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Neutrophil sequestration in liver and lung is differentially regulated by C-X-C chemokines during experimental
M A Mercer-Jones1, M S Shrotri, J C Peyton
1Veterans Affairs Medical Center, University of Louisville School of Medicine, Kentucky 40292, USA.
Abstract:
C-X-C chemokines play an important role in the migration and activation of neutrophils (PMNs) during an inflammatory event. We measured mRNA and protein expression of the murine C-X-C chemokines macrophage inflammatory protein-2 (MIP-2) and KC in the lungs, liver, blood, and peritoneal cavity of Swiss Webster mice after cecal ligation and puncture (CLP). Neutralizing antibodies to MIP-2 and KC were also used to determine the biological effects of these chemokines on neutrophil sequestration and organ injury in the CLP model. The data showed that early after CLP, MIP-2 mRNA and protein were expressed predominantly by the lung, whereas KC mRNA and protein were expressed by the liver. Inhibition of MIP-2 reduced both lung neutrophil sequestration and peritoneal neutrophil migration. Inhibition of KC had no effect on overall neutrophil sequestration in liver but reduced injury as measured by serum transaminases. An early survival benefit was found with anti-KC treatment, although overall survival was not different. Our study showed a differential expression by organs of C-X-C chemokines during sepsis and suggested that such chemokine effects are tissue-specific.
Insights
Sepsis involves C-X-C chemokines like macrophage inflammatory protein-2 (MIP-2) and KC. Their organ-specific expression influences neutrophil migration and injury, with MIP-2 affecting lung and peritoneal neutrophil movement and KC impacting liver injury.
Area of Science:
- Immunology
- Inflammation Research
- Sepsis Pathophysiology
Background:
- C-X-C chemokines are crucial for neutrophil (PMN) migration and activation during inflammation.
- Sepsis, a life-threatening condition, involves complex inflammatory responses.
- Understanding chemokine roles in sepsis is vital for therapeutic development.
Purpose of the Study:
- To investigate the organ-specific expression of macrophage inflammatory protein-2 (MIP-2) and KC during sepsis.
- To determine the functional impact of MIP-2 and KC on neutrophil sequestration and organ injury in a murine sepsis model.
- To evaluate the therapeutic potential of targeting these chemokines.
Main Methods:
- Cecal ligation and puncture (CLP) model in Swiss Webster mice to induce sepsis.
- Measurement of MIP-2 and KC mRNA and protein expression in lungs, liver, blood, and peritoneal cavity.
- Administration of neutralizing antibodies against MIP-2 and KC to assess their biological effects.
- Assessment of neutrophil sequestration and organ injury (serum transaminases).
Main Results:
- Early CLP induced predominant MIP-2 expression in the lung and KC expression in the liver.
- Anti-MIP-2 treatment reduced neutrophil sequestration in the lung and peritoneal cavity.
- Anti-KC treatment reduced liver injury (serum transaminases) and provided an early survival benefit, though overall survival was not improved.
Conclusions:
- Sepsis involves differential, organ-specific expression of C-X-C chemokines like MIP-2 and KC.
- These chemokines play distinct roles in neutrophil trafficking and tissue-specific injury during sepsis.
- Targeting specific chemokines may offer therapeutic benefits in sepsis, warranting further investigation.