The adult respiratory distress syndrome (ARDS) remains a significant cause of morbidity and mortality. Fibroproliferation is a key step in the evolution of ARDS. If excessive, it results in progressive replacement of functional lung units with fibrous tissue. Advanced fibrosis has been linked to a fatal outcome. The driving force behind this fibrosis is unclear. However, TGF-beta1 (transforming growth factor) has been implicated in chronic lung fibrosis. We hypothesize that TGF-beta1 may also play a significant role in ARDS. Thus the first specific aim of this study will be: 1) to determine whether ARDS bronchoalveolar lavage (BAL) fluid has elevated TGF-beta1 activity in comparison to normal controls, to determine clinical predictors of TGF-beta1 levels and correlate TGF-beta1 levels with procollagen III peptide levels. Fibrosis does not progress in isolation however. Damage to the lung epithelial cells is an early event. Research suggests that apoptosis of epithelial cells is a critical early event in ARDS. This may in part be mediated by TGF-beta1. However questions remain. What factors mediate epithelial cell apoptosis? How long does the apoptotic stimulus last? Can it be inhibited by specific interventions such as growth factors? Thus the second aim of the study will be: 2) to determine if ARDS BAL fluid contains apoptotic activity that is sustained over time and to assess whether the apoptotic activity can he prevented by apoptotic inhibitors or specific growth factors. The long-term goal of this proposal is to develop a translational research center specializing in acute lung injury at The Heart & Lung Research Institute, using the latest developments in basic sciences. It is expected that with a better understanding of the pathogenesis of ARDS novel therapies will be developed.
| Julian, Mark W; Bao, Shengying; Knoell, Daren L et al. (2011) Intestinal epithelium is more susceptible to cytopathic injury and altered permeability than the lung epithelium in the context of acute sepsis. Int J Exp Pathol 92:366-76 |
| Fahy, Ruairi J; Exline, Matthew C; Gavrilin, Mikhail A et al. (2008) Inflammasome mRNA expression in human monocytes during early septic shock. Am J Respir Crit Care Med 177:983-8 |
| Fahy, Ruairi J; Lichtenberger, Frank; McKeegan, Christine B et al. (2003) The acute respiratory distress syndrome: a role for transforming growth factor-beta 1. Am J Respir Cell Mol Biol 28:499-503 |
