the PCVs of remote organs in established bacterial sepsis. In this model, we found that bacterial sepsis reduced the degree of leukocyte adhesion and extravasation as compared with that seen in time-matched controls. This unexpected finding suggests that chronic bacterial sepsis does not upregulate leukocyte adhesion in a manner similar to that seen in acute endotoxemia (11). These data make it unlikely that the accumulation of leukocytes within venules can account for the microcirculatory abnormalities within skeletal muscle that are a feature of bacterial sepsis (8, 10).
Background, Animal Model, and Rationale
Remote organ dysfunction contributes to the morbidity and mortality of clinical sepsis (20); however, the pathogenesis of this complication remains poorly understood. Although several hypotheses for its pathogenesis have been proposed, the microvascular occurrence of large numbers of activated leukocytes coincident with increased microvascular permeability in models of endotoxemia (11) and acute respiratory distress syndrome (ARDS) (15, 16) support the opinion that, in acute sepsis, leukocytes are important mediators of microvascular and tissue injury. To our knowledge, no studies have sought to test the hypothesis that bacterial sepsis upregulates leukocyte- endothelial interaction leading to accumulation of leukocytes within PCVs, an occurrence that by itself may alter microvascular perfusion. In order to examine this hypothesis, we used intravital microscopy to study the flow behavior of leukocytes in venules of the EDL muscle of rats made septic by CLP.
A laparotomy complicated by bacterial infection is common cause of sepsis in the critically ill. We believe that CLP closely replicates the picture of established bacterial sepsis that classically precedes the development of multiple organ failure in humans. In particular, CLP is a chronic model that allows leukocyte flow behavior to be studied in the context of sepsis evolving over time and in the absence of septic shock. The use of this model for microvascular study in sepsis has been described elsewhere (8).
Leukocyte Accumulation in Remote Organs in Sepsis
The sequestration of leukocytes in remote organs such as the lung (4) and liver (5) is a feature of acute endotoxin models of sepsis. In a study of leukocyte occurrence in the liver after CLP, Zhang and colleagues (5) observed massive accumulation of leukocytes 7 h after the septic insult. After 20 h, however, the number of polymorphonuclear neutrophils in the liver was no different than in sham-treated animals. These data suggest that leukocyte extravasation in remote organs such as the liver may become downregulated as sepsis progresses over time. Our data are consistent with these observations, since we found that, as compared with leukocyte adhesion in sham-treated animals, bacterial sepsis reduced leukocyte adhesion to the endothelial lining of PCVs (i.e., stuck and extravasated leukocytes; Figure 3). The data presented in this study suggest that the leukopenia associated with bacterial sepsis contributed to this effect (Figure 4). To our knowledge, this is the first study to provide direct in vivo evidence that leukocyte accumulation within PCVs of remote organs, such as skeletal muscle, is reduced by established bacterial sepsis.
Leukocyte adhesion to venular endothelium is shear-rate dependent (21). We sought to determine whether the velocity of leukocytes passing through the microcirculatory unit was different in the sham and bacterial sepsis-treated experimental groups (Figure 5). Although we found no difference in the mean velocity of CFDASE-labeled leukocytes as they passed through the microcirculatory unit, we did observe a difference in the site-specific change in velocity between experimental groups (i.e., a significant group × site interaction; Figure 5). This raises the possibility that microvascular resistance to leukocyte flow is reduced in sepsis. However, we were unable to demonstrate corresponding changes in leukocyte mean velocity, a determinant of shear stress in PCVs (Figure 5).
In this study, the values for leukocyte rolling, sticking, and extravasation in sham-treated animals were similar to those seen in naive controls (Figure 3, [17]); however, there was a trend toward an increase in leukocyte firm adhesion over the course of the study period from 6 to 48 h. This activation of leukocytes within control rats suggests that low-grade stimuli, such as the surgical implantation and presence of intravascular lines, are sufficient to cause neutrophil activation and endothelial adhesion in peripheral tissues such as skeletal muscle.
Relevance to the Pathogenesis of Multiple Organ Failure
In the model of systemic sepsis used in our study, increased red blood cell flow heterogeneity and capillary stopped flow are seen 6 to 48 h after the onset of sepsis (8). The extent to which these changes in microvascular perfusion are due to leukocyte accumulation within PCVs is unknown, although acute endotoxin studies suggest that this is a major component of the microvascular injury associated with sepsis (11). The current study found that, independent of an effect of sham treatment on leukocyte firm adhesion, leukocyte accumulation in PCVs was reduced by bacterial sepsis. Therefore, these data do not support the hypothesis that the increase in heterogeneity in microvascular flow seen in chronic bacterial sepsis (8- 10) is due to the accumulation of leukocytes in PCVs.
Conclusions
In the model used in the present study, as compared with appropriate time-matched controls, chronic bacterial sepsis resulted in a reduction in leukocyte accumulation in PCVs within skeletal muscle, an effect attributable to sepsis-induced leukopenia. This unexpected finding suggests that chronic bacterial sepsis does not upregulate leukocyte adhesion in a manner similar to that seen in models of acute endotoxemia (11). This unique observation is important to our understanding of mechanisms leading to the development of multiple organ failure in the critically ill. In particular, it suggests that the accumulation of leukocytes within or around the PCV is an unlikely cause of the changes in microvascular perfusion associated with polymicrobial infection.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. W. J. Sibbald, The London Health Sciences Centre, Victoria Campus, 375 South Street, London, ON, N6A 4G5 Canada.
(Received in original form September 4, 1996 and in revised form August 21, 1997).
Dr. Sibbald was supported by the Medical Research Council of Canada and the Ontario Heart and Stroke Foundation.Dr. Piper was supported by the Medical Research Council of Canada and the National Health and Medical Research Council of Australia, Neil Hamilton Fairley Fellowship.
Acknowledgments: Supported by a grant from the Medical Research Council of Canada.
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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