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Keratinocyte Growth-Factor Promotes Epithelial Survival and Resolution in a Human Model of Lung Injury

Shyamsundar, M, McAuley, DF, Ingram, RJ, Gibson, David, O'Kane, D, McKeown, ST, Edwards, A, Taggart, C, Elborn, JS, Calfee, CS, Matthay, MA and O'Kane, CM (2014) Keratinocyte Growth-Factor Promotes Epithelial Survival and Resolution in a Human Model of Lung Injury. American Journal of Respiratory and Critical Care Medicine, 189 (12). pp. 1520-1529. [Journal article]

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URL: http://www.ncbi.nlm.nih.gov/pubmed/24716610

Abstract

Rationale Increasing epithelial repair and regeneration may hasten resolution of lung injury in patients with the Acute Respiratory Distress Syndrome (ARDS). In animal models of ARDS, Keratinocyte Growth Factor (KGF) reduces injury and increases epithelial proliferation and repair. The effect of KGF in the human alveolus is unknown. Objective To test whether KGF can attenuate alveolar injury in a human model of ARDS. Methods Volunteers were randomized to intravenous KGF (60 μg/kg) or placebo for 3 days, before inhaling 50μg lipopolysaccharide. Six hours later, subjects underwent bronchoalveolar lavage (BAL) to quantify markers of alveolar inflammation and cell-specific injury. Measurements and Main Results KGF did not alter leukocyte infiltration or markers of permeability in response to LPS. KGF increased BAL concentrations of Surfactant Protein D (SP-D), MMP-9, IL-1Ra, GM-CSF and CRP. In vitro, BAL fluid from KGF-treated subjects (KGF BAL) inhibited pulmonary fibroblast proliferation, but increased alveolar epithelial proliferation. Active MMP-9 increased alveolar epithelial wound repair. Finally, BAL from the KGF pre-treated group enhanced macrophage phagocytic uptake of apoptotic epithelial cells and bacteria compared with BAL from the placebo-treated group. This effect was blocked by inhibiting activation of the GM-CSF receptor. Conclusions KGF treatment increases BAL SP-D, a marker of type II alveolar epithelial cell proliferation in a human model of ALI. Additionally KGF increases alveolar concentrations of the anti-inflammatory cytokine IL-1Ra, and mediators that drive epithelial repair (MMP-9) and enhance macrophage clearance of dead cells and bacteria (GM-CSF).

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Stratified Medicine
ID Code:29483
Deposited By: Dr David Gibson
Deposited On:05 Sep 2014 11:09
Last Modified:08 Feb 2016 11:19

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