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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

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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.

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Abbreviations

BPD:

Bronchopulmonary dysplasia

FLAP:

5-Lipoxygenase activating protein

LAR:

Mean perimeter/area ratios (1/μm)

LT:

Leukotriene

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Acknowledgment

This study was supported by the Medical School Grant Program of Merck Sharp & Dohme Corp. The authors thank Hye Sun Yang for her excellent technical assistance throughout the experiments.

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Authors and Affiliations

  1. Department of Pediatrics, Yonsei University College of Medicine, 250 Seongsanno (134 Sinchon-dong) Seodaemun-gu, Seoul, 120-752, Korea

    Min Soo Park, Ran Namgung & Chul Lee

  2. Department of Pediatrics and Institute of Allergy, Severance Medical Research Institute, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, 120-752, Korea

    Myung Hyun Sohn & Kyu-Earn Kim

  3. Department of Pediatrics, Ajou University School of Medicine, Suwon, Gyeonggi-do, 443-749, Korea

    Moon Sung Park

  4. Department of Clinical Pharmacology, Severance Hospital, Yonsei University Health System, 250 Seongsanno (134 Sinchon-dong) Seodaemun-gu, Seoul, 120-752, Korea

    Min Soo Park

Authors
  1. Min Soo Park
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  2. Myung Hyun Sohn
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  3. Kyu-Earn Kim
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  4. Moon Sung Park
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  5. Ran Namgung
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  6. Chul Lee
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Correspondence to Min Soo Park.

Additional information

M. S. Park and M. H. Sohn contributed equally to this work.

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Park, M.S., Sohn, M.H., Kim, KE. et al. 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 189, 43–50 (2011). https://doi.org/10.1007/s00408-010-9264-1

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  • DOI: https://doi.org/10.1007/s00408-010-9264-1

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