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Prostaglandin E2 is activated by airway injury and regulates fibroblast cytoskeletal dynamics

Authors

  • Vlad C. Sandulache MD, PhD,

    1. Division of Pediatric Otolaryngology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
    2. Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.
    3. McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
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    • The first two authors contributed equally to this article.

  • Tripti Singh MD,

    1. Division of Pediatric Otolaryngology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
    2. Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.
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    • The first two authors contributed equally to this article.

  • Ha Sheng Li-Korotky MD, PhD,

    1. Division of Pediatric Otolaryngology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
    2. Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.
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  • Chia Y. Lo MS,

    1. Division of Pediatric Otolaryngology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
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  • Todd D. Otteson MD,

    1. Division of Pediatric Otolaryngology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
    2. Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.
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  • Mark Barsic BS,

    1. Division of Pediatric Otolaryngology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
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  • Joseph E. Dohar MD, MS,

    1. Division of Pediatric Otolaryngology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
    2. Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.
    3. McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
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  • Patricia A. Hebda PhD

    Corresponding author
    1. Division of Pediatric Otolaryngology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
    2. Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.
    3. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.
    4. McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
    • Department of Pediatric Otolaryngology/Rangos Research Center, Children's Hospital of Pittsburgh, 530 45th Street, Pittsburgh, PA 15201
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  • The authors have no financial or other conflict of interest regarding the content of this paper.

Abstract

Objectives/Hypothesis:

To characterize the activation of cyclooxygenase (COX)-2/prostaglandin (PG) E2 signaling during airway mucosal repair and its subsequent role during the wound healing process.

Study Design:

Prospective animal study.

Methods:

The subglottis was approached via cricothyroidotomy. Sham airways were closed, and wounded airways were subjected to laser injury and closed. Subglottic tissue was harvested at 12 hours, 24 hours, 48 hours, and 72 hours postinjury. Secretions were collected preoperatively and at time of sacrifice. Inflammatory gene expression was analyzed using quantitative reverse transcriptase polymerase chain reaction. Subglottic/tracheal explants were exposed to exogenous IL-1β in the presence or absence of COX inhibitors. Explant-produced PGE2 levels were assayed using enzyme linked immunoassays. Human airway fibroblast migration and collagen contraction were assayed in the presence or absence of prostaglandin E2.

Results:

Laser injury triggers a rapid, dose-dependent increase in mucosal IL-1β and COX-2 gene expression, with an anatomical distribution proportional to the distance from the site of injury. Gene upregulation correlates with dose-dependent increases in PGE2 mucosal secretion levels. Ex vivo analysis indicates IL-1β is responsible for the activation of the COX-2 / PGE2 pathway. Prostaglandin E2 differentially inhibits airway fibroblast migration and contraction in a specific, dose-dependent manner.

Conclusions:

PGE2 is activated during mucosal inflammation and acts to decrease fibroplastic activity in the mucosal wound bed. During subglottic stenosis (SGS) development, the levels of PGE2 generated in response to injury may be insufficient to blunt the intrinsically fibroplastic phenotype of SGS fibroblasts, resulting in excessive scarring. Laryngoscope, 2009

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