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Neutrophil-Derived Heparin-binding Protein*: A Monocyte-Specific Chemoattractant That Induces Monocyte Migration into Rabbit Lungs In Vivo FREE TO VIEW

Dennis E. Doherty, MD, FCCP; J. Nakano, MD, FCCP; K. Nakano
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*From the Division of Pulmonary and Critical Care Medicine, University of Kentucky Chandler Medical Center, Lexington Veterans Affairs Medical Center, Lexington, KY, and Department of Medicine National Jewish Medical and Research Center, Denver, CO.

Correspondence to: Dennis E. Doherty, MD, Division of Pulmonary and Critical Care Medicine, University of Kentucky Medical Center, 800 Rose St., MN 614, Lexington, KY 40536-0084

Chest. 1999;116(suppl_1):34S-35S. doi:10.1378/chest.116.suppl_1.34S-a
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During acute inflammatory processes in the lung, monocyte accumulation usually follows that of neutrophils. We and others have shown that in some systems, monocyte accumulation is a neutrophil-dependent event. One potential mechanism is that neutrophils generate monocyte chemoattractants.

Human heparin-binding protein (HBP) is a proteolytically inactive neutrophil elastase homologue with sequence identity to CAP37 and azurocidin. Activated neutrophils have been shown to secrete significant amounts of HBP. We have shown by immunohistochemistry that this cationic protein co-localizes with neutrophils in acute inflammatory lung lesions of patients with asthma and ARDS. We have also shown that human HBP, purified by ion exchange and molecular sieve chromatography (personal communication; Dr. Hans Flodgaard; Bagvaerd, Denmark), functions as a monocyte-specific chemoattractant in vitro.

To test if this protein is a monocyte chemoattractant in vivo, rabbit or human HBP was bronchoscopically instilled into the right or left cranial lobe of rabbits (25 to 100 μg in 1 mL) 10 min prior to an IV pulse infusion of rabbit 111In-monocytes (purified by elutriation, >90% pure), and lungs were lavaged (BAL) 2, 4, 6, 14, or 20 h later. HBP (rabbit or human) induced a significant migration of 111In-monocytes (gamma counter) into the lungs by 4 h after instillation compared with human serum albumin-treated (vehicle) control animals in a dose-dependent fashion. Monocyte accumulation was greatest by 20 h after rabbit HBP (p < 0.01) or 14 h after human HBP (p < 0.05) instillation, with 25 μg rabbit HBP or 50 μg human HBP inducing the greatest monocyte influx. The time course of migration and peak accumulation of animal’s native monocytes (nonspecific esterase/LeukoStat stains) in the alveolar space paralleled that of the radiolabeled monocytes. Neutrophil accumulation was increased compared with human serum albumin-treated control animals; however, initial migration occurred hours after that of monocytes. Preincubation of HBP with heparin abrogated monocyte chemotaxis in vitro and ablated monocyte, but not neutrophil, migration in vivo.

HBP induced significant monocyte migration into lungs of neutrophil-depleted animals, similar in magnitude to that observed in normal animals, suggesting that HBP was not inducing other neutrophil-derived monocyte chemoattractants in vivo. It is possible that HBP induces production of additional monocyte chemoattractants (chemokines); however, these data together suggest that HBP may play an important role in regulating monocyte accumulation in the lung during acute inflammation.




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