Impairment of Fatty Acid Oxidation in Alveolar Epithelial Cells Mediates Acute Lung Injury

Abstract

Profound impairment in cellular oxygen consumption, named cytopathic dysoxia, is one of the pathological hallmarks in the lungs of patients with pathogen-induced acute lung injury (ALI). However, the underlying mechanism for this functional defect remains largely unexplored. In this study, we found that primary mouse alveolar epithelial cells (AECs) conducted robust fatty acid oxidation (FAO). More importantly, FAO was strikingly impaired in AECs of mice with lipopolysaccharide (LPS) induced ALI. The metabolic deficiency in these cells was likely due to decreased expression of key mediators involved in FAO and mitochondrial bioenergenesis, such as PGC-1α, CPT1A and MCAD. We found that treatment of alveolar epithelial line MLE-12 cells with bronchoalveolar lavage fluids (BALFs) from mice with ALI decreased FAO and this effect was largely replicated in MLE-12 cells treated with pro-inflammatory cytokine TNF-α, which was consistent with downregulations of PGC-1α, CPT1A, LCAD and MCAD in the same treated cells. Furthermore, we found that the BALFs from ALI mice and TNF-α inhibited MLE-12 bioenergenesis and promoted cell apoptosis. In delineation of the role of FAO in ALI in vivo, we found that conditional ablation of AEC PGC-1α aggravated LPS induced ALI. In contrast, fenofibrate, an activator of the PPAR-α/ PGC-1α cascade, protected mice from this pathology. In summary, these data suggest that FAO is essential to AEC bioenergenesis and functional homeostasis. This study also indicates that FAO impairment induced AEC dysfunction is an important contributing factor to the pathogenesis of ALI.

The Peroxisome Proliferator-Activated Receptor α- Agonist Gemfibrozil Promotes Defense Against Mycobacterium abscessus Infections

“…Similar to the findings of previous studies of M. tuberculosis and M. bovis BCG [20], we found that PPARα deficiency increased the levels of proinflammatory cytokines and chemokines in the lung and macrophages during Mabc infection. These findings are in partial agreement with a recent report of a protective role of PPARα activation against lipopolysaccharide-induced acute lung injury in mice [11].…”

“…Due to its regulation of macrophage-mediated inflammation, PPARα is a promising target for various human pathologies, particularly cardiovascular and metabolic diseases [9,10]. In addition, PPARα expression is involved in protective role against numerous disease models including acute lung injury [11], sepsis-associated acute kidney injury [12], non-alcoholic steatohepatitis [13], etc. Indeed, PPARα as well as PPARγ play crucial roles in the modulation of host defenses against a variety of microbial infections [14][15][16][17] .…”

A metabolic handbook for the COVID-19 pandemic

“…In a mouse model of acute pulmonary endotoxemia-induced damage, alveolar epithelial cells show decreased expression of genes involved in mitochondrial biogenesis and fatty acid oxidation, including Ppargc1a and Cpt1a, as well as impaired fatty acid oxidation. The deletion of Ppargc1a, the gene encoding PGC-1A, from alveolar epithelial cells renders mice more susceptible to pulmonary damage caused by intranasal treatment with LPS, an effect associated with increased caspase-3 cleavage in epithelial cells, thus suggesting that the absence of fatty acid oxidation in the alveolar epithelial cells is necessary for the survival of these cells in response to acute lung injury 81 . PGC-1A cooperates with PPARα in the transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes, thereby inducing fatty acid oxidation 82 .…”

“…PGC-1A cooperates with PPARα in the transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes, thereby inducing fatty acid oxidation 82 . The treatment of mice with a PPARα agonist is sufficient to protect against LPS-induced lung injury; consequently, PGC-1A may promote disease tolerance in response to acute lung injury by promoting fatty acid oxidation in alveolar epithelial cells and consequently protect against cell death 81 . Therefore, promoting fatty acid oxidation in alveolar epithelial cells may be useful for increasing survival in patients with COVID-19 by maintaining the epithelial barrier.…”

<p>Mitochondria-Modulating Porous Se@SiO₂ Nanoparticles Provide Resistance to Oxidative Injury in Airway Epithelial Cells: Implications for Acute Lung Injury</p>

“…Bundles of studies observed mitochondrial dysfunction of airway epithelial cells (AECs) in ALI/ARDS. 5,9,10 Moreover, rescuing AECs from mitochondrial dysfunction through mitochondria transferring relieved LPS-induced ALI. 11 A more recent report also affirmed that compensation for mitochondrial impairment by enhancing cellular glycolytic activity could protect airway epithelium from acute injury.…”