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1 Department of Bioengineering and The Whitaker Institute for Biomedical Engineering and 2 Department of Surgery, University of California-San Diego, La Jolla, California 92093-0412; and 3 Angiology Division, Institut de Recherches Internationales Servier, 92415 Courbevoie Cedex, France
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Elevated venous pressure can be associated with severe tissue injury. Few links, however, between venous hypertension and tissue damage have been established. We examined here the effects of micropressure elevation on the outcome of venular occlusion/reperfusion in the mesenteric microvasculature of male Wistar rats. One hour of venular occlusion (diameter ~50 µm) by micropipette occlusion followed by reperfusion were carried out with sham surgery without occlusion as control. Leukocyte rolling, adhesion, and migration, oxygen radicals detected by dichlorofluorescein (DCF), and parenchymal cell death detected by propidium iodide (PI) were recorded simultaneously in the same vessel at a location upstream of the occlusion site with elevated micropressure and at a downstream location with low micropressure. The number of rolling, adhering, and migrating leukocytes increased on the upstream side of the occlusion to a higher level than downstream of the occlusion site. During occlusion, DCF intensity on the venular endothelium was greater on the upstream side than in the downstream side, but there were no differences during reperfusion. The number of PI-positive cells adjacent to the venules increased significantly compared with controls, and it remained greater on the upstream higher-pressure side than the downstream side. Leukocyte adhesion and transvascular migration in postcapillary venules as well as parenchymal cell death could be significantly reduced by the hydroxyl radical scavenger dimethylthiourea. Microhemorrhages of blood cells into the mesentery interstitium were observed only on the upstream side of the occlusion. These results indicate that an elevation of the venular blood pressure during occlusion/reperfusion exacerbates the inflammatory cascade and tissue injury. Venous occlusion may constitute an important mechanism for tissue injury.
rat mesentery; venules; free radicals; cell death; leukocytes; endothelium; propidium iodide; 2',4'-dichlorodihydrofluorescein; venous hypertension; microhemorrhage
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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PRIMARY AND SECONDARY VENOUS INSUFFICIENCY is characterized by destruction of venous valves and elevation of venous pressure. Under chronic conditions of venous pressure elevation, a number of indicators of inflammation can be detected (7, 23), including endothelial adhesion molecule expression (22), release of proteolytic enzymes (26), and the presence of leukocyte migration into valve tissue and the venous wall (19, 25). The trigger mechanisms that lead to development of the inflammatory reaction in venules with leukocyte and endothelial activation remain incompletely defined.
There is now a large body of evidence to suggest that temporary arterial occlusion followed by reperfusion leads to an inflammatory cascade with cell activation and injury (for a recent review, see Ref. 3). Mainly, such studies have been carried out with occlusion of the arteriolar blood flow. Arterial occlusion is accompanied by a significant reduction of the microvascular pressure in capillaries and venules. Upon reperfusion, the microvascular pressure is restored. Recent observations indicate that occlusion of venules, accompanied by elevation of microvascular pressure, also leads to leukocyte and endothelial cell activation and parenchymal cell death (29). But the impact of a hydrostatic pressure elevation on the inflammatory reaction during a venous occlusion remains undefined. We hypothesize that occlusion associated with enhancement of microvascular pressure may serve to enhance the inflammatory response. This form of inflammatory response may be attenuated with a hydroxyl radical scavenger, dimethylthiourea (DMTU).
Thus the current study was designed to examine the influence of high versus low microvascular pressure on the level of inflammation produced in an acute occlusion/reperfusion model in the rat mesentery (29). We took advantage of the fact that local occlusion of venules in the rat mesentery can be designed with and without elevation of the micropressure. Several key parameters of the inflammatory cascade were compared in the same venule with and without pressure elevation and otherwise subject to the same flow rates and fluid shear stresses.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The animal procedures in this study were reviewed and approved by the Animal Subjects Committee of the University of California-San Diego.
Mesentery
The left femoral artery and vein of male Wistar rats (250-300 g, n = 10, Charles River Laboratory; Wilmington, MA) were cannulated under general anesthesia (50 mg/kg im pentobarbital sodium). The animals breathed spontaneously without a tracheotomy. The rat mesentery was exposed through a midline incision and gently draped over a transparent pedestal on a heated animal stage (37°C). The mesentery tissue was continuously superfused (2.0 ml/min) with Krebs-Henseleit bicarbonate-buffered solution (37°C) containing 2% albumin and saturated with a 95% N2-5% CO2 gas mixture.Intravital Microscopy
Details of the rat mesenteric microcirculation were recorded with an intravital microscope (8) via a color charge-coupled device camera (DEI-470, Optronics Engineering; Goleta, CA; frame rate 1/125 s for bright field and 1/4 s for fluorescence light). All images were recorded on videotape (model AG-a270P, Panasonic; Tokyo, Japan) and digitally stored for analysis (Macintosh Laboratory Computer IIci, Apple Computer; Cupertino, CA).The tissue was viewed with a water immersion lens (×25, numerical aperture = 0.60, Leitz; Wetzlar, Germany). To elicit fluorescent images, the preparation was illuminated with a 200-W mercury lamp. For visualization, the light was passed through a quartz collector, heat filter (KG-2, Zeiss; Oberkochen, Germany), and fluorescent filter set (L3 filter cube, Ploempak, Leitz). Single microscopic fields (~200 × 250 µm) containing arterioles and venules were examined. Ten mesenteries were investigated with one obstruction of a venule in each tissue.
Microhemodynamics
Venular diameters were measured off-line on the video image with appropriate length calibration. All diameters reported in the study refer to inner lumen diameter; no corrections were made for noncircular cross sections. Red blood cell centerline velocity was measured by the cross-correlation technique (model 102, Vista Electronics; Ramona, CA) and calibrated against a rotating glass disk coated with erythrocytes. Mean red blood cell velocity (V) was calculated as V = centerline velocity/1.6. The venular shear rate was calculated based on the definition for a Newtonian fluid as 8 V/diameter.The fluid micropressures were measured in selected venules before and after occlusion with micropipettes using the servo-null technique (9).
Detection of Nonviable Cells and Oxidative Stress
Staining with propidium iodide (PI; Sigma; St. Louis, MO) has been shown to serve as a suitable marker for irreversible nuclear damage (12, 27, 32). PI can diffuse into the cytoplasm of all cells, where it remains undetectable until the nuclear membrane is damaged and it binds to DNA. To detect nonviable cells, PI was added 20 min before the in vivo measurements to the superfusion buffer at a final concentration of 1 µM.2',4'-Dichlorofluorescein (DCFH)-diacetate (Molecular Probes; Eugene, OR) can be oxidized by organic and inorganic hydroperoxidases to yield a fluorochrome, dichlorofluorescin (DCF) (4). DCFH was also added to the superfusion buffer at a final concentration of 1 µM. DCF fluorographs were recorded digitally and processed to determine the gray-level density (0-256) in selected regions of the tissue. All DCF fluorographs were recorded with a fixed-gain camera control setting (gain: 6.0; voltage: 6.5 mV). To minimize photobleaching, the exposure time for DCF fluorescence was limited over an observation period of 2 h to <1 s at intervals of 20 min.
Experimental Protocol
Venular occlusion/reperfusions.
Single unbranched venules with diameters ranging from 35 to
70 µm and lengths >350 µm were selected for the study. The
vascular areas to be investigated were positioned upstream and
downstream along the venules ~100 µm from the occlusion point. The
tissue in immediate proximity to the occlusion site was avoided (
100 µm) because it may be subject to cell injury due to vessel
compression. After the rat mesentery was exposed, its microvasculature
was monitored for a 20-min control period during superfusion with buffer containing PI and DCFH. Microvascular variables were recorded immediately before venular occlusion and at intervals of 20 min over a
period of 60-min occlusion and 60-min reperfusion. The microvascular
images were recorded on videotape (bright field for vessel diameter;
red blood cell velocity; leukocyte rolling, adhesion, and migration;
and fluorescent images of DCFH and PI) and analyzed during videotape replay.
Leukocyte kinetics. The number of rolling, adherent, and migrating leukocytes was determined off-line during videotape playback. A leukocyte was considered to be adherent to the venular endothelium after it remained stationary for a period of >30 s. Adherent leukocyte density was expressed as the number of cells per 100-µm length of the venule. Migrating leukocytes were determined as the number of cells in the interstitial space along a 100-µm-long segment of venule in a 100 × 100-µm tissue region.
Parenchymal cell death. The level of cell death in each area was determined from the video record and normalized by the number of PI-positive cells after superfusion with 100% ethanol when all cells became PI positive. The net increase in the amount of cell death was expressed as the percent increase in PI-positive cells above the value at the start of the experiment.
Oxidative stress. The average DCF fluorescence levels of the microvascular endothelium were determined on digitized images of the video record (NIH Image version 1.65 on a model IIci Macintosh Computer) using a series of 20 neighboring windows (5 × 5 pixels covering an area of ~2 × 2 µm). The DCF intensity was expressed as the increase of mean DCF intensity over the value at the beginning of the experiment.
Hydroxyl radical blockade. To examine the relationship between the hydroxyl radical and cell death in this model, DMTU (2 mM, Aldrich Chemical; Milwaukee, WI), a hydroxyl radical scavenger, was added to the superfusate. DMTU was dissolved in Krebs-Henseleit solution ~20 min before occlusion of the postcapillary venule to permit saturation in the tissue. Leukocyte kinetics and the number of PI-positive cells were determined at the upstream location of the venular occlusion. Ten mesenteries were investigated with this protocol.
Statistics
All values are expressed as means ± SE. Differences between the upstream and downstream tissue segments were analyzed by repeated-measures ANOVA combined with the Scheffé's-type multiple-comparison test. A value of P < 0.05 was considered significant. The analysis was performed with StatView (version 4.5, Abacus Concepts; Berkeley, CA).| |
RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Before the occlusion, the micropressures in the venules close to the occlusion site were, on average, 13 ± 4 mmHg. During occlusion, the micropressure remained constant on the downstream side of the occlusion but rose to ~44 ± 5 mmHg on the upstream side (28). Thus the upstream side of the occlusion was subject to a pressure elevation of ~30 mmHg, whereas the downstream micropressure remained unchanged during occlusion. We will refer in the following sections to the hypertensive upstream region and the normal pressure downstream region along the venule. There was no shift in heart rate (355 ± 15 beats/min) or central blood pressure (105 ± 8 mmHg) during occlusion or reperfusion of the small venules in the mesentery.
Before occlusion, venular diameters were identical within accuracy of
measurement along the entire vessel segment that was used in the
experiments. After the occlusion, the diameter increased on the
upstream side of the occlusion compared with the value before
occlusion, whereas the downstream side remained the same (Fig.
1). The distension along the upstream
segment closely followed the time course of the microvascular pressure
and represented mostly a passive viscoelastic distension
(24).
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Flow rates and wall shear rates remained virtually identical in the upstream and downstream segments of the occluded venule because there were no side branches along the particular segments selected in these studies (Fig. 1 in Ref. 29). There was a slow motion of red blood cells (of the order of 5 µm/min) on the upstream segment of the occluded venule in the direction of the occlusion point, possibly due to some fluid filtration across the venular wall.
During occlusion, 6 of 10 mesenteries developed microhemorrhages at the
position of the postcapillary venules (with diameters in the range
between 10 and 20 µm) (Fig. 2). The
microhemorrhages grew in size during occlusion and during early periods
of reperfusion. While the blood cells escaped into the mesentery
interstitium, there was no evidence of hemorrhage across the
mesothelial layers. The microhemorrhages occurred exclusively on the
hypertensive side of the occlusion. None were encountered on the
downstream, low-pressure side.
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The average number of leukocytes rolling on and adhering to the venous
endothelium before occlusion was the same upstream and downstream from
the obstruction site. During reperfusion, the number of rolling
leukocytes was significantly increased on the hypertensive side (Fig.
3, A and B). The
average number of leukocytes migrating across the venular wall into
adjacent tissue parenchyma increased almost linearly during the
experiments and reached significantly higher numbers on the
hypertensive side (Fig. 3C).
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On the hypertensive venous side, the DCF fluorescence levels (Fig.
4) were significantly higher early during
the occlusion period, but the discrepancy between the upstream and
downstream values disappeared after release of the occlusion and was
undetectable during reperfusion (Fig. 5).
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Parenchymal cell death, as detected by the number fraction of
PI-positive cells (Fig. 6), increased in
both upstream and downstream locations during occlusion and reperfusion
(Fig. 7, A and B). This pattern was observed both in tissue regions that were in proximity
to the venular wall (100 µm; Fig.
8A) as well as in avascular
tissue regions remote from the occluded venule (
500 µm distance
from the endothelium; Fig. 8B). PI-positive cells were also
detected in the interstitial space between venules and their paired
arterioles. The upstream hypertensive segment of the venule had
significantly higher numbers of PI-positive cells compared with the
downstream normotensive venular segments during both occlusion and
reperfusion (Fig. 8). PI-positive cells were detected in the tissue
parenchyma surrounding the venule (Fig. 6) and did not include
endothelial cells, in line with previous observations (12, 29,
30). No significant colocalization of PI-positive cells at the
site of the microhemorrhages could be detected at the end of the
reperfusion.
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Scavenging of hydroxyl radicals by DMTU reduced the number of
leukocytes rolling on and adhering to the venular endothelium (Fig.
9, A and B) or
migrating into the tissue (Fig. 9C). The number of the
PI-positive cells in the mesentery parenchyma was significantly
attenuated by DMTU during reperfusion (Fig. 9D).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Acute venous flow reduction produces microvascular hemorrhages, leukocyte adhesion to the endothelium and migration of cells into the interstitium, and free radical production as well as parenchymal cell death (29). The current results in mesenteric venules demonstrate that these inflammatory reactions are enhanced if associated with micropressure elevation, as encountered in patients with lower extremity venous hypertension (11).
Traditionally, the role of venous occlusions, venous hypertension, and subsequent reperfusion in human disease has not been assigned a particularly high significance. But it should be kept in mind that under the influence of gravity or the body weight, venous obstructions might occur. Because venous occlusions may involve the capillary network, depending on the details of the microvascular topology that connect the capillaries to the venules and on the number of available draining veins, the impact according to the current results may be potentially serious and comparable to an arteriolar occlusion.
In recent years, a number of general mechanisms have been identified that are associated with ischemia and reperfusion (3). These mechanisms include oxygen deprivation and depletion of high energy phosphates, a shift in oxygen free radicals and nitric oxide production, and a transient shift in fluid shear stress with several intracellular signaling cascades. There is expression of leukocyte and endothelial cell adhesion molecules followed by an inflammatory cascade with production of proinflammatory mediators. Few of these mechanisms have been uniquely linked to a particular aspect of ischemia and reperfusion. In the present study, both the high and low venous pressure regions along an occluded venule exhibited similar kinetics of the leukocyte adhesion cascade. Thus the influence of an elevated micropressure on the progression of the inflammation in the current model may be more quantitative than qualitative in nature.
The upstream region with high pressure during occlusion and the downstream region with low blood pressure differ in a number of respects. The elevated venous pressure causes distension of the venule, so that the reduction of the physiological fluid shear during occlusion is accompanied by a stretch of the venous endothelium in circumferential direction. The consequences of such stretch may be an enhanced P-selectin expression on the plasma membrane (unpublished observations of mesentery specimen exposed to venous occlusions after labeling with an antibody against rat P-selectin). Cyclic strain of endothelial cells activates extracellular signal-regulated kinases 1/2 (15). It shifts the redox potential (5), enhances oxidative stress with NADPH oxidase and nitric oxide synthase activity (1, 14, 16), and causes expression of cytokines (33, 36) as well as membrane adhesion molecules (6, 37). These inflammatory responses are sensitive with respect to the fluid shear applied to the endothelial cells (2, 20) and remain to be examined in the case of the postcapillary endothelium. Endothelial mechanical stretch may also be associated with enhanced permeability and formation of endothelial pores, as seen in pulmonary or mesentery microvessels (18, 34). The escape of blood cells serves as evidence in this respect.
A question arises: Is it possible that the formation of microhemorrhages may be associated with an enhanced inflammatory reaction? While hemoglobin may catalyze the formation of oxygen free radicals, microinjection of fresh blood cells directly into the mesenteric interstitium actually leads to a reduction in the number of PI-positive cells compared with noninjection control mesenteries (35). Enhancement of PI-positive cell numbers can be achieved by preincubation of the red blood cells in a buffer with oxygen free radicals for several hours, a condition that does not occur in the present experiments. The lack of colocalization between the PI-positive cells and the sites of microhemorrhages also indicates that the blood cells in the interstitium may exert a relatively small influence on the development of parenchymal cell death.
Another difference between the upstream and downstream locations is plasma fluid filtration into the interstitial space. The mesenteric microvasculature in the immediate vicinity of the intestine may be a carrier of humoral activating factors derived from the intestine. This situation is encountered especially in intestinal ischemia (17) and may still be present to some degree even in the nonischemic intestine. The mesenteric microcirculation exhibits a stronger inflammatory reaction than other peripheral organs, such as skeletal muscle (12). It remains to be determined whether inflammatory mediators may be filtered into the interstitial space during venous stasis in the mesentery.
The mesenteric microcirculation is ideally suited for the protocol used in this experiment. In contrast to other venular networks with a high level of connectivity, such as skeletal muscle (10), one find microvascular segments with single and also longer venous outflow vessels. Occlusion of such outflow venules leads to a significant capillary pressure elevation, which is not achieved to the same degree in venular networks with shorter interconnections. Other microvascular networks remain to be examined in this respect, because venous occlusions, especially in the skin, may be a common phenomenon.
The fact that DMTU serves to attenuate the inflammatory reaction in this model is in line with many other studies that have demonstrated that oxygen radical species, and especially the hydroxyl radical, play a significant role in ischemia and reperfusion injury (3). The DCF fluorescence pattern suggests that the endothelium and adhesive or migrating leukocytes form free radicals, possibly due in part to xanthine oxidase (27) and/or NADPH oxidase (13, 21, 31). Parenchymal cell death can be significantly attenuated but not completely blocked by superfusion of DMTU on this thin tissue, a situation also observed in the presence of inflammatory mediators (30).
In conclusion, the current evidence in the mesentery indicates that occlusion with microvascular pressure elevation followed by reperfusion leads to an inflammatory reaction with oxidative stress, leukocyte adhesion, and parenchymal cell death to levels above those encountered in an occlusion without microvascular pressure elevation.
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ACKNOWLEDGEMENTS |
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The authors thank Barrick P.-W. Lo and Jonathan M. Cannata for excellent assistance with the image analysis.
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FOOTNOTES |
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10.1152/ajpheart.01003.2000
This work was supported in part by National Heart, Lung, and Blood Institute Grants HL-43026 and HL-10881.
Address for reprint requests and other correspondence: G. W. Schmid-Schönbein, Dept. of Bioengineering, The Whitaker Institute for Biomedical Engineering, Univ. of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0412 (E-mail: gwss{at}bioeng.ucsd.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 25 October 2000; accepted in final form 29 October 2001.
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METHODS
RESULTS
DISCUSSION
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P < 0.05 relative to initial control values.
