Novel therapeutic strategies for acute lung injury induced by lung damaging agents: The potential role of growth factors as treatment options

Abstract

The increasing threat from terrorism has brought attention to the possible use of toxic industrial compounds (TICs) and other lung-damaging agents as weapons against civilian populations. The way in which these agents could be used favours the development of generic countermeasures. Improved medical countermeasures would increase survivability and improve the quality of recovery of lung damaged casualties. It is evident that there is a dearth of therapeutic regimes available to treat those forms of lung damage that currently require intensive care management. It is quite possible that mass casualties from a terrorist incident or major industrial accident involving the release of large quantities of inhaled TICs would place a severe burden on already scarce intensive care facilities. The development of effective pharmacological approaches to assist the recovery of casualties suffering from acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) may improve the prognosis of such patients (which is currently poor) and would ideally be used as a means of preventing subjects from developing the pulmonary oedema characteristic of ALI/ARDS. Many promising candidate pharmacological treatments have been evaluated for the treatment of ALI/ARDS, but their clinical value is often debatable. Thus, despite improvements in ventilation strategies, pharmacological intervention for ALI/ARDS remains problematical. A new approach is clearly required for the treatment of patients with severely compromised lungs. Whilst the pathology of ALI/ARDS associated with exposure to a variety of agents is complex, numerous experimental studies suggest that generic therapeutic intervention directed at approaches that aim to upregulate repair of the damaged alveolar blood/air barrier of the lung may be of value, particularly with respect to chemical-induced injury. To this end, keratinocyte growth factor (KGF), epithelial growth factor (EGF) and basic fibroblast growth factor (bFGF) are emerging as the most important candidates. Hepatocyte growth factor (HGF) does not have epithelial specificity for lung tissue. However, the enhanced effects of combinations of growth factors, such as the synergistic effect of HGF upon vascular endothelial growth factor (VEGF)-mediated endothelial cell activity, and the combined effect of HGF and KGF in tissue repair should be investigated, particularly as the latter pair of growth factors are frequently implicated in processes associated with the repair of lung damage. Synergistic interactions also occur between trefoil factor family (TFF) peptides and growth factors such as EGF. TFF peptides are most likely to be of value as a short term therapeutic intervention strategy in stimulating epithelial spreading activities which allow damaged mucosal surfaces to be rapidly covered by epithelial cells.