Pulmonary fibrosis is a debilitating lung disease which affects over five million people worldwide and is responsible for over 40,000 deaths per year. No cure yet exists for this disease, and current therapies are of limited efficacy and are primarily symptomatic treatments. New therapeutic strategies aimed at halting progression of this disease are therefore needed. Excessive injury to, and insufficient repair of, the lung airway epithelium leads to an overactivation of lung fibroblasts and an overproduction of collagen characteristic of fibrosis. Activation of the death receptor, Fas, in epithelial cells induces cell death through recruitment and activation of caspases 8 and 3, and inhibition or neutralization of Fas or Fas ligand attenuates the effects of bleomycin in a mouse model of fibrosis. Our group has previously demonstrated that apoptosis occurs following S-glutathionylation of Fas at cysteine 294 in mouse lung epithelial cells. S-glutathionylation, the reversible conjugation of glutathione to reactive cysteine residues, is catalyzed in part by the enzyme glutathione S-transferase pi 1 (GSTP1). GSTP1 expression has been linked to both asthma and lung cancer, but to date, little is known about the role of GSTP1 in the development of pulmonary fibrosis. Based on these observations, I hypothesize that GSTP1 is a critical mediator of Fas S-glutathionylation-mediated apoptosis in airway epithelial cells and subsequent fibrotic remodeling in the lung. I hypothesize that decreased GSTP1 expression or activity will ablate progression of fibrosis by preventing Fas S-glutathionylation and apoptosis of lung airway epithelial cells. Likewise, increased GSTP1 expression in airway epithelial cells would increase susceptibility of the lung to a profibrotic phenotype. To study this, I have created two specific aims. First, I will determine the effects of GSTP1 inhibition and knockout on airway lung epithelial cell apoptosis and the progression of lung fibrosis. Secondly, I will determine the effects of GSTP1 overexpression on lung epithelial cell apoptosis and the progression of lung fibrosis. I will also inhibit GSTP1 concurrent with its overexpression to confirm that administration of a GSTP1-specific inhibitor will decrease the profibrotic effects of GSTP1 overexpression. Completion of this proposal will provide crucial new insight into the manifestation of pulmonary fibrosis, and possibly the development of new therapeutic strategies for this deadly disease.
Pulmonary fibrosis, a devastating disease characterized by the development of excess fibrous tissue in the lung, affects over five million people worldwide and is responsible for over 40,000 deaths each year. No cure yet exists, and current therapies are limited to primarily symptomatic treatments, so new therapeutic strategies are needed. Further insight into the mechanisms involved in Fas S-glutathionylation and airway epithelial cell apoptosis in settings of fibrosis may lead to new, more efficacious strategies for the treatment of fibroproliferative diseases of the lung.
| McMillan, David H; van der Velden, Jos L J; Lahue, Karolyn G et al. (2016) Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase ?. JCI Insight 1: |
