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

Am J Respir Crit Care Med. 2014 Jun 15;189(12):1520-9. doi: 10.1164/rccm.201310-1892OC.

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.

Keywords: acute lung injury; acute respiratory distress syndrome; clinical trial; keratinocyte growth factor; lipopolysaccharide.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / drug therapy*
  • Acute Lung Injury / metabolism
  • Acute Lung Injury / prevention & control
  • Administration, Intravenous
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers / metabolism
  • Bronchoalveolar Lavage
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Administration Schedule
  • Epithelial Cells / drug effects*
  • Epithelial Cells / physiology
  • Female
  • Fibroblast Growth Factor 7 / pharmacology
  • Fibroblast Growth Factor 7 / therapeutic use*
  • Fibroblasts / drug effects
  • Fibroblasts / physiology
  • Humans
  • Lipopolysaccharides
  • Male
  • Middle Aged
  • Models, Biological*
  • Protective Agents / pharmacology
  • Protective Agents / therapeutic use*
  • Pulmonary Alveoli / drug effects*
  • Pulmonary Alveoli / physiology
  • Respiratory Distress Syndrome, Adult / drug therapy*
  • Respiratory Distress Syndrome, Adult / metabolism
  • Respiratory Distress Syndrome, Adult / prevention & control
  • Wound Healing / drug effects
  • Young Adult

Substances

  • Biomarkers
  • Lipopolysaccharides
  • Protective Agents
  • Fibroblast Growth Factor 7

Associated data

  • ISRCTN/ISRCTN98813895