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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. OBJECTIVES: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 50 μg LPS. 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, matrix metalloproteinase (MMP)-9, IL-1Ra, granulocyte-macrophage colony-stimulating factor (GM-CSF), and C-reactive protein. In vitro, BAL fluid from KGF-treated subjects inhibited pulmonary fibroblast proliferation, but increased alveolar epithelial proliferation. Active MMP-9 increased alveolar epithelial wound repair. Finally, BAL from the KGF-pretreated 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 surfactant protein D, a marker of type II alveolar epithelial cell proliferation in a human model of acute lung injury. Additionally, KGF increases alveolar concentrations of the antiinflammatory cytokine IL-1Ra, and mediators that drive epithelial repair (MMP-9) and enhance macrophage clearance of dead cells and bacteria (GM-CSF). Clinical trial registered with ISRCTN 98813895.

journal_name

Am J Respir Crit Care Med

journal_title

American journal of respiratory and critical care medicine

authors

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

doi

10.1164/rccm.201310-1892OC

subject

Has Abstract

pub_date

2014-06-15 00:00:00

pages

1520-9

issue

eissn

1073-449X

issn

1535-4970

journal_volume

189

pub_type

杂志文章,随机对照试验

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Keratinocyte growth factor promotes epithelial survival and resolution in a human model of lung injury.