Published online before print December 12, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Article |
Department of Surgery, Malmö University Hospital, Lund University, Sweden
@ To whom correspondence should be addressed. E-mail: henrikthorlacius{at}hotmail.com.
Tissue accumulation of leukocytes constitutes a rate-limiting step in endotoxin-induced tissue injury. Chemokines have the capacity to regulate leukocyte trafficking. However, the role of CXC chemokines, i.e., macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC), in leukocyte recruitment, microvascular perfusion failure, cellular injury, and apoptosis in the liver remains elusive. Herein, mice were challenged with lipopolysaccharide (LPS) in combination with D-galactosamine, and intravital microscopy of the liver microcirculation was conducted 6 h later. It was found that immunoneutralization of MIP-2 and KC did not reduce LPS-induced leukocyte rolling and adhesion in postsinusoidal venules. In contrast, pretreatment with monoclonal antibodies against MIP-2 and KC abolished (83% reduction) extravascular recruitment of leukocytes in the livers of endotoxemic mice. Notably, endotoxin challenge increased the expression of CXC chemokines, which was mainly confined to hepatocytes. Moreover, endotoxin-induced increases of liver enzymes and hepatocellular apoptosis were decreased by more than 82% and 68%, respectively, and sinusoidal perfusion was restored in mice passively immunized against MIP-2 and KC. In conclusion, this study indicates that intravascular accumulation of leukocytes in the liver is independent of CXC chemokines in endotoxemic mice. Instead, our novel data suggest that CXC chemokines are instrumental in regulating endotoxin-induced transmigration and extravascular tissue accumulation of leukocytes. Indeed, these findings demonstrate that interference with MIP-2 and KC functions protects against septic liver damage and may constitute a potential therapeutic strategy to control pathological inflammation in endotoxemia.
Key Words: adhesion • endotoxin • intravital microscopy • sepsis • transmigration
Related Articles
This article has been cited by other articles:
 |
|
 |
|
  B. Vollmar and M. D. Menger The Hepatic Microcirculation: Mechanistic Contributions and Therapeutic Targets in Liver Injury and Repair Physiol Rev, October 1, 2009; 89(4): 1269 - 1339. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Deng, J. P. Luyendyk, P. E. Ganey, and R. A. Roth Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models Pharmacol. Rev., September 1, 2009; 61(3): 262 - 282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Shaw, P. E. Ganey, and R. A. Roth Trovafloxacin Enhances the Inflammatory Response to a Gram-Negative or a Gram-Positive Bacterial Stimulus, Resulting in Neutrophil-Dependent Liver Injury in Mice J. Pharmacol. Exp. Ther., July 1, 2009; 330(1): 72 - 78. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. W. Ng, H. Zhang, A. Hegde, and M. Bhatia Role of preprotachykinin-A gene products on multiple organ injury in LPS-induced endotoxemia J. Leukoc. Biol., February 1, 2008; 83(2): 288 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Buanne, E. Di Carlo, L. Caputi, L. Brandolini, M. Mosca, F. Cattani, L. Pellegrini, L. Biordi, G. Coletti, C. Sorrentino, et al. Crucial pathophysiological role of CXCR2 in experimental ulcerative colitis in mice J. Leukoc. Biol., November 1, 2007; 82(5): 1239 - 1246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Patrick, J. Rullo, S. Beaudin, P. Liaw, and A. E. Fox-Robichaud Hepatic leukocyte recruitment in response to time-limited expression of TNF-{alpha} and IL-1beta Am J Physiol Gastrointest Liver Physiol, October 1, 2007; 293(4): G663 - G672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. W. Laschke, M. D. Menger, Y. Wang, G. Lindell, B. Jeppsson, and H. Thorlacius Sepsis-associated cholestasis is critically dependent on P-selectin-dependent leukocyte recruitment in mice Am J Physiol Gastrointest Liver Physiol, May 1, 2007; 292(5): G1396 - G1402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Thorlacius, J. E. Slotta, M. W. Laschke, Y. Wang, M. D. Menger, B. Jeppsson, and H. Thorlacius Protective effect of fasudil, a Rho-kinase inhibitor, on chemokine expression, leukocyte recruitment, and hepatocellular apoptosis in septic liver injury J. Leukoc. Biol., May 1, 2006; 79(5): 923 - 931. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Luyendyk, L. D. Lehman-McKeeman, D. M. Nelson, V. M. Bhaskaran, T. P. Reilly, B. D. Car, G. H. Cantor, X. Deng, J. F. Maddox, P. E. Ganey, et al. Coagulation-Dependent Gene Expression and Liver Injury in Rats Given Lipopolysaccharide with Ranitidine but Not with Famotidine J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 635 - 643. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Van Lint, B. Wielockx, L. Puimege, A. Noel, C. Lopez-Otin, and C. Libert Resistance of Collagenase-2 (Matrix Metalloproteinase-8)-Deficient Mice to TNF-Induced Lethal Hepatitis J. Immunol., December 1, 2005; 175(11): 7642 - 7649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. B. Dorman, J. S. Gujral, M. L. Bajt, A. Farhood, and H. Jaeschke Generation and functional significance of CXC chemokines for neutrophil-induced liver injury during endotoxemia Am J Physiol Gastrointest Liver Physiol, May 1, 2005; 288(5): G880 - G886. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Johnston, J. P. Mizgerd, and S. A. Shore CXCR2 is essential for maximal neutrophil recruitment and methacholine responsiveness after ozone exposure Am J Physiol Lung Cell Mol Physiol, January 1, 2005; 288(1): L61 - L67. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jaeschke and M. L. Bajt Critical role of CXC chemokines in endotoxemic liver injury in mice J. Leukoc. Biol., December 1, 2004; 76(6): 1089 - 1090. [Full Text] [PDF]
|
|
|
|
|
|
H. Thorlacius and D. Klintman Response to the letter by Dr. Jaeschke J. Leukoc. Biol., December 1, 2004; 76(6): 1091 - 1092. [Full Text] [PDF]
|
|
