Keratinocyte growth factor as a novel treatment in an in vivo human endotoxaemic model of lung injury

In many severe illnesses, such as pneumonia or following a road traffic accident, people develop acute lung problems. For reasons that are unclear, their lungs fail and fill with water making breathing difficult and they require support in an intensive care unit. This is termed ?acute lung injury? (ALI). There is no effective treatment for ALI.
The reason the lung fails involves damage to the delicate lining of cells that allow oxygen to pass into the body. This lining is called the alveolar epithelium. A protein called keratinocyte growth factor (KGF) improves lung repair by increasing the number of lining cells and helping them move to damaged parts of the lung. Humans produce KGF, however, patients who have ALI do not have enough and repair is inadequate.
This study will investigate if additional KGF helps lung repair in an established clinical model of ALI.
If effective, results of this study will lead to a clinical trial of this novel therapy in the prevention and treatment of ALI. This project will also provide new information about mechanisms in the development of ALI which could lead to new therapeutic targets.

Acute lung injury (ALI) is a common devastating clinical syndrome. ALI occurs in response to a variety of insults, such as trauma and severe pneumonia, and mortality is approximately 50%. ALI is associated with neutrophil activation with the release of cytokines and proteases. The resulting inflammatory damage to the alveolar epithelial and capillary endothelial barrier is central to the severity of lung injury causing pulmonary oedema and acute respiratory failure with the need for mechanical ventilation.
Proliferation of alveolar type II epithelial cells is critical to the restoration of alveolar architecture and recovery from ALI. Keratinocyte growth factor (KGF) specifically promotes epithelial proliferation. In addition, KGF promotes epithelial migration, differentiation and re-epithelialisation of wounds. KGF also downregulates pro-inflammatory cytokines and enhances endothelial cell resistance to injury. In animal models of ALI, KGF reduces alveolar capillary permeability, pulmonary oedema and improves mortality. Despite the therapeutic potential no human studies have investigated the effect of exogenous KGF in ALI. Palifermin is recombinant human KGF, and has biological activity analogous to the native protein. Palifermin is safe and is used clinically for treatment of oral mucositis; associated with chemo- and/or radio- therapy. This study will investigate in vivo if palifermin modulates mechanisms important in alveolar epithelial injury and repair in a safe and validated model of lung injury induced by inhalation of low dose lipopolysaccharide (LPS) in healthy volunteers.
Hypothesis: Treatment with palifermin will decrease lung injury induced by LPS inhalation in humans.
The specific aims of this study are to assess the ability of KGF to attenuate lung injury by measuring
1) alveolar and plasma inflammatory response
2) alveolar epithelial and endothelial function
3) alveolar matrix metalloproteinase activity
4) intracellular signalling and transcription factor activation in the alveolar space
This will be a prospective, randomised, double blind, placebo controlled clinical trial.
Subjects will be randomised to palifermin 60microg/kg or placebo intravenously for 3 days prior to LPS inhalation. The dose and duration of pre-treatment was determined on the basis of experimental and clinical data, and is the normal therapeutic dose for treatment of oral mucositis.
These experiments will represent the first study of exogenous KGF in a human model of ALI and will provide new understanding of the mechanisms by which KGF modulates alveolar injury. If effective this study will inform subsequent clinical trials of KGF in ALI.