title: Neutrophil elastase-induced elastin degradation mediates macrophage influx and lung injury in 60% O2-exposed neonatal rats.
abstract: Neutrophil (PMNL) influx precedes lung macrophage (LM) influx into the lung following exposure of newborn pups to 60% O2. We hypothesized that PMNL were responsible for the signals leading to LM influx. This was confirmed when inhibition of PMNL influx with a CXC chemokine receptor-2 antagonist, SB-265610, also prevented the 60% O2-dependent LM influx, LM-derived nitrotyrosine formation, and pruning of small arterioles. Exposure to 60% O2 was associated with increased lung contents of neutrophil elastase and α-elastin, a marker of denatured elastin, and a decrease in elastin fiber density. This led us to speculate that neutrophil elastase-induced elastin fragments were the chemokines that led to a LM influx into the 60% O2-exposed lung. Inhibition of neutrophil elastase with sivelestat or elafin attenuated the LM influx. Sivelestat also attenuated the 60% O2-induced decrease in elastin fiber density. Daily injections of pups with an antibody to α-elastin prevented the 60% O2-dependent LM influx, impaired alveologenesis, and impaired small vessel formation. This suggests that neutrophil elastase inhibitors may protect against neonatal lung injury not only by preventing structural elastin degradation, but also by blocking elastin fragment-induced LM influx, thus preventing tissue injury from LM-derived peroxynitrite formation.
authors.affiliation: Lung Biology Programme, Physiology and Experimental Medicine, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; and.
authors.forename: Azhar
authors.initials: A
authors.lastname: Masood
authors.affiliation: Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada;
authors.forename: Man
authors.initials: M
authors.lastname: Yi
authors.affiliation: Lung Biology Programme, Physiology and Experimental Medicine, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada;
authors.forename: Rosetta
authors.initials: R
authors.lastname: Belcastro
authors.affiliation: Lung Biology Programme, Physiology and Experimental Medicine, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada;
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Lung Biology Programme, Physiology and Experimental Medicine, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada;
authors.forename: Lianet
authors.initials: L
authors.lastname: Lopez
authors.affiliation: Lung Biology Programme, Physiology and Experimental Medicine, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada;
authors.forename: Crystal
authors.initials: C
authors.lastname: Kantores
authors.affiliation: Lung Biology Programme, Physiology and Experimental Medicine, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; and Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Jankov
authors.affiliation: Lung Biology Programme, Physiology and Experimental Medicine, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada; Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; and keith.tanswell@sickkids.ca.
authors.forename: A Keith
authors.initials: AK
authors.lastname: Tanswell
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002465:Cell Movement / Q000276:immunology; D053492:Elafin / Q000494:pharmacology; D004549:Elastin / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008168:Lung / Q000473:pathology; D055370:Lung Injury / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D018811:Maternal Exposure; D009504:Neutrophils / Q000276:immunology*; D010100:Oxygen / Q000494:pharmacology / Q000633:toxicity*; D030421:Peroxynitrous Acid / Q000096:biosynthesis; D010671:Phenylurea Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D066253:Vascular Remodeling
chemical_list: C549500:1-(2-bromophenyl)-3-(7-cyano-3H-benzotriazol-4-yl)urea; D053492:Elafin; D010671:Phenylurea Compounds; D023063:Receptors, Interleukin-8B; D013449:Sulfonamides; D014230:Triazoles; D030421:Peroxynitrous Acid; D004549:Elastin; C069195:sivelestat; D019272:Leukocyte Elastase; D010100:Oxygen; D005998:Glycine
keywords: BPD; elastin fragments; macrophages; neonatal lung injury; oxygen toxicity