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Departments of 1 Surgery and 2 Pathology, Harvard Medical School, and Brigham and Women's Hospital, Boston, Massachusetts 02115
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ABSTRACT |
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 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Intestinal ischemia-reperfusion injury is dependent on complement. This study examines the role of the alternative and classic pathways of complement and IgM in a murine model of intestinal ischemia-reperfusion. Wild-type animals, mice deficient in complement factor 4 (C4), C3, or Ig, or wild-type mice treated with soluble complement receptor 1 were subjected to 40 min of jejunal ischemia and 3 h of reperfusion. Compared with wild types, knockout and treated mice had significantly reduced intestinal injury, indicated by lowered permeability to radiolabeled albumin. When animals deficient in Ig were reconstituted with IgM, the degree of injury was restored to wild-type levels. Immunohistological staining of intestine for C3 and IgM showed colocalization in the mucosa of wild-type controls and minimal staining for both in the intestine of Ig-deficient and C4-deficient mice. We conclude that intestinal ischemia-reperfusion injury is dependent on the classic complement pathway and IgM.
immunoglobulin M; rodent; inflammation; complement; transgenic/knockout
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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ORGAN ISCHEMIA AND REPERFUSION generate a multitude of inflammatory mediators, including the complement system, cytokines, eicosanoids, adhesion molecules, as well as the products of activated neutrophils (6, 16, 19). The period of ischemia, as well as the size of the ischemic region, determines the local and remote reperfusion injuries. The degree of injury is also related to the particular tissue involved. Thus skeletal muscle ischemia leads to local permeability and pulmonary abnormalities after 2-3 h, whereas 45 min of small bowel ischemia leads to destruction of the mucosa, but minimal alteration of the surrounding smooth muscle (7).
In the case of intestinal reperfusion, injury is related to the activation of complement. This was shown by the attenuation of histological mucosal injury, reduction in intestinal vascular permeability, and increased survival in rats subjected to intestinal ischemia and reperfusion that were treated with the complement inhibitor soluble complement receptor 1 (sCR1) (7). This recombinant extramembranous portion of CR1 binds and degrades both complement factor 4b (C4b) and C3b (21). Other work, using transgenic mice deficient in complement components or immunoglobulin to investigate skeletal muscle ischemia and reperfusion, has shown that the injury-related increases in muscle vascular permeability results from activation of the classic pathway via natural antibody (20). Thus mice genetically deficient in C4 or C3 or immunoglobulin were protected from muscle injury. Consonant with these findings are those of Czurco and Nashino (3), who demonstrated in reperfused rat brain the localization of immunoglobulin in the same sites where C3 was deposited. In contrast, work with sCR1 and murine cremaster ischemia-reperfusion has suggested a role for alternative pathway, non-antibody-dependent scheme of complement activation (13). To test the role of complement and immunoglobulin in intestinal reperfusion injury, we examined strains of mice deficient in either C3 or C4 or immunoglobulin in a new murine model of jejunal ischemia-reperfusion.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals.
Mice deficient in either C4 (C4
/) or C3
(C3/) were constructed by one of the authors (M. C. Carroll; 4, 22) by using the technique of homologous recombination in
embryonic stem cells. Both strains had undetectable levels of serum C4
or C3, respectively, as measured by ELISA (4, 22). Mice totally
deficient in immunoglobulins but with normal levels of complement
components, i.e., recombination-activating gene-1-deficient
(RAG1/[C57BL/6JRAG1tm 1 Mom]) and control [F1(B6/129)] mice
were purchased from the Jackson Laboratory (Bar Harbor, ME).
Animal model.
Rommel tourniquets were fashioned from 100-cm loops of 3-0 Prolene
suture (Ethicon, Somerville, NJ) and 1-cm lengths of PE-90 Intramedic
polyethylene tubing (Becton-Dickinson, Parsippany, NJ), which were used
as snuggers. Mice, 6-8 wk old, were anesthetized with
intraperitoneal pentobarbital (90 mg/kg). A laparotomy was performed,
and the tourniquet was applied to the most proximal 6-cm segment of
jejunum. Tourniquets were placed to occlude the mesenteric vessels and
jejunal lumen and were secured with a microvascular clip.
Ischemia was confirmed by the lack of pulsation in the
mesentery and by intestinal pallor. The laparotomy incision was closed
and then was reopened after 40 min. The tourniquet was removed, and reperfusion of the mesenteric vasculature was confirmed by the return
of pulsation to the vascular arcade. The incision was again closed, and
all animals were kept anesthetized in a supine position and warm with
electric heating pads at 38°C for 3 h of reperfusion. Sham control
animals underwent laparotomy without the application of tourniquets.
All animals received 1 µCi
125I-labeled bovine serum albumin
(in 0.25 ml normal saline) intravenously 5 min before reperfusion. The
group treated with sCR1 (T Cell Sciences, Needham, MA) received 20 mg/kg of this complement antagonist intravenously, mixed with the
125I-labeled albumin in 0.25 ml
PBS. Those animals reconstituted with IgM received 400 µg in 0.35 ml
saline intravenously 30 min before the initial laparotomy. Each animal
received the same amount of intravenous fluid before laparotomy (0.60 ml in total). All animals received 0.2 ml saline intravenously 1 h
after the start of reperfusion. Approximately 0.2-0.5 ml of blood
was obtained by cardiac puncture before euthanasia by intraperitoneal
pentobarbital injection. The ischemic segment of jejunum was then
harvested and washed with 10 ml of saline to remove excess stool. The
jejunal segments were then counted for radioactivity in a gamma counter (Packard, Downers Grove, IL) and dried to constant weight at 90°C for 3 days. The intestinal permeability index (PI) was determined by
the ratio
[(counts · min
1 · g1
of jejunal
loop)/(counts · min1 · g1
of blood)] as described previously (5).
Purification of IgM from nonimmune normal mouse serum. Whole serum from F1 (B6/129) mice was precipitated by ammonium sulfate (50% saturation). The precipitate was dissolved in 1× PBS (10 mM Na2HPO4, 150 mM NaCl, pH 7.25) and dialyzed against the same buffer. Recovered dialysate was then passed through a 0.45-µm syringe filter (Acrodisc, Gelman Sciences, Ann Arbor, MI) and applied to a 2-ml protein G column (GammaBind Sepharose, Pharmacia Biotech, Uppsala, Sweden). After successive rounds of sample binding, washing, and elution (0.1 M glycine-HCl, 0.15 M NaCl, pH 2.5), the protein G flow through was adjusted to 0.5 M NaCl with 10× buffer and applied to a 2-ml anti-IgM agarose column (Sigma Chemical). Elution was achieved with 0.1 M glycine buffer. Protein-containing fractions were pooled, dialyzed, and concentrated and assessed by SDS-PAGE (2), isotype-specific ELISA (Southern Biotechnologies, Birmingham, AL), and limulus amoebocyte lysate assay (Associates of Cape Cod, Woods Hole, MA) to confirm lack of lipopolysaccharide contamination. IgM was found to be pure and devoid of contaminating IgG, Clq, or lipopolysaccharide.
Reconstitution of antibody-deficient mice.
RAG1/ mice were reconstituted by intravenous
administration of 400 µg of purified IgM in 0.35 ml PBS 30 min before
initial laparotomy. Serum levels of IgM were measured at harvest by
isotype-specific ELISA (Southern Biotechnologies).
Immunohistological analysis. Immunoperoxidase labeling of IgM, IgG, and C3 was performed on paraformaldehyde-fixed cryostat serial sections of intestine by using goat anti-mouse IgM (Sigma Chemical), goat anti-mouse IgG (Sigma Chemical), or goat anti-mouse C3 (5 µg/ml; Organon Teknia, Durham, NC) and a standard avidin-biotin protocol (8). Semiquantitative estimation of staining intensity was performed by a pathologist (L. Kobzik) in a blinded fashion.
Statistics. Groups were subjected to analysis of variance, and, when significance was found, a Student's t-test with the Bonferroni correction for multiple comparisons was applied.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Reperfusion edema is mediated by the classic pathway of complement
(Fig. 1).
Reperfusion of ischemic intestine resulted in endothelial cell injury
characterized by increased vascular permeability and edema. The
intestinal vascular PI of injured wild-type mice F1(B6/129) (n = 12) was 3.26 ± 0.30 compared
with 0.70 ± 0.04 in sham animals (n = 5). In contrast,
C3/ (n = 8) animals had
a significant reduction in permeability with a PI of 2.25 ± 0.27 (P < 0.05). Thus deficiency in C3,
which impairs both classic and alternative pathways of complement,
resulted in a 40% reduction in permeability. Similarly, sCR1
(n = 5), which binds and degrades both
C3b and C4b, thus inhibiting the alternative as well as the classic
pathway, led to a 66% reduction in permeability, with a PI of 1.58 ± 0.19 (P < 0.05).
C4/ mice (n = 8), which
have an intact alternative pathway but cannot form the classic pathway
C3 convertase (C2aC4b), were also protected to a degree similar to that
for C3/ mice, with a PI of 2.20 ± 0.28, a
42% reduction (P < 0.05). Thus the permeability increases caused by
ischemia-reperfusion are mediated by activation of the classic
and not the alternative
pathway.
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Classic complement activation is dependent on IgM (Fig.
2).
RAG1/ mice (n = 4),
deficient in IgM and IgG but with normal levels of complement, were
protected from changes in permeability with a 75% reduction in PI of
1.34 ± 0.20 (P < 0.05).
RAG1/ mice reconstituted with IgM
(n = 5) had injuries similar to those in control mice with a PI of 2.86 ± 0.13 (Fig. 2). Levels of IgM after reconstitution were 468 ± 7 µg/ml compared with levels in normal mice of 437.5 ± 5 µg/ml as measured by isotype-specific ELISA. RAG1/ unreconstituted mice did not have detectable
levels of IgM.
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Immunohistochemistry.
Macroscopic examination showed marked differences in appearance of the
ischemic segments of bowel, with more evidence of infarction and
hemorrhage in control animals compared with those treated with sCR1.
There was also an apparent, although less marked, reduction in injury
in the complement-deficient animals compared with control rats.
Histologically, all specimens were graded 0-5 according to the
system of Chiu et al. (1), where 0 corresponded to normal mucosal villi
and 5 corresponded to digestion and disintegration of lamina propria
with hemorrhage and ulceration. Those animals with less severe injury
(scored in a blinded fashion by L. Kobzik) corresponded to those with
reduced PI (correlation coefficient of 0.92, Table 1).
Sections of reperfused and sham control intestine were stained for
mouse IgM. IgM was deposited on mucosa from reperfused mice but was
absent from sham controls (Fig. 3,
A and
E, respectively). Thus IgM binds to
reperfused tissue. Immunostaining of intestine for C3 demonstrated
colocalization with IgM on mucosa of reperfused complement-sufficient
mice but was absent from sections of intestine from sham animals (Fig.
3, B and
F, respectively). Reperfused intestine
from C4- and C3-deficient animals showed less staining for IgM and
minimal staining for C3 compared with control-complement-sufficient mice (Fig. 3, C and
D). Similarly, reperfused intestine
from RAG1/ animals had minimal staining for C3 and IgM
(Fig. 4, A and
B), whereas RAG1/
animals reconstituted with IgM showed increased staining and
colocalization of C3 with IgM (Fig. 4,
C and
D). Staining for IgG deposition was
minimal in all groups.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The dependence of intestinal ischemia-reperfusion injury on complement is confirmed in these studies, with significant reduction in injury in animals treated with sCR1. This is consistent with previous reports from several laboratories that have looked at amelioration of injury in rat intestine (7), cardiac muscle (21), and skeletal muscle (13) by prevention of complement activation. The observation that C4-deficient mice are protected from injury to a degree similar to that for C3-deficient mice supports the thesis that this injury is mediated by the classic pathway of complement. The primary mechanism for activation is fixation of serum antibody to antigen. Animals deficient in immunoglobulin but sufficient in complement components were protected from permeability changes associated with intestinal ischemia-reperfusion. This is similar to our findings in hindlimb ischemia and reperfusion (20). Further similarity is the observation that IgM but not IgG localized to the reperfused, injured endothelium. In the present study, reconstitution of immunoglobulin-deficient animals with IgM completely restored the change in intestinal permeability to levels seen in wild-type animals undergoing ischemia. These results indicate that fixation of natural IgM antibody, normally present in mouse serum, is responsible for the complement activation that then leads to jejunal injury and increased vascular permeability.
Antibody triggers inflammation by both cellular and humoral mechanisms. Binding of C1q to antigen bound antibody initiates the humoral classic cascade, whereas binding of antibody to leukocyte Fc receptors initiates the cellular response. IgG and IgE but not IgM have been shown to initiate the cellular mechanism (14). Thus, after jejunal ischemia, in the absence of complement, binding of IgM would not be expected to result in an inflammatory reaction characterized by vascular leakage. This is confirmed in the present study, in which complement-deficient animals have reduced levels of intestinal vascular permeability after reperfusion, despite normal levels of immunoglobulin. Conversely, those animals deficient in immunoglobulin have reduced vascular permeability after reperfusion, despite normal levels of complement.
The mechanism by which reperfused tissue acquires IgM-binding capacity and subsequent complement deposition is not known. Hypoxia is known to result in cell synthesis of membrane-associated proteins (11), which may function as antigens for natural antibody. Furthermore, natural antibodies are known to circulate in normal individuals and are often implicated in autoimmune vasculitis (15). Anti-endothelial cell antibodies are found in a variety of human diseases as well as in normal sera (9, 12, 17). A mechanism of injury that starts with neoantigen exposure, allowing IgM binding followed by complement activation by the classic pathway, would be expected to demonstrate control levels of IgM binding to reperfused tissue in C4-deficient animals. However, levels of IgM staining in reperfused C4-deficient animals were reduced compared with those in complement-sufficient animals. This may be because the amount of IgM binding reflects the overall injury and neoantigen exposure, which are greater in the complement-sufficient mouse.
Binding of natural antibody to injured endothelial cells could allow the initiation of the complement cascade via the classic pathway. Activation of complement may mediate local injury by several routes. Integration of the terminal components of complement C5b-C9 in the membranes of vascular endothelium may lead to ionic flux through the pore. In addition, release of anaphylatoxins C3a and C5a induces vascular leakage and enhances infiltration and activation of neutrophils. Adhesion and activation of neutrophils are also promoted by covalent deposition of iC3b at the site of reperfusion (10). Our prior studies conducted in rats have shown the intestinal injury to be relatively independent of neutrophils (18). However, in the present mouse study, which is a different model, it is possible that neutrophil-mediated injury is occurring. This might explain the residual vascular leakage in the C3- and C4-deficient mice.
These data indicate that the local inflammatory injury after intestinal ischemia is largely dependent on activation of the classic complement pathway. The initiating event may be a reperfusion-induced alteration of the endothelial membrane, allowing a neoantigen to be expressed. Thereafter, IgM natural antibody binds to this antigen, thereby triggering injury via the classic complement cascade.
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ACKNOWLEDGEMENTS |
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The authors thank D. Smith and R. Mercier for help with the surgical preparations and A. C. Imrich for performing the immunohistochemistry.
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FOOTNOTES |
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This work was supported in part by National Institute of General Medical Sciences Grants GM-24891-18A1, GM-35141-10, and GM-52585-02, The Brigham Surgical Group, Inc., and The Trauma Research Foundation.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: H. B. Hechtman, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115 (E-mail: HBHechtman{at}BICS.BWH.Harvard.EDU).
Received 28 May 1998; accepted in final form 23 October 1998.
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REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Chiu, C.-J.,
A. McArdle,
R. Brown,
H. Scott,
and
F. Gurd.
Intestinal mucosal lesion in low-flow states.
Arch. Surg.
101:
478-483,
1970
2.
Cleveland, D.,
S. Fischer,
M. Kirschner,
and
U. Laemmli.
Peptide mapping by limited proteolysis in sodium dodecyl sulfate and analysis by gel electrophoresis.
J. Biol. Chem.
252:
1102-1106,
1977
3.
Czurko, A.,
and
H. Nashino.
Appearance of immunoglobulin G and complement factor C3 in the striatum after transient focal ischemia in the rat.
Neurosci. Lett.
166:
51-54,
1994[Medline].
4.
Fischer, M.,
M. Ma,
S. Georg,
X. Zhou,
J. Xia,
O. Finco,
S. Han,
G. Kelso,
R. Howard,
T. Rothstein,
E. Kremmer,
F. Rosen,
and
M. Carroll.
Regulation of the B cell response to T-dependent antigens by classical pathway complement.
J. Immunol.
157:
549-556,
1996[Abstract].
5.
Gibbs, S. A. L.,
M. R. Weiser,
L. Kobzik,
C. R. Valeri,
D. Shepro,
and
H. B. Hechtman.
P-selectin mediates intestinal ischemic injury by enhancing complement deposition.
Surgery
119:
652-656,
1996[Medline].
6.
Grace, P.
Ischaemia-reperfusion injury.
Br. J. Surg.
81:
637-647,
1994[Medline].
7.
Hill, J.,
T. F. Lindsay,
F. Ortiz,
C. G. Yeh,
H. B. Hechtman,
and
F. D. Moore, Jr.
Soluble complement receptor type 1 ameliorates the local and remote organ injury after intestinal ischemia-reperfusion in the rat.
J. Immunol.
149:
1723-1728,
1992[Abstract].
8.
Kobzik, L.,
D. S. Bredt,
C. J. Lowenstein,
J. Drazen,
B. Gaston,
D. Sugarbaker,
and
J. S. Stamler.
Nitric oxide synthase in human and rat lung; immunocytochemical and histochemical localization (Abstract).
Am. J. Respir. Cell Mol. Biol.
9:
371,
1993.
9.
Leung, D.,
T. Collins,
L. Lapierre,
and
R. Geha.
IgM antibodies present in the acute phase of Kawasaki syndrome lyse cultured vascular endothelial cells stimulated by gamma interferon.
J. Clin. Invest.
77:
1428-1435,
1986.
10.
Marks, R. M.,
R. F. Todd III,
and
P. A. Ward.
Rapid induction of neutrophil-endothelial adhesion by endothelial complement fixation.
Nature
339:
314-317,
1989[Medline].
11.
Ogawa, S.,
M. Clauss,
K. Kuwabara,
R. Shreeniwas,
C. Butura,
S. Koga,
and
D. Stern.
Hypoxia induces endothelial cell synthesis of membrane associated proteins.
Proc. Natl. Acad. Sci. USA
88:
9897-9901,
1991
12.
Papa, N.,
G. Conforti,
D. Gambini,
L. LaRosa,
A. Tincani,
D. D'Cruz,
M. Khamashta,
G. Hughes,
G. Balestrieri,
and
P. Meroni.
Characterization of the endothelial surface proteins recognized by anti-endothelial antibodies in primary and secondary autoimmune vasculitis.
Clin. Immunol. Immunopathol.
70:
211-216,
1994[Medline].
13.
Pemberton, M.,
G. Anderson,
V. Vetvicka,
D. Justus,
and
G. Ross.
Microvascular effects of complement blockade with soluble CR1 on ischemia/reperfusion injury of skeletal muscle.
J. Immunol.
150:
5104-5113,
1993[Abstract].
14.
Ravetch, J.
Fc receptors: rubor redux.
Cell
78:
553-560,
1994[Medline].
15.
Ronda, N.,
M. Haury,
A. Nobrega,
S. Kaveri,
A. Coutinho,
and
M. Kazatchkine.
Analysis of natural and disease-associated autoantibody repertoires: anti-endothelial cell IgG autoantibody activity in the serum of healthy individuals and patients with systemic lupus erythematosus.
Int. Immunol.
6:
1651-1660,
1994
16.
Rubin, B.,
A. Smith,
S. Liauw,
D. Isenman,
A. Romaschin,
and
P. Walker.
Complement activation and white cell activation in postischemia skeletal muscle.
Am. J. Physiol.
259 (Heart Circ. Physiol. 28):
H525-H531,
1990
17.
See, J. V. D.,
A. Heurkens,
E. V. D. Voort,
M. Daha,
and
F. Breedveld.
Characterization of anti-endothelial antibodies in patients with rheumatoid arthritis complicated by vasculitis.
Clin. Exp. Immunol.
9:
589-594,
1991.
18.
Simpson, R.,
R. Alon,
L. Kobzik,
C. R. Valeri,
D. Shepro,
and
H. B. Hechtman.
Neutrophil and nonneutrophil-mediated injury in intestinal ischemia-reperfusion.
Ann. Surg.
218:
444-454,
1993[Medline].
19.
Ward, P.
Ischemia, reperfusion and organ dysfunction: biochemical and cellular events.
J. Vasc. Surg.
18:
111,
1993.
20.
Weiser, M. R.,
J. P. Williams,
F. D. Moore, Jr.,
L. Kobzik,
M. Ma,
H. B. Hechtman,
and
M. C. Carroll.
Reperfusion injury of skeletal muscle is mediated by natural antibody and complement.
J. Exp. Med.
183:
2343-2348,
1996
21.
Weisman, H.,
T. Bartow,
M. Leppo,
H. Marsh,
G. Carson,
M. Concino,
M. Boyle,
K. Roux,
M. Weisfeldt,
and
D. Fearson.
Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis.
Science
249:
146-151,
1990
22.
Wessels, M. R.,
P. Butko,
M. Ma,
H. B. Warren,
A. L. Lage,
and
M. Carroll.
Studies of group B streptococcal infection in mice deficient in complement C3 or C4 demonstrate an essential role for complement in both innate and acquired immunity.
Proc. Natl. Acad. Sci. USA
92:
11490-11494,
1995
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 L. J. Thomas, K. Panneerselvam, D. T. Beattie, M. D. Picard, B. Xu, C. W. Rittershaus, H. C. Marsh Jr., R. A. Hammond, J. Qian, T. Stevenson, et al. Production of a complement inhibitor possessing sialyl Lewis X moieties by in vitro glycosylation technology Glycobiology, October 1, 2004; 14(10): 883 - 893. [Abstract] [Full Text] [PDF]
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S. D. Fleming, M. Monestier, and G. C. Tsokos Accelerated Ischemia/Reperfusion-Induced Injury in Autoimmunity-Prone Mice J. Immunol., September 15, 2004; 173(6): 4230 - 4235. [Abstract] [Full Text] [PDF]
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E. von Dobschuetz, O. Bleiziffer, S. Pahernik, M. Dellian, T. Hoffmann, and K. Messmer Soluble complement receptor 1 preserves endothelial barrier function and microcirculation in postischemic pancreatitis in the rat Am J Physiol Gastrointest Liver Physiol, May 1, 2004; 286(5): G791 - G796. [Abstract] [Full Text] [PDF]
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M. Zhang, W. G. Austen Jr., I. Chiu, E. M. Alicot, R. Hung, M. Ma, N. Verna, M. Xu, H. B. Hechtman, F. D. Moore Jr., et al. Identification of a specific self-reactive IgM antibody that initiates intestinal ischemia/reperfusion injury PNAS, March 16, 2004; 101(11): 3886 - 3891. [Abstract] [Full Text] [PDF]
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K. Yamada, T. Miwa, J. Liu, M. Nangaku, and W.-C. Song Critical Protection from Renal Ischemia Reperfusion Injury by CD55 and CD59 J. Immunol., March 15, 2004; 172(6): 3869 - 3875. [Abstract] [Full Text] [PDF]
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 S. Saadi, T. Takahashi, R. A. Holzknecht, and J. L. Platt Pathways to Acute Humoral Rejection Am. J. Pathol., March 1, 2004; 164(3): 1073 - 1080. [Abstract] [Full Text] [PDF]
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R. J. Quigg Complement and the Kidney J. Immunol., October 1, 2003; 171(7): 3319 - 3324. [Full Text] [PDF]
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M. J. Burne-Taney, D. B. Ascon, F. Daniels, L. Racusen, W. Baldwin, and H. Rabb B Cell Deficiency Confers Protection from Renal Ischemia Reperfusion Injury J. Immunol., September 15, 2003; 171(6): 3210 - 3215. [Abstract] [Full Text] [PDF]
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 A. E. Fiane, V. Videm, P. S. Lingaas, L. Heggelund, E. W. Nielsen, O. R. Geiran, M. Fung, and T. E. Mollnes Mechanism of Complement Activation and Its Role in the Inflammatory Response After Thoracoabdominal Aortic Aneurysm Repair Circulation, August 19, 2003; 108(7): 849 - 856. [Abstract] [Full Text] [PDF]
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N. C. Riedemann and P. A. Ward Complement in Ischemia Reperfusion Injury Am. J. Pathol., February 1, 2003; 162(2): 363 - 367. [Full Text] [PDF]
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G. L. Stahl, Y. Xu, L. Hao, M. Miller, J. A. Buras, M. Fung, and H. Zhao Role for the Alternative Complement Pathway in Ischemia/Reperfusion Injury Am. J. Pathol., February 1, 2003; 162(2): 449 - 455. [Abstract] [Full Text] [PDF]
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J. M. Thurman, D. Ljubanovic, C. L. Edelstein, G. S. Gilkeson, and V. M. Holers Lack of a Functional Alternative Complement Pathway Ameliorates Ischemic Acute Renal Failure in Mice J. Immunol., February 1, 2003; 170(3): 1517 - 1523. [Abstract] [Full Text] [PDF]
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R. R. Reid, S. Woodcock, A. Shimabukuro-Vornhagen, W. G. Austen Jr., L. Kobzik, M. Zhang, H. B. Hechtman, F. D. Moore Jr., and M. C. Carroll Functional Activity of Natural Antibody is Altered in Cr2-Deficient Mice J. Immunol., November 15, 2002; 169(10): 5433 - 5440. [Abstract] [Full Text] [PDF]
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S. D. Fleming, T. Shea-Donohue, J. M. Guthridge, L. Kulik, T. J. Waldschmidt, M. G. Gipson, G. C. Tsokos, and V. M. Holers Mice Deficient in Complement Receptors 1 and 2 Lack a Tissue Injury-Inducing Subset of the Natural Antibody Repertoire J. Immunol., August 15, 2002; 169(4): 2126 - 2133. [Abstract] [Full Text] [PDF]
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 H. Zhao, M. C. Montalto, K. J. Pfeiffer, L. Hao, and G. L. Stahl Murine model of gastrointestinal ischemia associated with complement-dependent injury J Appl Physiol, July 1, 2002; 93(1): 338 - 345. [Abstract] [Full Text] [PDF]
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 S. SAADI, L. E. WRENSHALL, and J. L. PLATT Regional manifestations and control of the immune system FASEB J, June 1, 2002; 16(8): 849 - 856. [Abstract] [Full Text] [PDF]
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 P. Dimayuga, B. Cercek, S. Oguchi, G. N. Fredrikson, J. Yano, P. K. Shah, S. Jovinge, and J. Nilsson Inhibitory Effect on Arterial Injury-Induced Neointimal Formation by Adoptive B-Cell Transfer in Rag-1 Knockout Mice Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 644 - 649. [Abstract] [Full Text] [PDF]
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S. Rehrig, S. D. Fleming, J. Anderson, J. M. Guthridge, J. Rakstang, C. E. McQueen, V. M. Holers, G. C. Tsokos, and T. Shea-Donohue Complement Inhibitor, Complement Receptor 1-Related Gene/Protein y-Ig Attenuates Intestinal Damage After the Onset of Mesenteric Ischemia/Reperfusion Injury in Mice J. Immunol., November 15, 2001; 167(10): 5921 - 5927. [Abstract] [Full Text] [PDF]
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 C. Kyriakides, Y. Wang, W. G. Austen Jr., J. Favuzza, L. Kobzik, F. D. Moore Jr., and H. B. Hechtman Moderation of skeletal muscle reperfusion injury by a sLex-glycosylated complement inhibitory protein Am J Physiol Cell Physiol, July 1, 2001; 281(1): C224 - C230. [Abstract] [Full Text] [PDF]
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P. PARK, M. HAAS, P. N. CUNNINGHAM, J. J. ALEXANDER, L. BAO, J. M. GUTHRIDGE, D. M. KRAUS, V. M. HOLERS, and R. J. QUIGG Inhibiting the Complement System Does Not Reduce Injury in Renal Ischemia Reperfusion J. Am. Soc. Nephrol., July 1, 2001; 12(7): 1383 - 1390. [Abstract] [Full Text] [PDF]
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J. G. Younger, N. Sasaki, J. Delgado, A. C. Ko, T. X. Nghiem, M. D. Waite, G. O. Till, and P. A. Ward Systemic and lung physiological changes in rats after intravascular activation of complement J Appl Physiol, June 1, 2001; 90(6): 2289 - 2295. [Abstract] [Full Text] [PDF]
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 M. J. Walport Complement- Second of Two Parts N. Engl. J. Med., April 12, 2001; 344(15): 1140 - 1144. [Full Text] [PDF]
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C. Kyriakides, S. A. Woodcock, Y. Wang, J. Favuzza, W. G. Austen Jr., L. Kobzik, F. D. Moore Jr., R. C. Valeri, D. Shepro, and H. B. Hechtman Soluble P-selectin moderates complement-dependent reperfusion injury of ischemic skeletal muscle Am J Physiol Cell Physiol, August 1, 2000; 279(2): C520 - C528. [Abstract] [Full Text] [PDF]
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 C. Caliezi, W. A. Wuillemin, S. Zeerleder, M. Redondo, B. Eisele, and C. E. Hack C1-Esterase Inhibitor: An Anti-Inflammatory Agent and Its Potential Use in the Treatment of Diseases Other Than Hereditary Angioedema Pharmacol. Rev., March 1, 2000; 52(1): 91 - 112. [Abstract] [Full Text] [PDF]
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C. Kyriakides, W. Austen Jr., Y. Wang, J. Favuzza, L. Kobzik, F. D. Moore Jr., and H. B. Hechtman Skeletal muscle reperfusion injury is mediated by neutrophils and the complement membrane attack complex Am J Physiol Cell Physiol, December 1, 1999; 277(6): C1263 - C1268. [Abstract] [Full Text] [PDF]
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 P. Park, M. Haas, P. N. Cunningham, L. Bao, J. J. Alexander, and R. J. Quigg Injury in renal ischemia-reperfusion is independent from immunoglobulins and T lymphocytes Am J Physiol Renal Physiol, February 1, 2002; 282(2): F352 - F357. [Abstract] [Full Text] [PDF]
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P. Dimayuga, B. Cercek, S. Oguchi, G. N. Fredrikson, J. Yano, P. K. Shah, S. Jovinge, and J. Nilsson Inhibitory Effect on Arterial Injury-Induced Neointimal Formation by Adoptive B-Cell Transfer in Rag-1 Knockout Mice Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 644 - 649. [Abstract] [Full Text] [PDF]
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