|
|
Prepublished online as a Blood First Edition Paper on May 17, 2002; DOI 10.1182/blood-2002-03-0752.
 Previous Article | Table of Contents | Next Article 
Blood, 15 September 2002, Vol. 100, No. 6, pp. 2077-2080
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
The caspase inhibitor z-VAD is more effective than CD18 adhesion
blockade in reducing muscle ischemia-reperfusion injury: implication
for clinical trials
Akiko Iwata,
John M. Harlan,
Nicholas B. Vedder, and
Robert K. Winn
From the Departments of Surgery and Medicine,
University of Washington, Seattle.
Ischemia-reperfusion (I/R) leads to organ injury and organ
dysfunction in a variety of clinical disorders. Preclinical
investigations examining leukocyte adhesion molecules in I/R provided
overwhelming evidence that blocking the function of leukocyte adhesion
molecules would be highly effective in improving outcome in clinically
relevant diseases. Unfortunately, all 9 of the recently completed phase 2 and 3 clinical trials examining antiadhesion therapy have failed. In
this report, we show that a modest increase in ischemic time results in
conversion from a CD18-dependent to a CD18-independent injury. This
fundamental change in the mechanism of injury can be reduced by
inhibition of caspases leading to blockade of apoptosis. Muscle injury
resulting from aortic clamping was measured by release of creatine
kinase. I/R injury following ischemia of 60 minutes or less and 3 hours
of reperfusion was significantly reduced by pretreatment with anti-CD18
monoclonal antibody. However, 90 minutes of ischemia resulted in a
marked increase in injury that was not reduced by CD18 blockade.
Importantly, the injury resulting from 90 or 120 minutes of ischemia
was reduced by the pancaspase inhibitor z-VAD. We propose that the
length of ischemia can result in a fundamental change in the mechanism
of injury and that all preclinical investigations of I/R must be
evaluated with increasing ischemia if they are to model the clinical
disease. The result showing CD18-independent I/R injury is not unique;
likewise, protection by caspase inhibitors is not unique. However, we
show for the first time that caspase inhibitors are effective when CD18
blockade is not.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
J. A. Emamaullee, L. Stanton, C. Schur, and A.M. J. Shapiro
Caspase Inhibitor Therapy Enhances Marginal Mass Islet Graft Survival and Preserves Long-Term Function in Islet Transplantation
Diabetes,
May 1, 2007;
56(5):
1289 - 1298.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Yonekawa and J. M. Harlan
Targeting leukocyte integrins in human diseases
J. Leukoc. Biol.,
February 1, 2005;
77(2):
129 - 140.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. A. Rongen, W. J.G. Oyen, B. P. Ramakers, N. P. Riksen, O. C. Boerman, N. Steinmetz, and P. Smits
Annexin A5 Scintigraphy of Forearm as a Novel In Vivo Model of Skeletal Muscle Preconditioning in Humans
Circulation,
January 18, 2005;
111(2):
173 - 178.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. S. Cummings, G. R. Kinsey, L. J. C. Bolchoz, and R. G. Schnellmann
Identification of Caspase-Independent Apoptosis in Epithelial and Cancer Cells
J. Pharmacol. Exp. Ther.,
July 1, 2004;
310(1):
126 - 134.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. de Vries, J. Kohl, W. K. G. Leclercq, T. G. A. M. Wolfs, A. A. J. H. M. van Bijnen, P. Heeringa, and W. A. Buurman
Complement Factor C5a Mediates Renal Ischemia-Reperfusion Injury Independent from Neutrophils
J. Immunol.,
April 1, 2003;
170(7):
3883 - 3889.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. H. Merchant, D. M. Gurule, and R. S. Larson
Amelioration of ischemia-reperfusion injury with cyclic peptide blockade of ICAM-1
Am J Physiol Heart Circ Physiol,
April 1, 2003;
284(4):
H1260 - H1268.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
