Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) secondary to sepsis (indirect ALI) is a devastating condition that results in a significant morbidity and mortality. Pneumonia and aspiration of gastric contents are the two major causes of direct acute lung injury (direct ALI) and it is estimated that 55% of ARDS is caused by direct lung injury. Although the pathophysiology of ALI is far from understood, exuberant production of pro-inflammatory cytokines and chemokines is known to play a central role. However, it remains unclear how these pro-inflammatory mediators are regulated. Tristetraprolin (TTP) is an mRNA binding protein that regulates mRNA levels by binding to adenylate-uridylate-rich elements (AREs) in the 3'-untranslated regions (3'UTRs) of specific mRNAs resulting in their rapid turnover. Deletion of TTP in mice results in systemic inflammation that is mediated by enhanced stability of TTP target mRNAs, such as Tnf. Along the same lines, myeloid-specific TTP deficiency results in extreme sensitivity to low dose endotoxin exposure resulting in the development of endotoxemia and organ damage. Therefore, we hypothesize that TTP mediated post-transcriptional regulation of pro-inflammatory gene expression modulates the pathogenesis of ALI; enhancing TTP levels protects from ALI; and that hematopoietic-cell TTP is necessary and sufficient for this effect. We will test our hypothesis through two specific aims:
In Aim 1, we will test the effect of loss of TTP (whole body and myeloid cell-lineage) on the pathogenesis of direct and indirect ALI.
In Aim 2, we will test whether enhanced expression of TTP protects against the development of ALI and whether hematopoietic cell lineage-specific TTP overexpression is necessary and sufficient for protection. The overall goal of the proposed research is to improve therapeutic options in ALI (direct and indirect) by providing rationale for drug development aimed at cell-specific stabilization/enhanced expression of TTP. Successful completion of these studies will advance our understanding of the role of TTP mediated post-transcriptional mechanisms of gene expression in regulating the pathogenesis of ALI. The knowledge gained will have potential applications towards the identification of TTP-regulated mRNAs as biomarkers of ALI and the development of therapeutic interventions to enhance TTP levels for the treatment of ALI.
