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Intra-alveolar macrophage-inflammatory peptide 2 induces rapid neutrophil localization in the lung
1Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesvile 22908, USA.
Abstract:
Endotoxin-induced lung injury is characterized by neutrophil infiltration of the lungs. The various mechanisms which mediate movement of neutrophils from vascular space to lung interstitium and alveoli remain unclear. Macrophage-inflammatory protein 2 (MIP-2) is a potent chemoattractant for neutrophils and may play a significant role in recruiting neutrophils in acute lung injury in rats. Experiments were performed in male Sprague Dawley rats to: (1) evaluate the kinetics of neutrophil influx in the lung following intraperitoneal administration of Salmonella enteritidis lipopolysaccharide (LPS); (2) determine the expression of transcripts for chemokines and adhesion molecules in the lung following intraperitoneal LPS; and (3) elucidate the effects of intra-alveolar instillation of recombinant rat MIP-2 on neutrophil influx into the lung. Intraperitoneal LPS resulted in an increase in neutrophil sequestration in the lung capillaries of rats as early as 45 min following administration, and there was a parallel increase in lung myeloperoxidase activity. There were also major increases in mRNA in whole-lung homogenates of LPS-treated rats for chemokines MIP-2 and KC (cytokine-induced neutrophil chemoattractant) and adhesion molecules P- and E-selectin at 1 and 2 h following LPS. When recombinant rat MIP-2 was instilled into the alveolar space of rats through a catheter wedged into a bronchus, there was profound neutrophil localization both in the vascular and alveolar space which significantly differed (P < 0.05) from the contralateral lungs of the same animals, and lungs of control animals instilled with control buffer. These observations reveal that MIP-2 is a potent chemoattractant in rat lungs, and suggest that chemoattractants locally released in alveoli can recruit neutrophils to those alveoli. This suggests that alveolar macrophages may play an important role in neutrophil sequestration in sepsis and other inflammatory lung diseases which produce a neutrophilic alveolitis.
Insights
Macrophage-inflammatory protein 2 (MIP-2) is a potent chemoattractant that recruits neutrophils to the lungs during endotoxin-induced lung injury. Local release of MIP-2 in alveoli drives neutrophil influx, highlighting the role of alveolar macrophages in lung inflammation.
Area of Science:
- Pulmonary Medicine
- Immunology
- Cell Biology
Background:
- Endotoxin-induced lung injury involves neutrophil infiltration.
- Mechanisms of neutrophil migration into lung interstitium and alveoli are not fully understood.
- Macrophage-inflammatory protein 2 (MIP-2) is a known neutrophil chemoattractant.
Purpose of the Study:
- Evaluate neutrophil influx kinetics after lipopolysaccharide (LPS) administration.
- Determine chemokine and adhesion molecule gene expression in LPS-treated rat lungs.
- Investigate the effect of intra-alveolar MIP-2 on neutrophil recruitment.
Main Methods:
- Male Sprague Dawley rats received intraperitoneal LPS.
- Neutrophil sequestration and myeloperoxidase activity were measured.
- Lung mRNA for MIP-2, KC, and selectins was analyzed.
- Recombinant rat MIP-2 was instilled intra-alveolarly.
Main Results:
- LPS increased neutrophil sequestration and myeloperoxidase activity within 45 minutes.
- LPS elevated MIP-2 and KC mRNA, and P- and E-selectin mRNA at 1-2 hours.
- Intra-alveolar MIP-2 caused significant neutrophil localization in vascular and alveolar spaces.
Conclusions:
- MIP-2 is a potent chemoattractant in rat lungs.
- Locally released alveolar chemoattractants recruit neutrophils to alveoli.
- Alveolar macrophages may be crucial in neutrophil sequestration during sepsis and neutrophilic alveolitis.