Mechanisms of alveolar epithelial repair in acute lung injury--a translational approach

Abstract

In patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), extensive damage to the alveolar epithelial and endothelial barrier is observed, resulting in the influx of protein-rich oedema fluid into the air spaces. Efficient alveolar epithelial repair is crucial to ALI/ARDS patients' recovery. Future therapeutic strategies may therefore include acceleration of the epithelial repair process in the injured lung. However, a better understanding of the cellular and molecular mechanisms that promote alveolar epithelial repair is needed if novel therapeutic strategies are to be developed. Pulmonary oedema fluid from patients with ALI/ARDS and from patients with hydrostatic oedema as control was obtained, and the effect on alveolar epithelial repair in vitro using our alveolar epithelial wound repair bioassay was studied. In contrast to the initial hypothesis, pulmonary oedema fluid from ALI/ARDS patients increased alveolar epithelial repair in vitro by an interleukin-1beta (IL-1beta)-dependent mechanism, demonstrating a novel, possibly beneficial role for IL-1beta in patients with ALI/ARDS. Further studies using primary alveolar epithelial cells from rats revealed that IL-1beta induced alveolar epithelial repair by an epidermal growth factor (EGF)/transforming growth factor-alpha (TGF-alpha)-dependent pathway. Besides EGF and TGF-alpha, keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF)--both present in pulmonary oedema fluid obtained from patients with ALI/ARDS--stimulate alveolar epithelial repair in vitro. Further experimental and clinical studies will show whether acceleration of alveolar epithelial repair by modulating cytokines and growth factors in the injured lung represents a promising new therapeutic strategy in patients with ALI/ARDS.