This is a revised application to study the regulation and the role of mitochondrial biogenesis and mitophagy in experimental sepsis and acute lung injury (ALI) caused by S. aureus. It is relevant to ICU patients who survive an initial episode of severe sepsis and ARDS/multiple organ dysfunction syndrome (MODS), but die with so- called "immune paralysis" characterized by effector cell apoptosis, anti-inflammatory cytokine over-expression, suppression of pro-inflammatory cytokine synthesis and recurrent infections. One important pro-resolution mechanism discovered by our group is the powerful control over innate immunity by the redox-regulated bi- genomic transcriptional network of mitochondrial biogenesis, which is strongly activated by the induction of the heme oxygenase-1/carbon monoxide system (HO-1/CO) to protect energy metabolism and mitochondrial mass, but which we think may also promote the clearance of damaged organelles (mitophagy) and limit further inflammatory damage in MODS. Published and preliminary data raise the novel possibility that the transcriptional program for mitochondrial biogenesis integrates mitophagy, counter-inflammation, and anti- oxidant defenses into a coherent injury resolution network in alveolar epithelium, the major site of lung damage in ALI. We propose that the program of mitochondrial biogenesis mediates lung protection through HO-1/CO activation of Nfe2l2 and NRF-1 leading to 1) anti-inflammatory Socs3 and IL10 gene expression, 2) suppression of inflammasome-mediated IL-1? production, and 3) activation of mitophagy through Bnip3 and Atg5, promoting alveolar epithelial cell survival and resolution of barrier dysfunction. Using live S. aureus sepsi and pneumonia in mice and complementary lung cell studies, we will investigate how this integrated genetic network of mitochondrial biogenesis impacts on lung inflammation and ALI resolution. Proof-of-concept would mean the lung in sepsis/pneumonia has counter-regulatory safeguards involving the induction of mitochondrial biogenesis to prevent further mitochondrial damage from the systemic inflammatory response and clear damaged mitochondria to restore mitochondrial health and capacity for alveolar epithelial repair, e.g. though the type 2 (AT2) cell We propose translational studies to test the concept in diffuse alveolar damage (DAD) in human lung, which if successful, would open up therapeutic avenues for the improvement of mitochondrial function and the resolution of ALI/ARDS.
Our Specific Aims are:
Aim 1 : Determine whether Nfe2l2 and NRF1 induction of lung mitochondrial biogenesis in murine S. aureus sepsis and pneumonia up-regulates Socs3 and Il10 anti-inflammatory gene expression, suppresses caspase1 cleavage and IL-1? production and mitigates lung inflammation and ALI.
Aim 2 : Use gain and loss of function studies to determine whether Nfe2l2 and NRF1 induction of lung of mitochondrial biogenesis a) regulates the autophagy genes Bnip3 and Atg5 and b) activates pro- survival mitophagy through HO-1/CO-related mitochondrial ROS generation in murine S. aureus pneumonia.
Aim 3 : Assess the extent, location, and relationship of mitochondrial biogenesis to mitophagy in the alveolar epithelium of human ALI/ARDS patients compared with healthy human lung. Completion of these Aims would link transcriptional regulation of mitochondrial biogenesis to mitophagy and to immune counter-regulation, anti-oxidant defenses, and cell survival. Positive predictive studies in human ALI/ARDS would have a high impact on our understanding of the resolution of sepsis and MODS.
|Schumacker, Paul T; Gillespie, Mark N; Nakahira, Kiichi et al. (2014) Mitochondria in lung biology and pathology: more than just a powerhouse. Am J Physiol Lung Cell Mol Physiol 306:L962-74|
|Cherry, Anne D; Suliman, Hagir B; Bartz, Raquel R et al. (2014) Peroxisome proliferator-activated receptor ? co-activator 1-? as a critical co-activator of the murine hepatic oxidative stress response and mitochondrial biogenesis in Staphylococcus aureus sepsis. J Biol Chem 289:41-52|
|Suliman, Hagir B; Piantadosi, Claude A (2014) Mitochondrial biogenesis: regulation by endogenous gases during inflammation and organ stress. Curr Pharm Des 20:5653-62|