1 Department of Medicine, Section of Nephrology, University of Chicago, Chicago, Illinois 60637; and 2 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Ischemia-reperfusion injury
(IRI) is a complex and incompletely understood process involving a
cascade of events that culminates in apoptotic and/or necrotic cell
death. Natural IgM antibodies and complement have been implicated
in the pathogenesis of IRI in a variety of organ systems as have T
lymphocytes in renal IRI. To investigate the role of Ig and T
lymphocytes in renal IRI, recombination-activating gene
(RAG)-1-deficient mice were studied. RAG-1(/
) mice were not
protected from acute renal failure induced by 27.5 min of bilateral
renal ischemia and subsequent reperfusion [serum urea nitrogen
levels 30 h after reperfusion, 155.2 ± 5.6 and 152.8 ± 11.4 mg/dl in RAG-1(
/
) and wild-type mice, respectively; n = 13 each]. Histological examination showed acute
tubular necrosis and neutrophilic infiltration with no significant
differences between groups. In contrast with other organ systems, Igs
were not found in kidneys at time points ranging from 1 min to 30 h after ischemia. Thus Igs and mature T lymphocytes do not
appear to play a significant role in the pathogenesis of IRI in the kidney.
acute renal failure; neutrophils; complement; recombination activating gene
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A SERIES OF COMPLEX EVENTS occurs during tissue ischemia and reperfusion including cell-surface expression of intracellular P-selectin as well as antigens that are normally hidden and upregulated expression of a number of proteins such as E-selectin and intercellular adhesion molecule (ICAM)-1 (12, 31). Once reperfusion occurs, the access of inflammatory mediators such as antibodies, complement, and blood cells sets off an inflammatory reaction in which neutrophils and molecular oxygen are key mediators (27, 32). Not surprisingly given its direct exposure to blood-borne inflammatory elements, the endothelial surface appears to be the key cell type in the early events that occur in ischemia-reperfusion injury (IRI), as it produces multiple factors such as adhesion molecules, cytokines, leukotrienes, endothelin, and platelet-activating factor, all of which contribute to the inflammation (31, 36).
An elegant series of experiments performed by Carroll, Hechtman, and colleagues (33, 35) has defined events in skeletal muscle and intestinal IRI. Mice deficient in complement components C3 and C4 as well as in Igs were protected from IRI. Reconstitution of IgM in Ig-deficient mice restored IRI. Taken together, these data indicate that IgM natural antibody-mediated activation of the classical pathway on endothelium is a proximate event in IRI in these two organs.
In renal IRI, tubular cells are also prominently injured, which leads to the pathological picture of acute tubular necrosis. This complicated process involves complement activation on endothelial cells, endothelial cell P- and E-selectin (but not L-selectin) engagement of neutrophils, and an ensuing inflammatory reaction that ultimately leads to necrotic and apoptotic tubular cell death through as yet incompletely characterized mechanisms (8, 12, 25, 31). A role for membrane attack complex C5b-9-mediated tubular injury has also been proposed through the use of mice with both targeted and natural deficiencies of various complement proteins (37). In addition, mice lacking T lymphocytes were also protected from IRI, owing in part to decreased neutrophil influx into the kidneys (23). These data also suggested that T lymphocytes may have direct toxicity to renal tubular epithelia.
To evaluate the roles of Igs and T lymphocytes in renal IRI, we have
used mice deficient in recombination-activating gene (RAG)-1. RAG-1 and
RAG-2 encode for the lymphocyte-specific V(D)J recombinase (19,
26). As a consequence, RAG-1(/
) mice have no mature B or T
lymphocytes and fail to produce either Ig or T cell receptor proteins.
Contrary to our expectations, we show here that these Ig and T
lymphocyte-deficient mice are not protected from renal IRI.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Mice. All work with animals was approved by the University of Chicago Animal Care and Use Committee and was performed in accord with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All mice were obtained from Jackson Laboratories (Bar Harbor, ME). These included normal male C57BL/6 mice and mice with targeted deletions of RAG-1 on pure C57BL/6 and mixed C57BL/6 and 129 (B6129) backgrounds.
In all RAG-1(Experimental protocol. One hour before IRI, animals were given 5 U of subcutaneous heparin (9, 14). Mice anesthetized with inhalational isoflurane had baseline blood samples drawn for serum urea nitrogen (SUN) and creatinine determinations before undergoing laparotomy. Core body temperatures were maintained between 37 and 38°C. Both renal arteries were isolated by blunt dissection, and a nontraumatic vascular clamp was applied directly to the arteries thereby leaving the renal veins unoccluded. Cessation of blood flow was documented by visual inspection and by Doppler ultrasound (Koven Technology, St. Louis, MO). After a 27.5-min period of ischemia, the clamps were released and reflow was verified by visual inspection of the kidneys and by Doppler ultrasound. Fluid resuscitation was via 1 ml of normal saline administered subcutaneously after closure of the abdomen.
To study the effects of Ig deficiency on IRI, RAG-1(Renal histology. Sagittal sections of kidneys were fixed in buffered formalin. Sections (4 µm) were stained with periodic acid-Schiff base. The extent of epithelial necrosis and neutrophil infiltration was graded according to the schema of Kelly and colleagues (12). In this, the percentage of tubules in the outer medulla and corticomedullary junction that had epithelial cell necrosis and/or necrotic debris was estimated, and a score was assigned as follows: 0, none; 1+, <10%; 2+, 10-25%; 3+, 26-75%; and 4+ >75%. The extent of neutrophil infiltration was derived from the estimated mean number of neutrophils per high-power field (×400) in 5-10 consecutive fields from the outer medulla and corticomedullary junction starting at the most-involved area and proceeding in the direction of greatest involvement. Scores were assigned based on these counts as follows: 0, 0-1; 1+, 2-10; 2+, 11-20; 3+, 21-40; and 4+, >40 or too many to count. In some instances where scoring was borderline between two scores, an average value was assigned (e.g., 2.5+). All sections were provided as coded slides so the observer (M. Haas) was blinded as to treatment group and duration of ischemic injury.
IF microscopy. For IF microscopy, 4-µm cryostat sections of frozen tissue were processed for direct microscopy as described previously (21). For Ig staining, a dual-labeling technique was performed in which sections were incubated with heavy-chain-specific fluorescein isothiocyanate-conjugated rabbit anti-mouse IgM (Cappel Laboratories, Durham, NC) and rhodamine-conjugated anti-mouse IgG (Dako, Carpenteria, CA). C3 deposition was analyzed with fluorescein isothiocyanate-conjugated anti-mouse C3 (Cappel). As a second measure of renal neutrophil infiltration, kidney sections were stained with monoclonal anti-mouse neutrophil antibody 7/4 (Serotec, Oxford, UK) as previously described (22). The number of neutrophils in the corticomedullary junction was counted, and the average from 5-10 high-power fields was recorded for each animal.
Statistics. Statistical analyses were performed with Minitab software (State College, PA). All data are expressed as means ± SE. Two-sample t-testing and one-way ANOVA with subsequent Tukey's pairwise comparisons were used. Correlations among variables were examined by regression analysis.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Effects of Ig- and T-lymphocyte deficiencies on renal function
after IRI.
In our hands, renal injury in IRI is dependent on the length of
ischemia. In this study, we used 27.5 min of ischemia,
which leads to reliable renal failure upon reperfusion and corresponds to conditions used in similar studies of mouse IRI (12, 16, 25,
28). In initial studies, IRI was induced in RAG-1(/
) mice on
a mixed B6129 background (n = 5). All animals developed acute renal failure (SUN 30 h after ischemia, 161.4 ± 6.5 mg/dl). To ensure that the observed findings were not dependent
on background strain (3), further studies were done using
RAG-1(
/
) mice on a pure C57BL/6 background (n = 8).
As with the mixed-background mice, all animals developed acute renal
failure (SUN, 151.3 ± 8.2 mg/dl). Figure
1 shows SUN values 30 h after
ischemia for individual RAG-1(
/
) animals as well as control
C57BL/6 mice in which IRI was induced. SUN values at baseline were no
different between groups. Similar results were obtained using serum
creatinine as a marker of renal function [serum creatinine at 30 h of reperfusion, 3.2 ± 0.1 and 2.7 ± 0.1 mg/dl in
RAG-1(
/
) mice on B6129 and C57BL/6 backgrounds, respectively].
Figure 2 illustrates the course of renal
failure in wild-type and RAG-1(
/
) mice. Thus renal IRI occurs
independently from the presence of Ig.
|
|
Histology.
The histological indices of injury measured in this study were
epithelial cell necrosis (ENS) and extent of neutrophil infiltration (NIS). As expected, both of these measures were remarkably elevated in
all groups of animals subjected to IRI, and there were no differences among any of the groups (Table 1). Figure
3A shows a representative field from a wild-type control animal, and Fig. 3B shows one
from a RAG-1(/
) mouse. SUN levels and the values for ENS and NIS were markedly elevated. As such, there was not a significant
correlation between these histological measures and the functional
measure of renal failure as assessed by SUN values.
|
|
IF findings.
There was no IgG or IgM in the vasculature or the tubulointerstitium of
wild-type or RAG-1(/
) mice after 27.5 min of ischemia with subsequent 30 h of reperfusion (data not shown).
Complement was activated equally on the basolateral tubular surfaces in
the kidneys of both strains with no statistical differences between the
two (see Table 1 and Fig. 4). As with the
studies by Zhou and colleagues (37) in which C3 was
deposited in C4-deficient mice, these data support the concept that any
complement activation that takes place in renal IRI must be occurring
through the alternative pathway. As with histological estimates of
neutrophil infiltration, histochemical enumeration of neutrophils
indicated there was marked influx of these inflammatory cells into the
kidneys (Fig. 5) with no difference
between RAG-1(
/
) and wild-type mice (see Table 1).
|
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In the last decade, a clear role for the complement system in IRI
involving a number of organ systems has emerged. Specifically, inhibiting complement activation lessens IRI in the heart
(34), intestine (10), liver (5),
skeletal muscle (15, 20), and lung (9).
Similarly, preventing normal complement regulation in stomach worsens
IRI in that organ (11). As C3, C4, and RAG(/
) mouse
strains were resistant to IRI in skeletal muscle and intestine, a
compelling explanation for the involvement of complement in IRI
involves natural IgM antibodies binding to antigens newly expressed on
endothelia as a result of ischemia; these endothelia-bound IgM
antibodies can then lead to subsequent complement activation (33,
35). Given this underlying rationale, it was our expectation that Ig deficiency would attenuate classic pathway activation of
complement and thus limit IRI in the kidney. In addition to preventing
complement activation through the classic pathway, the absence of IgG
would similarly eliminate potential interactions with Fc receptors on
infiltrating leukocytes, the presence of which is key in IRI (13,
36). Surprisingly, our results unequivocally show that renal IRI
proceeds independently from Ig, as RAG-1(
/
) mice were equally
susceptible to IRI as wild-type controls.
Given the finding of intense deposition of IgM in organs subjected to IRI such as skeletal muscle and intestine (33, 35), we investigated whether similar deposition was occurring in kidney. After 30 h of reperfusion, no IgM or IgG deposits were found in kidney, other than for the variable presence of IgG and IgM in the glomerular mesangium, which is a normal finding in unmanipulated wild-type mice (22). As the deposition of natural IgM antibodies to antigens newly expressed during ischemia is likely to occur quickly after reperfusion, the possibility was investigated that the antibody-antigen complexes on the endothelial surfaces were shed (1) before this 30-h time point. Even at times of 1-60 min of reperfusion, no IgG or IgM was found in the kidney, either in the vasculature or in the cells of the tubulointerstitium. Thus by functional and immunohistochemical criteria, Ig does not appear to be playing a role in renal IRI.
The data of Zhou and colleagues (37) implicate the complement system in renal IRI. Their studies using mice deficient in C3, C4, C5, and C6 allowed dissection of the roles of various complement-activation products and showed that C5b-9-mediated tubular cell damage was etiologic in their model. From their results and our studies presented here, classical pathway activation does not appear to be relevant in the kidney, as renal IRI can proceed independently from C4 and Ig. In cultured human umbilical vein endothelial cells made hypoxic and subsequently reoxygenated, complement activation occurred. This activation was originally considered to occur through the classic pathway (6), but with the development of more specific reagents it was actually found to be via the lectin pathway (7). However, activation through the lectin pathway also necessitates the involvement of C4, which does not appear to be involved in renal IRI (37). Taken together, if complement activation is truly etiologic in renal IRI, this must be occurring through the alternative pathway. The site of activation could be on the apical surface of tubules [because this site lacks complement regulators (2)] or on the basolateral surface [a site that is clearly susceptible to spontaneous complement activation (17) as is illustrated by the finding of C3 deposits in this location in normal animals (22)].
A recent interesting finding by Rabb and co-workers (23)
concerns the role of T lymphocytes in renal IRI. Mice lacking CD4- and
CD8-bearing lymphocytes had accelerated recovery from renal IRI.
Pathologically, there was less tubular necrosis and neutrophil infiltration. In contrast, we observed no recovery from renal failure
nor any difference in histological scores for tubular epithelial cell
damage or neutrophil infiltration between RAG-1(/
) mice lacking
mature T lymphocytes and wild-type controls. An explanation for the
discrepancy between the two studies is likely related to the distinct
proteins targeted to result in the T lymphocyte-deficient phenotype. In
the CD4- and CD8-deficient mice, other T lymphocytes are likely to be
present such as
/
- and coreceptor-independent T lymphocytes.
These may be considerably altered by the induced deficiency of CD4- and
CD8-bearing lymphocytes (29). In contrast, the
RAG-1(
/
) phenotype is a purer (or, less "leaky") phenotype for
T lymphocyte deficiency. Nonetheless, the contrasting results in the
two studies support further investigation into the role of T
lymphocytes in renal IRI.
Renal IRI has been examined by a number of groups. From these studies,
there are several candidate mediator systems that originate from
endothelial, tubular epithelial, and infiltrating inflammatory cells
(27, 32). Renal vascular endothelial cells are stimulated in IRI to express adhesion molecules, which results in recruitment and
activation of inflammatory cells, particularly neutrophils. In addition
to expressing adhesion molecules, endothelial cells also produce
phospholipid products such as leukotriene B4 and platelet-activating factor, which can stimulate inflammatory cells (4). Therefore, blockade of platelet-activating factor as
well as the adhesion molecules, ICAM-1 (12, 24), P- and
E-selectins (28, 31) [but not L-selectin
(25)], and 2-integrins (30) all reduce the extent of renal IRI. The resulting situation in which
endothelial cells and leukocytes are activated results in production of
reactive oxygen species including superoxide (4). Nitric
oxide is also clearly involved in IRI, as mice deficient in inducible
nitric oxide synthase are protected from renal IRI (16).
Tubular epithelial cell alterations in IRI include cell adhesion
molecule alterations (38) and cellular death. Although commonly termed acute tubular necrosis, the tubular cell death in renal
IRI clearly can proceed through the process of apoptosis (8, 18). Thus renal IRI involves a number of mediator
systems; however, our data support that Ig and T lymphocytes are not
involved in the pathogenesis of renal IRI.
In summary, here we show that renal IRI can proceed independently of the presence of the RAG-1 protein. Its absence translates into a deficiency of T and B lymphocytes and secreted Ig proteins, none of which appear to be necessary for renal IRI. In addition to susceptibility to renal IRI by functional and morphological criteria, we provide evidence that Ig deposition in the kidney is not a feature at any time after reperfusion. These results are in contrast to other organ systems such as the intestine and skeletal muscle, in which Ig and in particular natural IgM antibodies are key for IRI to occur.
![]() |
ACKNOWLEDGEMENTS |
---|
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grants R01-DK-41873 and R01-DK-55357, and by a Biomedical Sciences Grant from the National Arthritis Foundation. P. Park and P. N. Cunningham were supported by NIDDK Training Grant T32-DK-07510.
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: R. J. Quigg, Univ. of Chicago, Section of Nephrology, 5841 S. Maryland Ave., MC5100, Chicago, IL 60637 (E-mail: rquigg{at}medicine.uchicago.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.
10.1152/ajprenal.00284.2001
Received 5 September 2001; accepted in final form 14 September 2001.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Barba, LM,
Caldwell PR,
Downie GH,
Camussi G,
Brentjens JR,
and
Andres G.
Lung injury mediated by antibodies to endothelium. I. In the rabbit a repeated interaction of heterologous anti-angiotensin-converting enzyme antibodies with alveolar endothelium results in resistance to immune injury through antigenic modulation.
J Exp Med
158:
2141-2158,
1983[Abstract].
2.
Biancone, L,
David S,
Della Pietra V,
Montrucchio G,
Cambi V,
and
Camussi G.
Alternative pathway activation of complement by cultured human proximal tubular epithelial cells.
Kidney Int
45:
451-460,
1994[ISI][Medline].
3.
Burne, MJ,
Haq M,
Matsuse H,
Mohapatra S,
and
Rabb H.
Genetic susceptibility to renal ischemia reperfusion injury revealed in a murine model.
Transplantation
69:
1023-1025,
2000[ISI][Medline].
4.
Carden, DL,
and
Granger DN.
Pathophysiology of ischaemia-reperfusion injury.
J Pathol
190:
255-266,
2000[ISI][Medline].
5.
Chavez-Cartaya, RE,
DeSola GP,
Wright L,
Jamieson NV,
and
White DJ.
Regulation of the complement cascade by soluble complement receptor type 1. Protective effect in experimental liver ischemia and reperfusion.
Transplantation
59:
1047-1052,
1995[ISI][Medline].
6.
Collard, CD,
Vakeva A,
Bukusoglu C,
Zund G,
Sperati CJ,
Colgan SP,
and
Stahl GL.
Reoxygenation of hypoxic human umbilical vein endothelial cells activates the classic complement pathway.
Circulation
96:
326-333,
1997
7.
Collard, CD,
Vakeva A,
Morrissey MA,
Agah A,
Rollins SA,
Reenstra WR,
Buras JA,
Meri S,
and
Stahl GL.
Complement activation after oxidative stress: role of the lectin complement pathway.
Am J Pathol
156:
1549-1556,
2000
8.
Daemen, MA,
van't Veer C,
Denecker G,
Heemskerk VH,
Wolfs TG,
Clauss M,
Vandenabeele P,
and
Buurman WA.
Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation.
J Clin Invest
104:
541-549,
1999
9.
Eppinger, MJ,
Deeb GM,
Bolling SF,
and
Ward PA.
Mediators of ischemia-reperfusion injury of rat lung.
Am J Pathol
150:
1773-1784,
1997[Abstract].
10.
Hill, J,
Lindsay TF,
Ortiz F,
Yeh CG,
Hechtman HB,
and
Moore FD, 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
11.
Iwata, F,
Joh T,
Tada T,
Okada N,
Morgan BP,
Yokoyama Y,
and
Itoh M.
Role of complement regulatory membrane proteins in ischaemia-reperfusion injury of rat gastric mucosa.
J Gastroenterol Hepatol
14:
967-972,
1999[ISI][Medline].
12.
Kelly, KJ,
Williams WW, Jr,
Colvin RB,
Meehan SM,
Springer TA,
Gutierrez-Ramos JC,
and
Bonventre JV.
Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury.
J Clin Invest
97:
1056-1063,
1996
13.
Kyriakides, C,
Austen W, Jr,
Wang Y,
Favuzza J,
Kobzik L,
Moore FD, Jr,
and
Hechtman HB.
Skeletal muscle reperfusion injury is mediated by neutrophils and the complement membrane attack complex.
Am J Physiol Cell Physiol
277:
C1263-C1268,
1999
14.
Lee, HT,
and
Emala CW.
Protective effects of renal ischemic preconditioning and adenosine pretreatment: role of A1 and A3 receptors.
Am J Physiol Renal Physiol
278:
F380-F387,
2000
15.
Lindsay, TF,
Hill J,
Ortiz F,
Rudolph A,
Valeri CR,
Hechtman HB,
and
Moore FD, Jr.
Blockade of complement activation prevents local and pulmonary albumin leak after lower torso ischemia-reperfusion.
Ann Surg
216:
677-683,
1992[ISI][Medline].
16.
Ling, H,
Edelstein C,
Gengaro P,
Meng X,
Lucia S,
Knotek Wangsiripaisan A,
Shi Y,
and
Schrier R.
Attenuation of renal ischemia-reperfusion injury in inducible nitric oxide synthase knockout mice.
Am J Physiol Renal Physiol
277:
F383-F390,
1999
17.
Nath, KA,
Hostetter MK,
and
Hostetter TH.
Pathophysiology of chronic tubulo-interstitial disease in rats. Interactions of dietary acid load, ammonia, and complement component C3.
J Clin Invest
76:
667-675,
1985[ISI][Medline].
18.
Nogae, S,
Miyazaki M,
Kobayashi N,
Saito T,
Abe K,
Nakane PK,
Nakanishi Y,
and
Koji T.
Induction of apoptosis in ischemia-reperfusion model of mouse kidney: possible involvement of Fas.
J Am Soc Nephrol
9:
620-631,
1998[Abstract].
19.
Oettinger, MA,
Schatz DG,
Gorka C,
and
Baltimore D.
RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination.
Science
248:
1517-1523,
1990[ISI][Medline].
20.
Pemberton, M,
Anderson G,
Vetvicka V,
Justus DE,
and
Ross GD.
Microvascular effects of complement blockade with soluble recombinant CR1 on ischemia/reperfusion injury of skeletal muscle.
J Immunol
150:
5104-5113,
1993
21.
Quigg, RJ,
Abrahamson DR,
Cybulsky AV,
Badalamenti J,
Minto AWM,
and
Salant DJ.
Studies with antibodies to cultured rat glomerular epithelial cells: subepithelial immune deposit formation after in vivo injection.
Am J Pathol
134:
1125-1133,
1989[Abstract].
22.
Quigg, RJ,
Lim A,
Haas M,
Alexander JJ,
He C,
and
Carroll MC.
Immune complex glomerulonephritis in C4- and C3-deficient mice.
Kidney Int
53:
320-330,
1998[ISI][Medline].
23.
Rabb, H,
Daniels F,
O'Donnell M,
Haq M,
Saba SR,
Keane W,
and
Tang WW.
Pathophysiological role of T lymphocytes in renal ischemia-reperfusion injury in mice.
Am J Physiol Renal Physiol
279:
F525-F531,
2000
24.
Rabb, H,
Mendiola CC,
Saba SR,
Dietz JR,
Smith CW,
Bonventre JV,
and
Ramirez G.
Antibodies to ICAM-1 protect kidneys in severe ischemic reperfusion injury.
Biochem Biophys Res Commun
211:
67-73,
1995[ISI][Medline].
25.
Rabb, H,
Ramirez G,
Saba SR,
Reynolds D,
Xu J,
Flavell R,
and
Antonia S.
Renal ischemic-reperfusion injury in L-selectin-deficient mice.
Am J Physiol Renal Fluid Electrolyte Physiol
271:
F408-F413,
1996
26.
Schatz, DG,
Oettinger MA,
and
Baltimore D.
The V(D)J recombination activating gene, RAG-1.
Cell
59:
1035-1048,
1989[ISI][Medline].
27.
Sheridan, AM,
and
Bonventre JV.
Cell biology and molecular mechanisms of injury in ischemic acute renal failure.
Curr Opin Nephrol Hypertens
9:
427-434,
2000[ISI][Medline].
28.
Singbartl, K,
Green SA,
and
Ley K.
Blocking P-selectin protects from ischemia/reperfusion-induced acute renal failure.
FASEB J
14:
48-54,
2000
29.
Steinman, L.
Some misconceptions about understanding autoimmunity through experiments with knockouts.
J Exp Med
185:
2039-2041,
1997
30.
Tajra, LC,
Martin X,
Margonari J,
Blanc-Brunat N,
Ishibashi M,
Vivier G,
Panaye G,
Steghens JP,
Kawashima H,
Miyasaka M,
Treille-Ritouet D,
Dubernard JM,
and
Revillard JP.
In vivo effects of monoclonal antibodies against rat 2-integrins on kidney ischemia-reperfusion injury.
J Surg Res
87:
32-38,
1999[ISI][Medline].
31.
Takada, M,
Nadeau KC,
Shaw GD,
Marquette KA,
and
Tilney NL.
The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand.
J Clin Invest
99:
2682-2690,
1997
32.
Weight, SC,
Bell PR,
and
Nicholson ML.
Renal ischaemia-reperfusion injury.
Br J Surg
83:
162-170,
1996[ISI][Medline].
33.
Weiser, MR,
Williams JP,
Moore FD, Jr,
Kobzik L,
Ma M,
Hechtman HB,
and
Carroll MC.
Reperfusion injury of ischemic skeletal muscle is mediated by natural antibody and complement.
J Exp Med
183:
2343-2348,
1996[Abstract].
34.
Weisman, HF,
Bartow T,
Leppo MK,
Marsh HC, Jr,
Carson GR,
Concino MF,
Boyle MP,
Roux KH,
Weisfeldt ML,
and
Fearon DT.
Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis.
Science
249:
146-151,
1990[ISI][Medline].
35.
Williams, JP,
Pechet TT,
Weiser MR,
Reid R,
Kobzik L,
Moore FDJ,
Carroll MC,
and
Hechtman HB.
Intestinal reperfusion injury is mediated by IgM and complement.
J Appl Physiol
86:
938-942,
1999
36.
Winn, RK,
Ramamoorthy C,
Vedder NB,
Sharar SR,
and
Harlan JM.
Leukocyte-endothelial cell interactions in ischemia-reperfusion injury.
Ann NY Acad Sci
832:
311-321,
1997[ISI][Medline].
37.
Zhou, W,
Farrar CA,
Abe K,
Pratt JR,
Marsh JE,
Wang Y,
Stahl GL,
and
Sacks SH.
Predominant role for C5b-9 in renal ischemia/reperfusion injury.
J Clin Invest
105:
1363-1371,
2000
38.
Zuk, A,
Bonventre JV,
Brown D,
and
Matlin KS.
Polarity, integrin, and extracellular matrix dynamics in the postischemic rat kidney.
Am J Physiol Cell Physiol
275:
C711-C731,
1998[Abstract].