Novel broad-spectrum chemokine inhibitor protects against lung ischemia-reperfusion injury.

Abstract

BACKGROUND:

Functional roles for chemokines have been demonstrated in several models of ischemia-reperfusion injury. The redundancy inherent to chemokine pathways makes administration of neutralizing antibodies to any single chemokine ineffective in ameliorating injury. This study was undertaken to define the pattern of chemokine expression in lung ischemia-reperfusion injury (LIRI), and to determine whether a broad-spectrum chemokine inhibitor, NR58-3.14.3, could confer significant protection against LIRI.

METHODS:

Left lungs of rats were rendered ischemic for 90 minutes and then reperfused for 4 hours. Chemokine secretion into the alveolar space was quantified by enzyme-linked immunoassay. Treated animals received NR58-3.14.3 prior to reperfusion. Vascular injury was measured by lung permeability index, neutrophil accumulation in lung parenchyma was determined by myeloperoxidase (MPO) activity, and alveolar leukocyte counts were quantified in bronchoalveolar lavage (BAL) effluent. A ribonuclease protection assay evaluated mRNA expression of various chemokines.

RESULTS:

Lavage effluent in untreated animals demonstrated significant increases in the secretion of cytokine-induced neutrophil chemoattractant (CINC), tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2 (MIP-2), MIP-1alpha and monocyte chemoattractant protein-1 (MCP-1). Animals receiving NR58-3.14.3 demonstrated a 37% (p < 0.001) reduction in vascular injury and a marked reduction in lung MPO activity (p < 0.001) and alveolar cell counts (p = 0.005). Chemokine inhibition decreased mRNA expression of a number of early response cytokines when compared with positive control animals, and caused a significant decrease (p < 0.04) in the secretion of TNF-alpha.

CONCLUSIONS:

These studies demonstrate that chemokines are expressed after lung ischemia and reperfusion, and that broad-spectrum chemokine inhibition ameliorates reperfusion injury. mRNA expression of early response cytokines was modulated, and the secretion of TNF-alpha was decreased.

• Authors: Babu V Naidu, Alexander S Farivar, Steven M Woolley, David Grainger, Edward D Verrier, Michael S Mulligan
• Journal: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation (J Heart Lung Transplant) Vol. 23 Issue 1 Pg. 128-34 (Jan 2004) ISSN: 1053-2498 [Print] United States
• PMID: 14734138 (Publication Type: Journal Article)

Chemical References

• Chemokines, CC
• Peptides, Cyclic
• cyclo(cysteinyl-glutaminyl-isoleucyl-tryptophyl-lysyl-glutaminyl-lysyl-prolyl-aspartyl-leucyl-cysteinyl-amide)

Topics

• Animals
• Chemokines, CC (antagonists & inhibitors)
• Disease Models, Animal
• Lung (blood supply)
• Macrophages, Alveolar (drug effects, immunology)
• Male
• Neutrophils (drug effects, immunology)
• Peptides, Cyclic (pharmacology, therapeutic use)
• Rats
• Rats, Long-Evans
• Reperfusion Injury (immunology, prevention & control)