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

M Shyamsundar, DF McAuley, RJ Ingram, David Gibson, D O'Kane, ST McKeown, A Edwards, C Taggart, JS Elborn, CS Calfee, MA Matthay, CM O'Kane

Research output: Contribution to journalArticle

46 Citations (Scopus)

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).
LanguageEnglish
Pages1520-1529
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume189
Issue number12
DOIs
Publication statusPublished - 15 Jun 2014

Fingerprint

Fibroblast Growth Factor 7
Lung Injury
Bronchoalveolar Lavage
Survival
Adult Respiratory Distress Syndrome
Matrix Metalloproteinases
Pulmonary Surfactant-Associated Protein D
Interleukin 1 Receptor Antagonist Protein
Alveolar Epithelial Cells
Wounds and Injuries
Granulocyte-Macrophage Colony-Stimulating Factor
Granulocyte-Macrophage Colony-Stimulating Factor Receptors
Macrophages
Placebos
Bacteria
Bronchoalveolar Lavage Fluid
Inhalation
Lipopolysaccharides
Regeneration
Volunteers

Cite this

Shyamsundar, M ; McAuley, DF ; Ingram, RJ ; Gibson, David ; O'Kane, D ; McKeown, ST ; Edwards, A ; Taggart, C ; Elborn, JS ; Calfee, CS ; Matthay, MA ; O'Kane, CM. / Keratinocyte Growth-Factor Promotes Epithelial Survival and Resolution in a Human Model of Lung Injury. In: American Journal of Respiratory and Critical Care Medicine. 2014 ; Vol. 189, No. 12. pp. 1520-1529.
@article{64649e37e00d478da73f6b20bd1bd153,
title = "Keratinocyte Growth-Factor Promotes Epithelial Survival and Resolution in a Human Model of Lung Injury",
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).",
author = "M Shyamsundar and DF McAuley and RJ Ingram and David Gibson and D O'Kane and ST McKeown and A Edwards and C Taggart and JS Elborn and CS Calfee and MA Matthay and CM O'Kane",
year = "2014",
month = "6",
day = "15",
doi = "10.1164/rccm.201310-1892OC",
language = "English",
volume = "189",
pages = "1520--1529",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "12",

}

Shyamsundar, M, McAuley, DF, Ingram, RJ, Gibson, D, O'Kane, D, McKeown, ST, Edwards, A, Taggart, C, Elborn, JS, Calfee, CS, Matthay, MA & 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, vol. 189, no. 12, pp. 1520-1529. https://doi.org/10.1164/rccm.201310-1892OC

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; O'Kane, CM.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 189, No. 12, 15.06.2014, p. 1520-1529.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Keratinocyte Growth-Factor Promotes Epithelial Survival and Resolution in a Human Model of Lung Injury

AU - Shyamsundar, M

AU - McAuley, DF

AU - Ingram, RJ

AU - Gibson, David

AU - O'Kane, D

AU - McKeown, ST

AU - Edwards, A

AU - Taggart, C

AU - Elborn, JS

AU - Calfee, CS

AU - Matthay, MA

AU - O'Kane, CM

PY - 2014/6/15

Y1 - 2014/6/15

N2 - 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).

AB - 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).

U2 - 10.1164/rccm.201310-1892OC

DO - 10.1164/rccm.201310-1892OC

M3 - Article

VL - 189

SP - 1520

EP - 1529

JO - American Journal of Respiratory and Critical Care Medicine

T2 - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 12

ER -