Advisory Committee Chair
Jaroslaw W Zmijewski
Advisory Committee Members
Victor J Thannickal
Martin E Young
Olaf Kutsch
Jessy S Deshane
Edward Swords
Document Type
Thesis
Date of Award
2023
Degree Name by School
Master of Science (MS) School of Health Professions
Abstract
Lung injury and lung repair are two sides of the same coin, for where injury occurs, repair must follow. Lung fibrosis occurs when this repair process is dysfunctional and becomes trapped in a chronically incomplete state. The studies described here examine each side of this coin to ask the question of whether metabolism has a role in the pathophysiology of acute lung damage following severe trauma or in the chronic progression of idiopathic pulmonary fibrosis (IPF). In the first half of this work, we investigated the impact that severe lung injury and infection exert on the flux of metabolites in blood plasma. Patients who survive severe trauma and acute respiratory distress syndrome (ARDS) are known to enter a prolonged state of elevated susceptibility to secondary bacterial infections, significantly impairing their survival in the 3-5 years after trauma recovery. What has not been previously established is the role metabolism plays in this persistent change in immune competency. In addition, this study examines changes in immune cell (monocyte) bioenergetic capacity and glycolytic plasticity. We discovered, using mass spectrometry to quantify plasma metabolites, that there are distinct alterations in the global metabolic profile and monocyte bioenergetic capactity in trauma patients versus healthy controls, as well as a distinct metabolic profile in a sub-set of trauma patients who contracted secondary bacterial infections. These findings lay the groundwork for improving diagnosis of this vulnerable population and developing therapies to restore immune function after trauma recovery. In the second half of this work, we focused on the regulation of apoptotic susceptibility of pathogenic lung myofibroblasts in the context of idiopathic pulmonary fibrosis (IPF). IPF is an interstitial lung disease that occurs during chronically dysfunctional repair of lung damage, characterized by the progressive build-up of extracellular matrix (ECM), which inevitably impedes gas exchange and impairs survival. It is well established that this process is driven by a population of pathogenically activated myofibroblasts which perpetually secrete ECM and develop resistance to apoptotic (self-destruct) stimuli. What is previously unknown are the mechanistic causes by which myofibroblasts gain this apoptosis resistant phenotype in IPF patients and not in others. We found that a major metabolic enzyme, ATP citrate lyase (ACLY), is deficient in IPF myofibroblasts and plays a determining role in myofibroblast differentiation and apoptotic susceptibility. Furthermore, this apoptotic regulation functions through the AMPK signaling axis and can be rescued through pharmacologic induction of AMPK activation. Therefore, this study establishes ACLY as a potential target for reversing apoptosis resistance in IPF myofibroblasts and improving fibrosis resolution in the lung. Taken together, these studies indicate a key role for metabolism and metabolic regulatory enzymes in the pathophysiological processes involved in response to lung injury, susceptibility to post-traumatic infection and resolution of persistent lung fibrosis.
Recommended Citation
Smith, Samuel Robert, "Pathophysiological Metabolic Alteration in Lung Injury and Fibrosis" (2023). All ETDs from UAB. 3528.
https://digitalcommons.library.uab.edu/etd-collection/3528