5-Lipoxygenase-activating protein (FLAP) inhibitor MK-0591 prevents aberrant alveolarization in newborn mice exposed to 85% oxygen in a dose- and time-dependent manner

Lung. 2011 Feb;189(1):43-50. doi: 10.1007/s00408-010-9264-1. Epub 2010 Nov 5.

Abstract

Bronchopulmonary dysplasia is characterized by prolonged oxygen dependency due to compromised gas-exchange capability. This is attributable mainly to inadequate and aberrant alveolarization resulting from insults like hyperoxia. Leukotrienes are associated with hyperoxia-induced inhibition of alveolarization. We hypothesized that a 5-lipoxygenase-activating protein (FLAP) inhibitor given while newborn mice were exposed to 85% oxygen would prevent aberrant alveolarization in a dose- and time-dependent manner. Newborn mice were exposed to either room air or hyperoxia for 14 days. Pups were treated with either vehicle or MK-0591 10, 20, or 40 mg/kg subcutaneously daily for days 1-4, 5-9, or 10-14. On day 14, the lungs were inflated, fixed, and stained for histopathological and morphometric analyses. Hyperoxia groups treated with MK-0591 20 or 40 mg/kg during days P1-P4 or P10-P14 showed alveolarization that resembled that of room air controls while untreated hyperoxia groups showed definite evidence of aberrant alveolarization but no inflammation. In a hyperoxia-exposed newborn mice model, a FLAP inhibitor given during critical window periods may prevent aberration of alveolarization in a dose- and time-dependent manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Lipoxygenase-Activating Protein Inhibitors / administration & dosage
  • 5-Lipoxygenase-Activating Protein Inhibitors / pharmacology*
  • 5-Lipoxygenase-Activating Proteins / metabolism*
  • Animals
  • Animals, Newborn
  • Body Weight
  • Bronchopulmonary Dysplasia / enzymology
  • Bronchopulmonary Dysplasia / etiology
  • Bronchopulmonary Dysplasia / pathology
  • Bronchopulmonary Dysplasia / physiopathology
  • Bronchopulmonary Dysplasia / prevention & control*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Humans
  • Hyperoxia / chemically induced
  • Hyperoxia / drug therapy*
  • Hyperoxia / enzymology
  • Hyperoxia / pathology
  • Hyperoxia / physiopathology
  • Indoles / administration & dosage
  • Indoles / pharmacology*
  • Infant, Newborn
  • Injections, Subcutaneous
  • Mice
  • Oxygen
  • Pulmonary Alveoli / drug effects*
  • Pulmonary Alveoli / enzymology
  • Pulmonary Alveoli / growth & development
  • Pulmonary Alveoli / pathology
  • Quinolines / administration & dosage
  • Quinolines / pharmacology*
  • Time Factors

Substances

  • 5-Lipoxygenase-Activating Protein Inhibitors
  • 5-Lipoxygenase-Activating Proteins
  • Alox5ap protein, mouse
  • Indoles
  • Quinolines
  • MK 0591
  • Oxygen