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Program in Vascular Biology and Section of Vascular Surgery, Departments of Pharmacology and Physiology and of Surgery, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103
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ABSTRACT |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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To better understand the mechanisms of ischemia-reperfusion (I/R) injury, we tested the hypothesis that protein synthesis is involved in the production of tumor necrosis factor (TNF) and in the microvascular transport changes in I/R. To evaluate the hypothesis, we inhibited protein synthesis with topically applied actinomycin D (AMD), measured I/R-induced changes in microvascular transport, and bioassayed the venous plasma levels of TNF. The rat cremaster muscle I/R model consisted of 4 h of ischemia followed by 2 h of reperfusion. Changes in transport were determined by integrated optical intensity (IOI) using FITC-Dextran 150 as tracer. Animals were separated into four groups: 1) control (C), 2) control treated with AMD (C + AMD), 3) I/R, and 4) I/R treated with AMD (I/R + AMD). The mean (±SE) maximal IOI in C and C + AMD were 3.0 ± 1.0 and 3.7 ± 0.7 units, respectively. I/R elevated mean maximal IOI to 21.8 ± 1.9 units (P < 0.05 vs. C, C + AMD, I/R + AMD). Treatment with AMD reduced the I/R-induced mean maximal IOI to 9.7 ± 2.0 units (P < 0.05 vs. I/R). In I/R group, plasma TNF levels increased (relative to preischemia baseline) immediately after the release of the vascular occlusion to 250 pg/ml and reached a peak value of 342 pg/ml at 60 min of reperfusion. In the I/R + AMD group, AMD reduced TNF increase to 44 pg/ml. The C and C + AMD groups showed no differences in TNF values during the 6 h of observation. We conclude that protein synthesis and TNF generation are at least partially involved in I/R-induced changes in microvascular transport.
ischemia-reperfusion injury; actinomycin D; deoxyribonucleic acid transcription; skeletal muscle; tumor necrosis factor
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INTRODUCTION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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SKELETAL MUSCLE IS unique in its ability to tolerate long periods of ischemia compared with other organs such as brain, kidney, or heart. However, acute interruption of arterial blood flow to the extremities in humans is associated with high morbidity, frequent limb loss, and sometimes death. Reduction or interruption of arterial blood flow to skeletal muscle leads to a deficit in nutrient supply to cells, decreased energy production, and ultimately cellular dysfunction and death. The extent of the injury is not limited to the ischemic time. Reestablishment of blood flow, which is essential for maintenance of cell life, carries with it an exaggeration of these phenomena, resulting in further injury to the tissue and dissemination of the accumulated products to the body.
Various factors have been suggested as causes of tissue damage in
ischemia and reperfusion (I/R) of skeletal muscle, but the cellular mechanisms of action have not been fully elucidated. In
particular, there is suggestive evidence that tumor necrosis factor
(TNF)-
may play a significant role in these cellular interactions (17, 22, 23). TNF may be produced by postischemic tissue inasmuch as
the venous effluent from postischemic rat hindlimb perfused with a
nonrecirculating crystalloid-based buffer contains a high level of TNF
(23). The tissue sources for TNF may contribute to a reverberant cycle
in which neutrophil activation by TNF causes the upregulation of cell
adhesion molecules on both neutrophils and endothelial cells, then
adherent neutrophils migrate to the interstitium and generate
oxygen-derived free radicals and release toxic enzymes (1, 13, 26).
Activated leukocytes further generate cytokines such as TNF- and
interleukin-1 (5, 21). Thus this circuit will result in exaggerated
microvascular insults. Despite this conceptual framework, the
correlations between cytokine levels and microcirculatory dysfunction
have not been investigated systematically in striated muscle.
Because TNF is present in venous effluent of postischemic muscle (23), we reasoned that probably new synthesis of TNF occurred during ischemia. If I/R damage involves protein synthesis, then treatment with agents that interfere with protein synthesis may attenuate the reperfusion injury of postischemic tissue. In this study, we tested the hypothesis that newly synthesized proteins participate in and promote microcirculatory dysfunction in rat skeletal muscle I/R injury. We employed actinomycin D (AMD), an antibiotic (18) that binds to DNA and blocks the movement of RNA polymerase and thus prevents transcription, to prevent synthesis of new proteins during I/R phases in rat cremaster muscle. We posed the following questions: 1) Does protein synthesis occur in I/R? 2) If so, does it influence the production of TNF? 3) Are protein synthesis and TNF levels associated with changes in microvascular transport? We hypothesized that 1) TNF levels will be increased in I/R, 2) inhibition of protein synthesis should block the increase in TNF, and 3) inhibition of protein synthesis, and of the elevated TNF levels, should diminish the impact of I/R on microvascular transport.
To test the above hypotheses, the objectives of this study were 1) to inhibit protein synthesis during the ischemic and reperfusion periods and 2) to evaluate the effects of protein synthesis inhibition on TNF levels and on microvascular transport. Our results support the concept that protein synthesis and TNF levels are associated and promote changes in microvascular transport in the rat cremaster muscle subjected to I/R.
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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I/R model. This study was approved by the Animal Care and Use Committee at the New Jersey Medical School and complied with National Institutes of Health "Guide for the Care and Use of Laboratory Animals" [Department of Health and Human Services Publication No. (NIH) 85-23, Revised 1985]. Twenty-eight male Wistar Furth rats, weighing 140-200 g, were anesthetized with pentobarbital sodium (60 mg/kg ip). Body temperature was maintained at 37°C by placing the animal on a heating pad. Tracheotomy was performed to facilitate ventilation. The right jugular vein was cannulated with a catheter (PE-50; Clay Adams, Parsippany, NJ) for administration of fluorochrome tracer and supplementary doses of anesthetic. The right femoral vein was cannulated with a catheter (PE-10), and the catheter was advanced to collect blood samples from the inferior vena cava.
The left cremaster muscle was prepared for fluorescent intravital microscopy as previously described (6, 24, 25). In brief, the muscle was approached through a scrotal incision, separated from the skin, and cleared of connective tissue. The cremaster was incised longitudinally. Vessels connecting the cremaster and epididymis were divided with thermocautery. The testis was placed in the abdominal cavity. The cremaster was splayed in a modified chamber that allowed superfusion of both the upper and lower surface of the cremaster muscle (Fig. 1). After the surgical preparation, the cremaster was superfused with a bicarbonate buffer solution adjusted to pH 7.35, equilibrated with 95% N2-5% CO2, and maintained at 35°C. The composition of the buffer solution was (in mM) 131.9 NaCl, 4.7 KCl, 2.0 CaCl2, 1.2 MgSO4, and 18.0 NaHCO3. In this system, the turnover rate was 1 chamber volume/min. With the use of Evans blue as a visual index, no visible stagnant areas were present in either chamber. In addition, the vascular reactivity of the cremaster muscle preparation was normal.
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Microscopy. Observations were made with a Nikon microscope equipped with a television camera (Optronics, TEC-470) suitable for both trans- and epi-illumination. The fluorescence epi-illumination system consists of a 100-W mercury direct-current lamp source, a fluorescein exciter filter, a dichroic mirror, and a barrier filter. The optics include ×6.3 and ×32 long-distance working objectives and ×10 oculars. The recording system consists of a Sony television monitor (CVM-1900) and Sony videotape recorder (AG-6200).
Macromolecular tracer.
FITC-labeled 150,000 mol wt dextran (FITC-Dx 150; Sigma Chemical, St.
Louis, MO) was used as a macromolecular tracer. It was administered
intravenously initially as a bolus (100 mg/kg) during the stabilization
period, followed by continuous infusion (0.026 mg · kg
1 · min1)
to maintain a constant plasma concentration (2).
Measurement of microvascular transport. Microvascular transport of macromolecules was determined by intravital fluorometry using computer-assisted digital processing (2, 3). Three to five selected areas in the rat cremaster muscle were videorecorded during the experiment. Each experimental frame was played back and digitized into 512 by 512 picture elements (pixels) with an Image-1 image digitizer. Each pixel was associated with an eight-bit gray scale (a number between 0 and 255, in which 0 is black and 255 is white). Integrated optical intensity (IOI) was calculated as a measure of the total gray scale value in a selected area and averaged in 180 by 150 pixels. The interstitial IOI of the fluorescent tracer reflects its permeation through the microvascular wall (2, 3).
TNF assay.
Plasma TNF activity was measured by bioassay (19, 22). Briefly, 1.5 × 105 WEHI 164 cells (ATCC,
Rockville, MD) were added to each well of a 96-well microtiter plate
(Costar, Cambridge, MA) with 100 µl of the diluting media and 1 µg/ml AMD. The diluting media consisted of RPMI 1640 (Sigma
Chemical), 1% fetal bovine serum (GIBCO, Grand Island, NY), 2 mM
L-glutamine (Sigma Chemical), 50 µg/ml gentamicin (GIBCO), 10 mM HEPES (GIBCO), 1 mM sodium pyruvate
(Sigma Chemical), and 2 × 105 M mercaptoethanol
(Sigma Chemical). Plates were incubated for 4 h in a humidified 5%
CO2 atmosphere at 37°C.
Recombinant murine TNF- aliquots (25 µl, 50 ng/ml; Boehringer
Mannheim, Indianapolis, IN) were triplicated with 12 serial dilutions
to generate a standard curve. Experimental samples (25 µl)
were triplicated with eight serial dilutions. The plates
were incubated for 24 h in the same conditions.
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (Sigma
Chemical) was then prepared at 5 mg/ml, and 25 µl were added to each
well. After 2 h of incubation at the same conditions, 100 µl of
lysing buffer (10% SDS, 50% dimethylformamide, pH 4.7, Sigma
Chemical) were added to each well to stop the color change. The plates
were placed in the dark at room temperature for longer than 8 h. The
plates were then read at 570 nm on a Dynatech 5000 microplate reader.
This bioassay measures both TNF- and TNF-
. The TNF activity of
the experimental samples was calculated from a standard curve generated
using TNF- as a calibration index.
Experimental groups. Four experimental groups were studied. The first group was a sham group used to evaluate the effects of time and surgery on the preparation and was not subjected to ischemia and reperfusion (control, C; n = 7). The second group was used to assess the effect of AMD on the sham preparation (C + AMD; n = 7). The third group was subjected to I/R to determine the extent of microvascular dysfunction in the muscle, using changes in IOI as an index (I/R; n = 7). The fourth group was subjected to I/R and treatment with AMD to examine the effects of AMD on microvascular dysfunction (I/R + AMD; n = 7).
Experimental protocol.
The protocol used in this study is shown in Fig.
2. After 45 min of stabilization, three to
five postcapillary venules were randomly selected and videorecorded
every 10 min during the baseline period. A blood sample (0.2 ml) was
drawn before the induction of ischemia. After the basal data
collection period, the cremasteric vascular pedicle was cross-clamped
to interrupt blood flow to the muscle for global ischemia in
the third and fourth groups of animals. Ischemia was maintained
for 4 h to allow for potential induction of protein synthesis-related
processes. After ischemia, blood flow was restored by releasing
the vascular pedicle clamp. Blood samples were collected just after
restoration of blood flow (time 0)
and at 60 and 120 min after reperfusion. The selected areas in the
cremaster muscle were videorecorded every 10 min throughout 2 h of
reperfusion. In group C + AMD and group I/R + AMD, the muscle was
superfused with a buffer containing
106 M AMD during both
ischemia and reperfusion periods. In both control groups C and
C + AMD, the cremaster muscle was subjected to superfusion with
bicarbonate buffer for 6 h after the stabilization period to time match
the 4 h of ischemia plus 2 h of reperfusion in the I/R groups.
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Statistical analysis. All data are expressed as means ± SE. Comparisons between groups were performed with the Kruskal-Wallis one-way ANOVA. Each group mean value was subjected to the Student-Newman-Keuls post hoc test. Statistical significance for the differences was set at P < 0.05.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Quantitative changes in microvascular transport (IOI). The statistical analysis of the changes in microvascular transport is displayed in Fig. 3. The data represent the analysis of the reperfusion period. The time-matched controls (without and with AMD) reflect the measurement of IOI in the last 2 h of a 6-h sham muscle preparations. The maximal mean IOI values in the C and C + AMD control groups were 3.0 ± 1.0 and 3.7 ± 0.7 units, respectively. There was no significant difference between two groups. I/R elevated mean maximal IOI to 21.8 ± 1.9 (P < 0.05 vs. C). Treatment with AMD (I/R + AMD group) inhibited the I/R-induced increase in IOI to a mean maximal value of 9.7 ± 2.0 but did not abolish the change in microvascular transport (P < 0.05 vs. I/R and vs. C).
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Plasma TNF levels. The time course of plasma TNF is displayed in Fig. 4. The plasma levels of TNF remained constant throughout the final 120-min period in the C and C + AMD control groups. This 120-min period is equivalent to the reperfusion period in the I/R groups. There was no significant difference in plasma TNF levels between the two control groups. I/R significantly elevated TNF plasma levels. In the I/R group, the plasma TNF levels increased immediately after the release of the vascular clamp (time 0) to 250 pg/ml and reached a peak value of 342 pg/ml at 60 min after reperfusion. This value declined but remained still significantly elevated (259 pg/ml) at 120 min of reperfusion. Treatment with AMD inhibited the changes in plasma TNF levels. In the I/R + AMD group, a slight increase of TNF (44 pg/ml) was observed at reperfusion and subsequently decreased with time and became similar to the preischemic mean value.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Our main conclusions are as follows: 1) protein synthesis is associated, at least partially, with microvascular transport changes in postischemic striated muscle; and 2) TNF may participate in the events associated with changes in microvascular transport in I/R. These conclusions are supported by the reduction of the increment of interstitial IOI and the inhibition of the changes in TNF plasma levels after treatment with AMD in our I/R model.
TNF plasma levels.
We observed that plasma TNF levels increased immediately after the
onset of reperfusion and remained elevated throughout the experimental
period. Sternbergh et al. (23) showed similar results in isolated rat
hindlimbs that were perfused with a noncirculating crystalloid-based
buffer. They showed that reperfusion of the rat skeletal muscle
resulted in a very rapid and short-lived increase of plasma TNF
bioactivity. The exact mechanisms of the increase in plasma TNF remain
unknown. Endothelial cells and tissue macrophages are possible sources
of the trigger cytokines that initiate the interaction between the
endothelial cells and leukocytes. The biosynthesis of TNF is tightly
regulated by transcriptional and translational mechanisms (8). TNF does
not exist in a stored form in macrophages (8); however, production of
active TNF occurs in a period as short as 15 min after exposure to an
inflammatory stimulus (23). In the context of our experiments, TNF
levels were elevated in the plasma sample taken at
time 0, i.e., immediately at the onset
of reperfusion. Therefore, we speculate that the rapid increase of
plasma TNF level observed in the initial phase of reperfusion is most
likely due to washout of TNF generated during ischemia. An
alternative explanation would be to invoke a role for mast cells in
I/R. Mast cells can release both preformed and newly synthesized
TNF- upon activation of the cells (14, 15).
Microvascular transport, TNF, and protein synthesis. IOI values increased gradually with time during the reperfusion period and reached their maximal value at 120 min after reperfusion. Treatment with AMD significantly decreased but did not abolish the extravasation of FITC-Dx 150 induced by I/R. This observation is of interest because the TNF data indicate the dose of AMD was sufficiently efficacious to block protein synthesis. Thus our data support a partial role for protein synthesis in the changes in microvascular transport induced by I/R.
We have established an association between TNF synthesis and changes in microvascular transport. Our experiments demonstrate that 1) as TNF plasma levels are elevated by I/R, the blood-tissue transport of macromolecules is increased; and 2) upon inhibition of TNF production during I/R, the rate of macromolecular transport is reduced. On the basis of our data and reports by others, it is reasonable to conclude that ischemia stimulates elevated levels of TNF, which in turn activates the endothelium directly and indirectly by enhancing leukocyte adhesion. The sum of direct activation and leukocyte adhesion and migration would lead to increased microvascular transport. However, more direct experiments are necessary to probe and demonstrate this potential cause-effect relationship. Because AMD reduced but did not abolish the I/R-induced increase in IOI, our data also support the involvement of additional factors that do not require de novo protein synthesis. This conclusion agrees with data from several laboratories. We and others have shown that the vascular damage associated with I/R can be significantly ameliorated by several pharmacological interventions designed to block prostanoid production (7), to inhibit formation of free radicals (16), and to reduce leukocyte count (4, 19, 26). An additional attractive candidate for the role of promoter of transport changes is platelet-activating factor (PAF). Synthesis of PAF does not require DNA transcription because PAF is rapidly synthesized from membrane phospholipid by the activity of phospholipase A2 and acetyltransferase. We speculate that oxygen free radical released from endothelial cells and polymorphonuclear neutrophils early in the reperfusion phase may activate the production of PAF. This phospholipid is a potent chemotactic agent and promotes adhesion between endothelial cells and leukocytes (10) and directly increases microvascular transport in a dose-response manner (9, 10). Upon PAF stimulation, neutrophils release lysomal enzymes and superoxide anions and generate arachidonic acid metabolites. Additionally, PAF enhances the production of TNF by monocytes and macrophages (5, 11). This chain of events amplifies the PAF effects. Our speculation is supported by the experimental observations that blockade of PAF receptors decreases adhesion of leukocytes (12) and changes in macromolecular transport (20) in I/R. In summary, our results demonstrate that inhibition of protein synthesis eliminates the I/R-increased levels of TNF and significantly diminishes the changes in microvascular transport induced by ischemia and reperfusion in striated muscle.| |
ACKNOWLEDGEMENTS |
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This study was supported by National Heart, Lung, and Blood Institute Grants RO1-HL-43146 and KO7-HL-94015 and by American Heart Association, New Jersey Affiliate, Grant-in-Aid 92-G-045. H. Takenaka and A. Seyama were Research Scholars on leave from the First Department of Surgery, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan. H. Oshiro was a Research Scholar on leave from the First Department of Surgery, Tokyo University School of Medicine, Tokyo, Japan.
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FOOTNOTES |
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Address for reprint requests: W. N. Durán, Dept. of Pharmacology and Physiology, MSB H-609, UMDNJ-New Jersey Medical School, 185 South Orange Ave., Newark, NJ 07103.
Received 25 June 1996; accepted in final form 11 February 1998.
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REFERENCES |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
1.
Anderson, B. O.,
J. M. Brown,
and
A. H. Harken.
Mechanisms of neutrophil-mediated tissue injury.
J. Surg. Res.
51:
170-179,
1991[Medline].
2.
Armenante, P. M.,
D. Kim,
and
W. N. Durán.
Experimental determination of the linear correlation between in vivo TV fluorescence intensity and vascular and tissue FITC-Dx concentrations.
Microvasc. Res.
42:
198-208,
1991[Medline].
3.
Bekker, A. Y.,
A. B. Ritter,
and
W. N. Durán.
Analysis of microvascular permeability to macromolecules by video-image digital processing.
Microvasc. Res.
38:
200-216,
1989[Medline].
4.
Belkin, M.,
W. L. LaMorte,
J. G. Wright,
and
R. W. Hobson II.
The role of leukocytes in the pathophysiology of skeletal muscle ischemic injury.
J. Vasc. Surg.
10:
14-19,
1989[Medline].
5.
Bonavida, B.,
J. M. Mencia-Huerta,
and
P. Braquet.
Effect of platelet-activating factor on monocyte activation and production of tumor necrosis factor.
Int. Arch. Allergy Appl. Immunol.
88:
157-160,
1989[Medline].
6.
Bori
, M. P.,
J. S. Roblero,
and
W. N. Durán.
Quantitation of bradykinin-induced microvascular leakage of FITC-Dextran in rat cremaster muscle.
Microvasc. Res.
33:
397-412,
1987[Medline].
7.
Breitbart, G. B.,
P. K. Dillon,
W. D. Suval,
F. T. Padberg,
M. FitzPatrick,
and
W. N. Durán.
Dexamethasone attenuates microvascular ischemia-reperfusion injury in the rat cremaster muscle.
Microvasc. Res.
38:
155-163,
1989[Medline].
8.
Camussi, G.,
E. Albano,
C. Tetta,
and
F. Bussolino.
The molecular action of tumor necrosis factor-.
Eur. J. Biochem.
202:
3-14,
1991[Medline].
9.
Dillon, P. K.,
and
W. N. Durán.
The effect of platelet activating factor on microvascular permselectivity: dose-response relationships and pathways of action in the hamster cheek pouch microcirculation.
Circ. Res.
62:
732-740,
1988
10.
Dillon, P. K.,
M. F. FitzPatrick,
A. B. Ritter,
and
W. N. Durán.
Effect of platelet activating factor on leukocyte adhesion to microvascular endothelium: time-course and dose-response relationships.
Inflammation
12:
563-573,
1988[Medline].
11.
Dubois, C.,
E. Bissonnette,
and
M. Rola-Pleszczynski.
Platelet-activating factor (PAF) enhances tumor necrosis factor production by alveolar macrophages.
J. Immunol.
143:
964-970,
1989[Abstract].
12.
Durán, W. N.,
V. J. Milazzo,
F. Sabido,
and
R. W. Hobson II.
Platelet-activating factor modulates leukocyte adhesion to endothelium in ischemia-reperfusion injury.
Microvasc. Res.
51:
108-115,
1996[Medline].
13.
Durán, W. N.,
W. D. Suval,
M. P. Bori,
and
R. W. Hobson II.
Microcirculatory dysfunction in the pathophysiology of skeletal muscle ischemia.
In: Vascular Surgery, edited by F. J. Veith,
R. W. Hobson,
R. A. Williams,
and S. E. Wilson. New York: McGraw-Hill, 1994, p. 388-396.
14.
Gordon, J. R.,
and
S. J. Galli.
Mast cells as a source of both preformed and immunologically inducible TNF-/cachectin.
Nature
346:
274-276,
1990[Medline].
15.
Gordon, J. R.,
and
S. J. Galli.
Release of both preformed and newly synthesized tumor necrosis factor (TNF-)/cachectin by mouse mast cells stimulated via the Fc
RI. A mechanism for the sustained action of mast cell-derived TNF- during IgE-dependent biological responses.
J. Exp. Med.
174:
103-107,
1991
16.
Granger, D. N.,
J. N. Benoit,
M. Suzuki,
and
M. B. Grisham.
Leukocyte adherence to venular endothelium during ischemia-reperfusion.
Am. J. Physiol.
257 (Gastrointest. Liver Physiol. 20):
G683-G688,
1989
17.
Haskard, D. O.,
and
T. H. Lee.
The role of leukocyte-endothelial interaction in the accumulation of leukocytes in allergic inflammation.
Am. Rev. Respir. Dis.
145:
S10-S13,
1992[Medline].
18.
Hollstein, U.
Actinomycin. Chemistry and mechanism of action.
Chem. Rev.
74:
625-652,
1974.
19.
Kurtel, H.,
K. Fujimoto,
B. J. Zimmerman,
D. N. Granger,
and
P. Tso.
Ischemia-reperfusion-induced mucosal dysfunction: role of neutrophils.
Am. J. Physiol.
261 (Gastrointest. Liver Physiol. 24):
G490-G496,
1991
20.
Noel, A.,
R. W. Hobson II,
and
W. N. Durán.
Platelet-activating factor and nitric oxide mediate microvascular permeability in ischemia-reperfusion injury.
Microvasc. Res.
52:
210-220,
1996[Medline].
21.
Salem, P.,
S. Deryckx,
A. Dulioust,
E. Vivier,
Y. Denizot,
C. Damais,
C. A. Dinarello,
and
Y. Thomas.
Immunoregulatory functions of paf-acether. IV. Enhancement of IL-1 production by muramyl dipeptide-stimulated monocytes.
J. Immunol.
144:
1338-1344,
1990[Abstract].
22.
Seekamp, A.,
J. S. Warren,
D. G. Remick,
G. O. Till,
and
P. A. Ward.
Requirements for tumor necrosis factor- and interleukin-1 in limb ischemia/reperfusion injury and associated lung injury.
Am. J. Pathol.
143:
453-463,
1993[Abstract].
23.
Sternbergh, W. C., III,
T. M. Tuttle,
R. G. Makhoul,
H. D. Bear,
M. Sobel,
and
A. A. Fowler III.
Postischemic extremities exhibit immediate release of tumor necrosis factor.
J. Vasc. Surg.
20:
474-481,
1994[Medline].
24.
Suval, W. D.,
W. N. Durán,
M. P. Bori,
R. W. Hobson II,
P. B. Berendsen,
and
A. B. Ritter.
Microvascular transport and endothelial cell alterations preceding skeletal muscle damage in ischemia and reperfusion injury.
Am. J. Surg.
154:
211-218,
1987[Medline].
25.
Suval, W. D.,
R. W. Hobson II,
M. P. Bori,
A. B. Ritter,
and
W. N. Durán.
Assessment of ischemia reperfusion injury in skeletal muscle by macromolecular clearance.
J. Surg. Res.
42:
550-559,
1987[Medline].
26.
Walden, D. L.,
H. J. McCutchan,
E. G. Enquist,
J. R. Schwappach,
P. F. Shanley,
O. K. Reiss,
L. S. Terada,
J. A. Leff,
and
J. E. Repine.
Neutrophils accumulate and contribute to skeletal muscle dysfunction after ischemia-reperfusion.
Am. J. Physiol.
259 (Heart Circ. Physiol. 28):
H1809-H1812,
1990
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