Year: 2022
Type: article
Abstract: Acute lung injury (ALI) is a severe form of lung inflammation causing acute respiratory distress syndrome in patients. ALI pathogenesis is closely linked to uncontrolled alveolar inflammation. We hypothesize that specific enzymes of the glycolytic pathway could function as key regulators of alveolar inflammation. Therefore, we screened isolated alveolar epithelia from mice exposed to ALI induced by injurious ventilation to assess their metabolic responses. These studies pointed us toward a selective role for isoform 3 of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3). Pharmacologic inhibition or genetic deletion of Pfkfb3 in alveolar epithelia (Pfkfb3loxP/loxP SPC-ER-Cre+ mice) was associated with profound increases in ALI during injurious mechanical ventilation or acid instillation. Studies in genetic models linked Pfkfb3 expression and function to Hif1a. Not only did intratracheal pyruvate instillation reconstitute Pfkfb3loxP/loxP or Hif1aloxP/loxP SPC-ER-Cre+ mice, but pyruvate was also effective in ALI treatment of wild-type mice. Finally, proof-of-principle studies in human lung biopsies demonstrated increased PFKFB3 staining in injured lungs and colocalized PFKFB3 to alveolar epithelia. These studies reveal a specific role for PFKFB3 in counterbalancing alveolar inflammation and lay the groundwork for novel metabolic therapeutic approaches during ALI.
Source: JCI Insight
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,100
Funders: U.S. Department of Defense, Francis Family Foundation, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Alveolar epithelial carbohydrate metabolism in acute lung injury, SOD3 regulation of redox sensitive signaling in pulmonary vascular diseases, Targeting MicroRNA miR-122 for the Treatment of Perioperative Liver Injury, Training in Basic and Translational Child Health Research, microRNA miR-147 Dampens Alveolar Epithelial Inflammation During ARDS, MicroRNA Shuttling during Acute Respiratory Distress Syndrome, COVID-19 A RANDOMIZED PHASE 2 CLINICAL TRIAL OF HIF ACTIVATOR VADADUSTAT FOR PREVENTION OR TREATMENT OF ARDS IN HOSPITALIZED COVID-19 PATIENTS, Complement Mediated Remodeling in Pulmonary Vascular Disease, Hypoxia-Inducible Factors in Acetaminophen-Induced Liver Injury, Research Training of Anesthesiology Physician-Scientists
OpenAlex ID: W4308053562