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Principal Investigator: GR Scott Budinger
Organization: JESSE BROWN VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Project Summary/Abstract
Pulmonary fibrosis (PF) describes a group of disorders in which the alveolar space is progressively replaced by
fibrotic tissue which eventually leads to death from respiratory failure. Available therapies modestly slow disease
progression but are not curative, difficult to tolerate and most patients die unless they receive a lung transplant.
The prevalence of PF has tripled in the US Veterans Population between 2010 and 2019 and likely to continue
increasing in light of the COVID-19 pandemic. We were the first to show that some patients with severe COVID-
19 develop severe lung fibrosis that is indistinguishable from IPF even at the level of the single cell
transcriptome. These findings prompted us to perform the first of many lung transplants for patients with severe
COVID-19 in the US. Even more concerning, however, is the prevalence of respiratory symptoms in more than
30% of patients with post-acute sequelae of COVID-19 some of whom have PF. Thus, if even a small fraction
of the 66 million US survivors of COVID-19 to date develop fibrotic lung disease, the public health impact will be
enormous. Our laboratory has made important contributions to a model that hypothesizes that lung fibrosis
begins with damage to the alveolar epithelium which leads to the recruitment circulating monocytes to the
alveolar space where they differentiate into profibrotic alveolar macrophages to create a temporary seal over the
injured alveolar epithelium and in direct contact with alveolar fibroblasts. Trophic factors for fibroblasts are
released from alveolar macrophages and fibroblasts secrete G-CSF in response, which is necessary to sustain
alveolar macrophages and creates a profibrotic circuit that persists until the epithelial barrier is restored.
Metformin is an oral drug used for Type 2 diabetes that also ameliorates fibrosis in animal models but has not
been associated with improved outcomes in PF patients. Our preliminary data suggest these disparate findings
might reflect the pharmacokinetics of the drug—high levels of drug in the lung are only achieved with
intraperitoneal but not gut administration. Thus, while metformin may not be useful as a therapy for lung fibrosis,
small molecules that mimic its mechanism of action might be. However, this requires a mechanistic
understanding of metformin’s efficacy in lung fibrosis which is currently lacking. Metformin is concentrated in
mitochondria where it functions to inhibit Complex I of the mitochondrial electron transport chain. We have
identified a yeast protein, NDI1, that restores mitochondrial electron transport in the absence of complex I activity
and is insensitive to metformin. Using this construct, we have shown that many of metformin’s biologic effects
are attributable to its ability to inhibit complex I. We have also generated preliminary data suggesting a direct
activator of AMPK, an indirect target of metformin, prevents fibrosis after the intratracheal administration of
bleomycin. These data support our overarching hypothesis that modulation of mitochondrial metabolism is
necessary for the development of lung fibrosis, offering a novel therapeutic opportunity. We propose using novel
genetic tools to determine whether and how mitochondrial electron transport can be targeted for therapy to
ameliorate fibrosis in two interrelated Specific Aims. In the first aim we will determine whether metformin inhibits
complex I of the mitochondrial electron transport chain in the alveolar epithelium to activate AMPK and attenuate
lung fibrosis. In the second aim we will determine whether metformin inhibits complex I of the mitochondrial
electron transport chain and activates AMPK to prevent the recruitment or differentiation of profibrotic MoAM.
Our studies are founded on unbiased, rigorous and reproducible data from patients with PF and murine models
of lung fibrosis and will have immediate implications for therapy. We will credential a widely used metabolic
therapy with an acceptable risk profile, metformin, and determine its mechanism of action during lung fibrosis
which could be leveraged to identify drugs/formulations with more favorable pharmacokinetics in humans.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Ablation><Adult-Onset Diabetes Mellitus><Affect><Airway failure><Alveolar><Alveolar Macrophages><Animal Model><Animal Models and Related Studies><Anti-diabetic Agents><Anti-diabetic Drugs><Asbestos><Attenuated><Award><Biological><Bleo><Bleomycin><Blood monocyte><Body Tissues><Bronchioalveolar Lavage><Bronchoalveolar Lavage><Bronchopulmonary Lavage><Bronchoscopy><COVID crisis><COVID epidemic><COVID pandemic><COVID survivors><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infection survivors><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 survivors><COVID-19 virus><COVID-19 years><COVID19 virus><CSF-1><CSF3><CSF3 gene><Cell Body><Cells><Cessation of life><Cicatrix><Clinical><CoV-2><CoV2><Colony-Stimulating Factor 1><Complex><Complex I Dehydrogenase><Credentialing><Data><Death><Dimethylbiguanidine><Dimethylguanylguanidine><Disease><Disease Progression><Disorder><Disparate><Drug Kinetics><Drug usage><Drugs><Electron Transport><Electron Transport Complex I><Epithelium><Exposure to><Fibroblasts><Fibrosing Alveolitis><Fibrosis><Fibrotic lesions in lung><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Formulation><G-CSF><GCSF><Gases><Gene Expression><Genes><Genetic><Healing abnormal><Healing delayed><Human><Impaired healing><Injury><Ketosis-Resistant Diabetes Mellitus><Laboratories><Light><Lung><Lung Alveolar Epithelia><Lung Grafting><Lung Lavage><Lung Respiratory System><Lung Tissue Fibrosis><Lung Transplantation><Lung scar><Lung tissue scar><M-CSF><MGC45931><Macrophage><Macrophage Colony-Stimulating Factor><Malignant Cell><Marrow monocyte><Maturity-Onset Diabetes Mellitus><Medication><Metabolic><Metformin><Mice><Mice Mammals><Mitochondria><Mitochondrial Electron Transport Complex I><Modeling><Modern Man><Murine><Mus><Myofibroblast><Mφ><N,N-dimethyl-imidodicarbonimidic diamide><NADH DH I><NADH Dehydrogenase Complex 1><NADH Dehydrogenase I><NADH Q1 Oxidoreductase><NADH dehydrogenase (ubiquinone)><NADH-CoQ Reductase><NADH-Coenzyme Q Reductase><NADH-Ubiquinone Oxidoreductase><NADH-Ubiquinone Reductase><NIDDM><Natural regeneration><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Oral><Organoids><PASC><Pathway interactions><Patients><Pharmaceutical Preparations><Pharmacokinetics><Photoradiation><Post Acute Sequelae of COVID19><Post Acute Sequelae of SARS-CoV-2><Post Acute Sequelae of SARS-CoV2><Post Acute Sequelae of severe acute respiratory syndrome coronavirus 2><Post-Acute Sequelae of SARS-CoV-2 Infection><Prevalence><Proliferating><Public Health><Publishing><Pulmonary Fibrosis><Pulmonary Graft><Pulmonary Macrophages><Pulmonary Scar><Pulmonary Tissue fibrosis><Pulmonary Transplant><Pulmonary Transplantation><Regeneration><Reporting><Reproducibility><Respiratory Complex I><Respiratory Failure><Respiratory Signs and Symptoms><Risk><Rotenone-Sensitive Mitochondrial NADH-Ubiquinone Oxidoreductase><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV-2 survivors><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Scarring at the lung><Scarring in the lung><Scars><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Slice><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><System><T2 DM><T2D><T2DM><Testing><Tissues><Transplant Recipients><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Ubiquinone Reductase><Validation><Veterans><Work><Work of Breathing><Wuhan coronavirus><Yeasts><adult onset diabetes><adverse sequelae of COVID><adverse sequelae of COVID-19><adverse sequelae of coronavirus disease><adverse sequelae of coronavirus disease 2019><aged mice><aged mouse><airway symptom><alveolar epithelium><anti-diabetic><anti-tumor effect><antitumor effect><attenuate><attenuates><biologic><biological adaptation to stress><bronchopulmonary lavage therapy><cancer cell><chronic COVID-19 sequelae><complex 1 dehydrogenase><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><design><designing><diffuse interstitial pulmonary fibrosis><drug use><drug/agent><elderly mice><electron transfer><epithelial repair><experiment><experimental research><experimental study><experiments><fibrosis in the lung><fibrotic lung><fibrotic lung disease><fibrotic pulmonary disease><flow cytophotometry><gain of function><global gene expression><global transcription profile><hCoV19><idiopathic pulmonary fibrosis><improved outcome><in vivo><injured><injuries><intraperitoneal><ketosis resistant diabetes><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><long haul sequelae of COVID-19><long haul sequelae of coronavirus disease 2019><long-term sequelae of COVID-19><long-term sequelae of SARS-CoV-2><long-term sequelae of coronavirus disease 2019><long-term sequelae of severe acute respiratory syndrome coronavirus 2><loss of function><lung development><lung fibrosis><lung transplant><maturity onset diabetes><military veteran><mitochondrial><mitochondrial metabolism><model of animal><monocyte><mouse model><murine model><nCoV2><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><old mice><pandemic><pandemic disease><pathway><peripheral blood><pharmacologic><post COVID-19 sequelae><post acute sequelae following COVID-19><post-acute sequelae following SARS-CoV-2 infection><post-acute sequelae of COVID-19><post-acute sequelae of acute COVID infection><post-acute sequelae of coronavirus disease 2019><prevent><preventing><programs><protective effect><pulmonary><reaction; crisis><recruit><regenerate><repair><repaired><respiratory symptom><respiratory virus><response><scRNA-seq><seal><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><side effect><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><small molecule><stress response><stress; reaction><survive COVID-19><survive SARS-CoV-2><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><tool><transcriptome><transcriptomics><transplant patient><type 1 dehydrogenase><type 2 DM><type II DM><type two diabetes><validations><veteran population><yeast protein>