title: Inhibiting lung elastase activity enables lung growth in mechanically ventilated newborn mice.
abstract: BACKGROUND
  Mechanical ventilation with O₂-rich gas (MV-O₂) offers life-saving treatment for respiratory failure, but also promotes lung injury. We previously reported that MV-O2 of newborn mice increased lung elastase activity, causing elastin degradation and redistribution of elastic fibers from septal tips to alveolar walls. These changes were associated with transforming growth factor (TGF)-β activation and increased apoptosis leading to defective alveolarization and lung growth arrest, as seen in neonatal chronic lung disease.
  
  
  OBJECTIVE
  To determine if intratracheal treatment of newborn mice with the serine elastase inhibitor elafin would prevent MV-O₂-induced lung elastin degradation and the ensuing cascade of events causing lung growth arrest.
  
  
  METHODS
  Five-day-old mice were treated via tracheotomy with recombinant human elafin or vehicle (lactated-Ringer solution), followed by MV with 40% O₂ for 8-24 hours; control animals breathed 40% O₂ without MV. At study's end, lungs were harvested to assess key variables noted below.
  
  
  RESULTS
  MV-O₂ of vehicle-treated pups increased lung elastase and matrix metalloproteinase-9 activity when compared with unventilated control animals, causing elastin degradation (urine desmosine doubled), TGF-β activation (pSmad-2 tripled), and apoptosis (cleaved-caspase-3 increased 10-fold). Quantitative lung histology showed larger and fewer alveoli, greater inflammation, and scattered elastic fibers. Elafin blocked these MV-O₂-induced changes.
  
  
  CONCLUSIONS
  Intratracheal elafin, by blocking lung protease activity, prevented MV-O₂-induced elastin degradation, TGF-β activation, apoptosis, and dispersion of matrix elastin, and attenuated lung structural abnormalities noted in vehicle-treated mice after 24 hours of MV-O₂. These findings suggest that elastin breakdown contributes to defective lung growth in response to MV-O₂ and might be targeted therapeutically to prevent MV-O₂-induced lung injury.
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California 94305-5162, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Hilgendorff
authors.forename: Kakoli
authors.initials: K
authors.lastname: Parai
authors.forename: Robert
authors.initials: R
authors.lastname: Ertsey
authors.forename: Noopur
authors.initials: N
authors.lastname: Jain
authors.forename: Edwin F
authors.initials: EF
authors.lastname: Navarro
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Peterson
authors.forename: Rasa
authors.initials: R
authors.lastname: Tamosiuniene
authors.forename: Mark R
authors.initials: MR
authors.lastname: Nicolls
authors.forename: Barry C
authors.initials: BC
authors.lastname: Starcher
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
authors.forename: Richard D
authors.initials: RD
authors.lastname: Bland
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D004195:Disease Models, Animal; D053492:Elafin / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*; D051379:Mice; D038081:Organogenesis / Q000187:drug effects*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D012121:Respiration, Artificial; D012131:Respiratory Insufficiency / Q000201:enzymology / Q000503:physiopathology / Q000628:therapy*
chemical_list: D053492:Elafin; D011480:Protease Inhibitors; D010196:Pancreatic Elastase