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1 Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; and 2 Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Gastrointestinal ischemia-reperfusion (I/R) injury is often associated with remote tissue injury. Complement activation plays an important role in local and remote tissue injury associated with gastrointestinal I/R. We developed a new murine model of gastrointestinal I/R that has complement-dependent local and remote tissue injury. Twenty, but not thirty, minutes of gastrointestinal ischemia followed by 3 h of reperfusion induced a significant loss of intestinal lactate dehydrogenase that was significantly prevented by a murine anti-murine C5 monoclonal antibody. Anti-C5 also significantly decreased neutrophil infiltration into the gut and lung. Gastrointestinal I/R significantly increased pulmonary intercellular adhesion molecule-1 mRNA and protein expression that was significantly inhibited by anti-C5. Pulmonary macrophage inflammatory protein-2 mRNA was significantly induced by gastrointestinal I/R and inhibited by anti-C5 treatment. These data demonstrate that brief periods of murine gastrointestinal I/R activate complement, leading to tissue injury and neutrophil accumulation. Anti-C5 treatment attenuates tissue injury, neutrophil recruitment, and leukocyte adherence molecule and chemokine expression in the mouse. This model will be well suited to investigate the role of complement-mediated tissue injury and gene expression after gastrointestinal I/R.
pulmonary injury; lactate dehydrogenase; myeloperoxidase; intercellular adhesion molecule-1; macrophage inflammatory protein-2
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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GASTROINTESTINAL ISCHEMIA-REPERFUSION (I/R) is associated with many different clinical situations, ranging from surgery (cardiopulmonary bypass and abdominal aortic aneurysm repair) to hemorrhagic shock (10, 11, 21). Injury from gastrointestinal I/R can be divided into local and remote (i.e., second organ or remote organ) organ injury. Systemic release of various inflammatory mediators and activation of leukocytes play important roles in remote organ injury (11, 12, 15). Thus morbidity and mortality associated with gastrointestinal I/R are high, and specific therapeutic interventions for these clinical situations are needed.
Neutrophils play a major role in I/R injury, including remote organ injuries involving the lung (11, 15, 23). Neutrophil adhesion, diapedesis, and activation are mediated by the interaction of CD11b/CD18 on neutrophils to intercellular adhesion molecule-1 (ICAM-1) on the cell surface (13, 14, 22). Various chemoattractants (e.g., chemokines, cytokines, and activated peptides) can mediate the activation, adherence, and migration of neutrophils from the circulation to the tissue. In this regard, upregulation of C-X-C chemokines is required for neutrophil recruitment in many acute pulmonary inflammatory conditions (3, 18, 26).
Complement activation promotes neutrophil and endothelial cell activation, leading to a proinflammatory state. Recent animal studies have demonstrated that inhibition of complement at C5 or at C3 can inhibit tissue injury and neutrophil accumulation in the local tissue and remote lung after gastrointestinal ischemia in the rat (23, 29). There are many questions related to complement activation and its role in I/R injury that need to be addressed. What complement components are responsible for complement-mediated injury? What complement pathways play an important role in initial complement activation? What pathways play a role in tissue injury after gastrointestinal I/R? To specifically address these issues, many different species-specific complement component inhibitors [e.g., monoclonal antibodies (MAbs)] need to be made. Production and isolation of species-specific and functionally inhibitory MAbs are incredibly tedious processes and a time-consuming approach; therefore, initial studies with complement-deficient or knockout mice can be used to establish the relative importance of specific pathways and/or early vs. late complement components. To address these issues in the mouse, a mouse model of gastrointestinal I/R that displays complement-dependent local and remote tissue injury needs to be developed. In this report, we developed a mouse model of gastrointestinal injury that involves complement-mediated injury to the local gastrointestinal tract and complement-dependent pulmonary injury. This model is well suited to evaluate the role of complement-mediated tissue injury in complement-deficient as well as complement knockout mice.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Intestinal I/R Injury
Adult male C57B6 mice (Charles River Laboratories), aged 6-8 wk and weighing 20-22 g, were anesthetized with pentobarbital sodium (50 mg/kg ip) and ketamine (50 mg/kg ip). Intestinal ischemia was produced by occlusion of the superior mesenteric artery with surgical, microvascular clips (Roboz, Rockville, MD) for 20 min. Pilot studies revealed that reproducible and consistent data could not be obtained if the ischemic period exceeded 20 min (e.g., death, variations in tissue biochemical endpoints). Reperfusion was achieved by removing the clips; the wound sites were then closed, and mice were kept anesthetized and warm throughout the 3 h of reperfusion. Sham-operated controls underwent the same surgical procedures without clamping. Mice were euthanized by pentobarbital sodium overdose.Inhibition of the Terminal Complement Components Using Anti-Mouse C5 MAb
Murine anti-mouse C5 MAb (BB5.1) is an IgG1 subtype, which was purified from mouse ascites fluid by protein A chromatography. BB5.1 functionally blocks the cleavage of C5 and inhibits the formation C5a and C5b-9 (25). An isotype-matched control MAb (GS-1) was used as a control (19). Antibodies BB5.1 or GS-1 (50 mg/kg iv) were administered 5 min before the induction of intestinal ischemia.Lactate Dehydrogenase Activity in Intestinal Homogenates
Intestinal lactate dehydrogenase (LDH) activity from tissue homogenates was measured as an index for tissue injury (23). Tissue samples (starting 10 cm above cecum; 15 cm in total length) were collected, cleaned and flushed two times with 5 ml of ice-cold PBS, and frozen at
70°C. The tissue samples were
homogenized in 5 mmol/l phosphate buffer (pH 6.0) and centrifuged at
30,000 g at 4°C for 30 min. The supernatants were assayed
for LDH activity by using a commercial kit (LDH 500, Sigma Chemical,
St. Louis, MO). LDH activity was expressed as units per milligram of
protein [measured with a protein assay kit (Bio-Rad, Hercules, CA)],
and its loss from the tissue was used as a biochemical marker of
cellular injury.
Myeloperoxidase Activity in Tissue Homogenates
Myeloperoxidase (MPO) activity, an index of neutrophil infiltration, was measured as described previously (23). The LDH homogenate pellets or lung sections were homogenized in 0.5% hexadecyltrimethyl ammonium bromide (Sigma Chemical) dissolved in 50 mmol/l potassium phosphate buffer (pH 6.0; 10% wt/vol). After homogenates were frozen, thawed, and sonicated three times, the ice-cold samples were centrifuged at 12,500 g at 4°C for 15 min. The supernatants were collected and reacted with 0.167 mg/ml of o-dianisidine dihydrochloride (Sigma Chemical) and 0.0005% H2O2 (Sigma Chemical) in 50 mmol/l potassium phosphate buffer (pH 6.0). The change in absorbance was measured spectrophotometrically at 460 nm every 15 s for 4 min, and the linear portion of the tracing was used for analysis. One unit of MPO activity was defined as the quantity of enzyme that hydrolyzed 1 µmol H2O2/min at 25°C. MPO activity was expressed as units per 100 mg of wet tissue.Hematoxylin-Eosin Staining
Tissue samples for histological staining were taken and fixed in 10% formalin-PBS at 4°C overnight. The samples were dehydrated and embedded in paraffin. Sections (7 µm) were cut and stained with hematoxylin-eosin. Slides were evaluated in a blinded manner.Immunohistochemistry
Purified hamster anti-mouse CD54 (ICAM-1) antibody (BD Pharmingen, San Diego, CA) (1:100) and horseradish peroxidase-conjugated anti-hamster antibody (BD Pharmingen) were used for immunohistochemical staining. A purified hamster IgG (isotype control antibody: anti-keyhole limpet hemocyanin) was used as a negative control.Quantitative RT-PCR
Total RNA was extracted from frozen tissues as previously described with acid guanidinium thiocyanate extraction (4). RNA was incubated with RNase-free DNase (GIBCO Life Technologies, Gaithersburg, MD) at 10 units/100 µg RNA in the presence of 10 mmol/l MgCl2 and 10 units of RNase inhibitor (Boehringer Mannheim, Indianapolis, IN) at 37°C for 20 min. RNA was phenol-chloroform extracted and ethanol precipitated. cDNA was synthesized with random primers using the reverse transcription system from Promega (Madison, WI) according to the manufacturer's instructions. cDNA was amplified in 25-µl reactions containing 1× platinum quantitative PCR SuperMix-UDG buffer (GIBCO Life Technologies) supplemented with 0.133× SYBR green I nucleic acid gel stain (Molecular Probes, Eugene, OR), 1 µl of cDNA reaction mix, and 0.2 µmol/l of each primer.
-Actin, ICAM-1, and macrophage inflammatory
protein (MIP)-2 were amplified with an initial soak at 94°C for 10 min followed by 94°C for 30 s, 58°C for 30 s, and 72°C
for 30 s for a total of 40 cycles, followed by a 10-min extension
at 72°C with the following primers:
5'-gctacagcttcaccaccacag-3' and 5'-gctcatagctcttctccaggg-3' (-actin), 5'-ggagacgcagaggaccttaac-3' and 5'-cgctcagaagaaccaccttc-3' (ICAM-1), and 5'-atgcctgaagaccctgcc-3' and 5'-cgcccttgagagtggcta-3' (MIP-2). Amplification and analysis were performed with an iCycler detection system (Bio-Rad). The comparative threshold cycle
(CT) method was used to quantify the relative increases (in
fold) mRNA levels (28). The average CT value for seven
sham-operated controls was used as the calibrator. The efficiency of
amplification was confirmed to be near equal for the housekeeping gene
and the gene of interest. The value for efficiency was used in the
comparative CT equation as described (16). Water samples
or RNA samples containing no reverse transcriptase were amplified in
parallel to ensure that no contaminating DNA was present during PCR.
Validation of the Model
To validate the use of this model and to confirm the importance of the complement component C5, male C5-deficient and their congenic C5-sufficient (control) mice were purchased from Jackson Laboratories (Bar Harbor, ME). The mice underwent the same experimental conditions as outlined above and were evaluated for biochemical indexes of tissue injury.Statistical Analysis
All values are presented as means ± SE of n independent experiments. All data were subjected to one-way ANOVA followed by the Student-Newman-Keul's post hoc test with the use of SigmaStat software (SPSS Science, Chicago, IL). Differences were considered significant at P < 0.05. A Student's t-test was used to evaluate the pulmonary MPO or intestinal LDH data for the C5-deficient and C5-sufficient mice.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Assessment of Intestinal Injury
Histology.
Representative histological sections from the mouse jejunum in
sham-operated mice and I/R mice treated with isotype control MAb or
anti-C5 are presented in Fig. 1. We
observed a reduction in villi height, focal coagulative necrosis, and
acute inflammation in mice treated with the isotype control MAb after
20 min of ischemia and 3 h of reperfusion compared with
control sham-operated mice (Fig. 1, B and A,
respectively). Ghosts of preexisting villous cores and dead enterocytes
were observed. Mice treated with vehicle (i.e., PBS) and undergoing the
same period of I/R manifested the same degree of histological and
biochemical injury (see below) as control MAb-treated mice (data not
presented). Pretreatment with the mouse anti-mouse C5 MAb improved the
changes in histology induced by I/R (Fig. 1C). Focal mild
villous shortening was observed in anti-C5-treated mice.
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LDH activity analysis.
We analyzed tissue LDH activity in the intestine of sham-operated mice
as well as in isotype control or anti-C5 MAb-treated mice after
intestinal I/R as a biochemical index of tissue injury (Fig.
2). Isotype control MAb-treated mice
undergoing I/R demonstrated a significant loss of LDH activity compared
with sham-operated mice (P < 0.05; Fig. 2).
Pretreatment with anti-C5 MAb significantly reduced the loss of LDH
activity compared with isotype control MAb-treated mice. The LDH
activity of anti-C5 treated mice undergoing I/R was not significantly
different from sham-operated mice (Fig. 1). These data suggest that
local intestinal injury after I/R was dependent on C5 cleavage.
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MPO activity analysis.
The terminal complement components (i.e., C5a and C5b-9) play a
key role in the activation, adherence, recruitment, and accumulation of
neutrophils into I/R organs (20, 23). The intestinal MPO activity of sham-operated, isotype control-treated, and anti-C5-treated animals undergoing intestinal I/R is presented in Fig.
3. We observed a significant increase in
intestinal MPO activity of isotype control MAb-treated mice compared
with sham-operated mice (P < 0.05). Mice treated with
anti-C5 MAb had significantly lower MPO activity than isotype control
MAb-treated mice undergoing intestinal I/R (P < 0.05).
There was no significant difference in intestinal MPO activity between
anti-C5-treated mice undergoing I/R and sham-operated mice. These data
demonstrated that neutrophil infiltration in the I/R intestine could be
significantly attenuated by anti-C5 treatment.
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Assessment of Lung Injury
Histology.
A significant component of gastrointestinal I/R injury is the
involvement of an inflammatory response in the lung. Pulmonary injury
was observed microscopically in sham-operated mice and mice undergoing
I/R (Fig. 4). Hematoxylin-eosin staining
revealed marked pulmonary congestion and diffuse mild interstitial
neutrophilic infiltrates after gastrointestinal I/R in control
MAb-treated mice compared with sham-operated controls. Treatment with
anti-C5 MAb attenuated the pulmonary congestion and the influx of
inflammatory cells compared with control MAb-treated mice. These data
suggest that remote organ injury, secondary to gastrointestinal I/R, is mediated by C5 activation.
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MPO activity analysis.
MPO activity was used to quantify neutrophil accumulation in the lung.
Pulmonary MPO activity was significantly (P < 0.05) increased after gastrointestinal I/R in isotype control MAb-treated mice compared with sham-operated controls (Fig.
5). Pretreatment with anti-C5
significantly inhibited pulmonary MPO activity after gastrointestinal
I/R compared with isotype control-treated mice. There was no
significant increase in pulmonary MPO activity in anti-C5 MAb-treated
mice compared with sham-operated controls. These data suggest that
complement activation plays an important role in neutrophil trafficking
in the lung after gastrointestinal I/R.
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ICAM-I expression by quantitative RT-PCR.
An important component in pulmonary neutrophil trafficking is the
expression of leukocyte adhesion molecules (8). ICAM-1 mRNA expression in the lung was investigated with real-time
quantitative RT-PCR. We observed a significant (P < 0.05) twofold increase in the ICAM-1 mRNA expression in the murine lung
after gastrointestinal I/R relative to sham-operated controls (Fig.
6A). Anti-C5 MAb therapy
significantly reduced ICAM-1 mRNA expression compared with isotype
control-treated animals. The level of ICAM-1 expression in anti-C5
MAb-treated mice was similar to that in sham-operated controls (Fig.
6A).
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ICAM-1 protein expression. The action of anti-C5 MAb treatment on ICAM-1 protein expression in the lung was further examined by immunohistochemistry. Staining with the isotype control antibody (i.e., hamster anti-KLH IgG) revealed no staining in any sections (data not shown). ICAM-1 protein was constitutively expressed in very low amounts in sham-operated controls (Fig. 6B). Isotype control MAb-treated mice had elevated ICAM-1 protein expression in the lung after gastrointestinal I/R compared with sham-operated controls (Fig. 6, C and B, respectively). ICAM-1 protein expression was reduced in the lung of anti-C5-treated mice compared with isotype control-treated mice. The level of ICAM-1 expression in anti-C5 treated mice after gastrointestinal I/R was similar to sham-operated controls (Fig. 6D). These data demonstrate that inhibition of C5 decreases pulmonary ICAM-1 mRNA and protein expression after gastrointestinal I/R.
Regulation of the chemokine, MIP-2.
The chemokine, MIP-2, belongs to a superfamily of small proteins
that are produced on cellular activation and are involved in leukocyte
trafficking and recruitment (17). Pulmonary MIP-2 mRNA
expression was significantly (P < 0.05) increased
24 ± 8-fold in mice after gastrointestinal I/R and treatment with
isotype control MAb compared with sham-operated controls (Fig.
7). Anti-C5 MAb-treated animals had
significantly reduced MIP-2 mRNA expression compared with the control
MAb-treated animals. MIP-2 mRNA expression in anti-C5 MAb-treated
animals was 6 ± 3-fold greater than sham-operated controls, but
this was not statistically significant. These data suggest that in
addition to C5a- and C5b-9-mediated neutrophil activation and
chemotaxis, MIP-2 may also be involved in pulmonary neutrophil
sequestration following gastrointestinal I/R. Furthermore, it suggests
that complement activation at the level of C5 is a major contributor to
MIP-2 expression in the lung following gastrointestinal I/R.
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Validation of the Model
To validate the model and to state conclusively an important role of the complement component in this murine model of gastrointestinal I/R injury, C5-deficient and their congenic control mice were used. We have previously demonstrated that, after kidney ischemia and reperfusion in mice, MAb treatment with BB5.1 in wild-type mice or the use of C5-deficient mice yields similar tissue-protective action (30). As shown in Fig. 8, a significant decrease in pulmonary neutrophil accumulation (e.g., MPO activity) was observed in C5-deficient mice (Fig. 8A). Furthermore, intestinal injury was significantly less in the C5-deficient mice compared with the C5-sufficient controls (Fig. 8B). Thus these data confirm an important role for complement activation and tissue injury in local and remote tissues after gastrointestinal I/R. Furthermore, C5 is an important contributor to the local and remote tissue injury.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Gastrointestinal I/R is a common clinical problem caused by many medical conditions, including acute mesenteric ischemia, small bowel transplantation, abdominal aortic aneurysm, hemorrhagic shock, necrotizing enterocolitis, septic shock, and severe burns (5, 10-12, 21). Gastrointestinal I/R is often associated with the development of systemic inflammation, pulmonary microvascular dysfunction, and adult respiratory distress syndrome (5, 9, 10). Effective therapeutics to eliminate or attenuate local and remote tissue injury after gastrointestinal I/R are needed. Our laboratory has recently demonstrated that complement activation in the rat after gastrointestinal I/R mediates a substantial portion of the local tissue injury and identified several key proinflammatory genes that were regulated by complement C5 activation in the gut (23). In that report, we also observed significant pulmonary injury secondary to the gastrointestinal I/R. However, the potential molecular mechanisms of the pulmonary injury were not investigated in our rat model. The present study was developed to extend our previous findings in the rat, to investigate the pulmonary injury component after gastrointestinal I/R, and to establish a mouse model of complement-dependent local and remote organ injury after gastrointestinal I/R.
Our mouse model of gastrointestinal I/R (i.e., 20 min of ischemia and 3 h of reperfusion) led to local and remote tissue injury that was significantly attenuated by anti-C5 MAb. Furthermore, we extend and validate these findings by using the C5-deficient and the congenic control mice. Pulmonary neutrophil accumulation and intestinal damage (e.g., LDH activity) are shown to be significantly less in the C5-deficient mice after gastrointestinal I/R, thus validating the role of C5 in our mouse model. Furthermore, our laboratory previously demonstrated similar protective actions of either anti-C5 MAb or C5-deficient mice in a mouse model of renal ischemia and reperfusion (30). Previous models of gastrointestinal I/R in the mouse demonstrated that local intestinal injury was mediated by IgM, C5b-9, and classical complement pathway activation and was independent of neutrophils (1, 27). Our neutrophil data are at odds with these previous findings. We demonstrate that anti-C5, which inhibits formation of C5a and C5b-9, inhibits neutrophil infiltration into the gut as well as the lung after gastrointestinal I/R (Fig. 3). Furthermore, we also show that intestinal injury or pulmonary neutrophil infiltration is significantly less in the C5-deficient mice compared with their congenic controls (Fig. 8). The reason for the differences observed in our study and the studies in the literature may relate to the length of the ischemic period (e.g., 40 vs. 20 min in our study) (1). Furthermore, our laboratory demonstrated previously in the rat that inhibition of C5 attenuates neutrophil infiltration into the lung and gut after gastrointestinal I/R (23). Pilot studies used to develop the present model (data not presented) demonstrated significantly less protective actions of anti-C5 in mice subjected to ischemic periods greater than 20 min. However, it is clear from these studies that the terminal complement components mediate local and remote tissue injury following gastrointestinal I/R injury.
Our laboratory previously showed that the inhibition of the late
complement components attenuates neutrophil accumulation and preserves
tissue integrity in the intestine and lung in a rat model of
gastrointestinal I/R (23). In the present study, we extend
our previous findings to a new mouse model of gastrointestinal I/R and
investigate the potential molecular mechanisms regulating pulmonary
neutrophil trafficking into the lung. C5a, C5b-7, and C5b-9 are known
to have profound influences on neutrophil activation and adherence
molecule expression and appear to be the dominant players in vivo
during acute inflammation (2, 6, 24). We demonstrate that
anti-C5 significantly attenuates the expression of pulmonary ICAM-1
mRNA and protein expression in our model. Along with this finding, we
also observe a significant attenuation of neutrophil sequestration
within the lung. The chemokine, MIP-2, plays an important role in
neutrophil accumulation (6). In addition, bronchoalveolar
lavage MIP-2 protein levels during complement activation are decreased
by anti-tumor necrosis factor-
(TNF-) and/or anti-C5a treatment
(7). In the present study, we demonstrate that pulmonary
MIP-2 expression is significantly upregulated after gastrointestinal
I/R. Furthermore, inhibition of C5 significantly decreased MIP-2 mRNA
expression to sham-operated control levels. Because combined C5a and
TNF- expression can lead to increased MIP-2 expression
(7) and anti-C5 inhibits TNF- expression (e.g., mRNA
and protein) in a rat model of gastrointestinal I/R (23),
it is possible that the decreased pulmonary MIP-2 expression in our
murine model is a result of decreased TNF- and C5 activation. It is
possible that neutrophil accumulation in our model involved not only
C5a generation but also MIP-2 expression. These data demonstrate that
C5 inhibition significantly inhibited MIP-2 expression, as well as
pulmonary neutrophil accumulation in the lung after gastrointestinal
I/R. Our data confirm that inhibition of the terminal complement
components prevents local and remote pulmonary neutrophil accumulation
and the resulting I/R injury.
In summary, we developed a murine model of gastrointestinal I/R that induces local and remote organ injury that is mediated in part by complement activation. Anti-C5 attenuates gastrointestinal and lung injury after gastrointestinal I/R. Anti-C5 decreased the pulmonary expression of ICAM-1 and MIP-2. These results, as well as others in the literature, clearly demonstrate that inhibition of the terminal complement components leads to decreased expression of multiple proinflammatory genes in many different organs and protects local and remote tissue from I/R-mediated injury (20, 23, 30). This new mouse model coupled with the newly developed knockout animals will allow investigation into the importance of various complement pathways involved in local and remote tissues after gastrointestinal I/R.
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ACKNOWLEDGEMENTS |
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We thank Jessica R. L. Da Rossa for skillful technical assistance. We thank Dr. Scott A. Rollins for providing murine MAb anti-C5 (BB5.1).
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FOOTNOTES |
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Address for reprint requests and other correspondence: G. L. Stahl, Center for Experimental Therapeutics and Reperfusion Injury, Thorn 705, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115 (E-mail: gstahl{at}zeus.bwh.harvard.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.
First published March 29, 2002;10.1152/japplphysiol.00159.2002
Received 27 February 2002; accepted in final form 25 March 2002.
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RESULTS
DISCUSSION
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