INTRAALVEOLAR MACROPHAGE-INFLAMMATORY PEPTIDE-2 INDUCES RAPID NEUTROPHIL LOCALIZATION IN THE LUNG

Endotoxin-induced lung injury is characterized by neutrophil infiltrat ion of the lungs. The various mechanisms which mediate movement of neu trophils from vascular space to lung interstitium and alveoli remain u nclear. Macrophage-inflammatory protein 2 (MIP-2) is a potent chemoatt ractant for neutrophils and may play a significant role in recruiting neutrophils in acute lung injury in rats. Experiments were performed i n male Sprague Dawley rats to: (1) evaluate the kinetics of neutrophil influx in the lung following intraperitoneal administration of Salmon ella enteritidis lipopolysaccharide (LPS); (2) determine the expressio n of transcripts for chemokines and adhesion molecules in the lung fol lowing intraperitoneal LPS; and (3) elucidate the effects of intra-alv eolar instillation of recombinant rat MIP-2 on neutrophil influx into the lung. Intraperitoneal LPS resulted in an increase in neutrophil se questration in the lung capillaries of rats as early as 45 min followi ng administration, and there was a parallel increase in lung myelopero xidase 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-s electin at 1 and 2 h following EPS. When recombinant rat MIP-2 was ins tilled into the alveolar space of rats through a catheter wedged into a bronchus, there was profound neutrophil localization both in the vas cular and alveolar space which significantly differed (P < 0.05) from the contralateral lungs of the same animals, and lungs of control anim als instilled with control buffer. These observations reveal that MIP- 2 is a potent chemoattractant in rat lungs, and suggest that chemoattr actants locally released in alveoli can recruit neutrophils to those a lveoli. 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.