All ETDs from UAB

Advisory Committee Chair

Jaroslaw W Zmijewski

Advisory Committee Members

Kevin S Harrod

A Brent Carter

Jean-Francois Pittet

Victor J Thannickal

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Sepsis is the most frequent cause of death of hospitalized patients in modern ICUs. Severe infection, trauma, hemorrhage, burns, and surgery are significant causes of multi-organ injury and immune dysfunction that in turn primes for a high risk of secondary lung infections. In addition to detrimental inflammation, sepsis is linked to loss of metabolic plasticity due to mitochondrial dysfunction in immune cells and lung tissue. In particular, mitochondrial failure in lungs of critically ill septic patients is correlated with high mortality rates. We proposed that AMP-activated protein kinase (AMPK) activation, a major bioenergetic sensor and metabolic regulator, is a plausible target to diminish exaggerated immune pro-inflammatory activation, and also promote recovery of bioenergetic homeostasis, thus reducing severity of sepsis and acute lung injury (ALI). This possibility was explored in three subsequent studies that address (1) the effects of D1dopaminergic signaling on AMPK activity and endotoxin-induced ALI; (2) mechanistic insights into AMPK inactivation in sepsis and ALI, and use of new therapeutic interventions to recover AMPK activity; and (3) the impact of AMPK-autophagy signaling on immune cell regulation during ALI and microbial clearance. Our first studies revealed that the dopamine-D1R axis is linked to AMPK activation which resulted in reduced severity of ALI. We found in our second set of studies that severe sepsis caused phosphorylation and inhibition of AMPK by IKKβ and GSK3β. Notably, inhibition of GSK3β decreased inhibitory T479-AMPKα phosphorylation while T172-AMPKα activatory phosphorylation was increased. This event was associated with preservation of mitochondrial ETC components, improved bacterial clearance, and diminished sepsis related lung injury. In our third set of studies, we found that the autophagy-related protein Parkin is diminished in LPS treated immune cells and lungs of mice subjected to endotoxin-induced ALI. Importantly, AMPK activation was able to activate autophagy through a beclin-1 associated pathway, even in Parkin deficient mice. This resulted in diminished severity of ALI. Taken together, these studies provide substantial progress in understanding AMPK-bioenergetic maintenance of cellular homeostasis. Besides mechanistic insights, our studies indicate that AMPK activators may possibly be applied as therapies for sepsis and ARDS.

Share

COinS