Glucose metabolism in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a life-threatening interstitial lung disease of unknown aetiology characterized by progressive scarring of the lung parenchyma. Histologically, the hallmark of the disease is the presence of interspersed fibroblastic foci in the lung, composed of contractile myofibroblasts synthesizing a dense collagen-rich matrix. Transforming growth factor-β1 (TGFβ1) has been recognized as a key cytokine in the pathophysiology of IPF and other fibrotic disorders. Highly proliferative cells, such as cancer cells, reprogram their glucose metabolism through the activation of the PI3K-AKT-mTOR axis towards enhanced glycolysis, a process known as aerobic glycolysis. In view of the high biosynthetic nature of myofibroblasts, this thesis aimed to (1) describe the changes in glucose metabolism that occur during the process of TGFβ1-induced fibroblast to myofibroblast differentiation, (2) examine whether these changes are regulated by the PI3K-AKT-mTOR axis, and (3) examine the relationship between glucose uptake and fibrogenesis in an experimental model of lung fibrosis. For the in vitro experiments, the metabolic profile of primary human lung fibroblasts was assessed by examining cellular glucose uptake, glycolytic flux and mitochondrial respiration. Furthermore, using highly selective and potent pharmacological inhibitors, the role of the PI3K-AKT-mTOR pathway in promoting changes in glucose metabolism during fibroblast differentiation was examined. For the in vivo experiments, position emission tomography-computed tomography scanning and autoradiography were performed in the murine bleomycin model of lung injury and fibrosis following administration of radioactive 18F-labeled fluoro-2-deoxyglucose. Taken together, the data presented in this thesis demonstrate that the metabolic phenotype of fibroblasts changes during TGFβ1-induced fibroblast differentiation and is regulated by mTOR, in a PI3K-AKT-independent manner. This metabolic switch may further explain the observation of increased glucose uptake in the fibrotic lesions in the bleomycin model of lung fibrosis. These findings support the notion that pharmacological targeting of glucose metabolism and/or the mTOR kinase may be beneficial in preventing myofibroblast differentiation in IPF

Unilateral metastatic pulmonary calcification in context of ipsilateral central pulmonary embolism

We report a case of unilateral left metastatic pulmonary calcification (MPC) in a 30-year-old woman with systemic lupus erythematosus, acute nephritis, and left main pulmonary artery pulmonary embolism. Unilateral MPC is rare and is mostly seen in the context of ipsilateral pulmonary embolism. The proposed mechanism is the promotion of calcium salts precipitation by focal alkalosis resulting from reduced blood flow to the lung affected by the pulmonary arterial obstruction

Ventilator-induced diaphragmatic dysfunction in MDX mice

International audienceIntroduction: Patients with Duchenne muscular dystrophy (DMD) frequently undergo mechanical ventilation (MV) for treatment of hypoventilation, but the susceptibility of the dystrophic diaphragm to ventilator‐induced diaphragmatic dysfunction (VIDD) has not been examined.Methods: Dystrophic mice (mdx—genetic homolog of DMD) were assigned to non‐ventilated control (CTL) and MV (for 6 hours) groups. Biochemical markers of oxidative/cellular stress, metabolism, and proteolysis were compared along with ex‐vivo diaphragmatic force production.Results:MV significantly depressed maximal diaphragmatic force production compared with baseline values. In addition, MV triggered oxidative stress responses, STAT3 phosphorylation, and an upregulation of cellular pathways associated with muscle proteolysis and/or wasting (autophagy, E3 ubiquitin ligases, and myostatin).Discussion: Short‐term MV induces rapid diaphragmatic force loss and biochemical changes consistent with VIDD in mdx mice. This may have implications for the optimal use of intermittent MV in DMD patients

Involvement of the ACE2/Ang-(1–7)/MasR Axis in Pulmonary Fibrosis: Implications for COVID-19

Pulmonary fibrosis is a chronic, fibrotic lung disease affecting 3 million people worldwide. The ACE2/Ang-(1–7)/MasR axis is of interest in pulmonary fibrosis due to evidence of its anti-fibrotic action. Current scientific evidence supports that inhibition of ACE2 causes enhanced fibrosis. ACE2 is also the primary receptor that facilitates the entry of SARS-CoV-2, the virus responsible for the current COVID-19 pandemic. COVID-19 is associated with a myriad of symptoms ranging from asymptomatic to severe pneumonia and acute respiratory distress syndrome (ARDS) leading to respiratory failure, mechanical ventilation, and often death. One of the potential complications in people who recover from COVID-19 is pulmonary fibrosis. Cigarette smoking is a risk factor for fibrotic lung diseases, including the idiopathic form of this disease (idiopathic pulmonary fibrosis), which has a prevalence of 41% to 83%. Cigarette smoke increases the expression of pulmonary ACE2 and is thought to alter susceptibility to COVID-19. Cannabis is another popular combustible product that shares some similarities with cigarette smoke, however, cannabis contains cannabinoids that may reduce inflammation and/or ACE2 levels. The role of cannabis smoke in the pathogenesis of pulmonary fibrosis remains unknown. This review aimed to characterize the ACE2-Ang-(1–7)-MasR Axis in the context of pulmonary fibrosis with an emphasis on risk factors, including the SARS-CoV-2 virus and exposure to environmental toxicants. In the context of the pandemic, there is a dire need for an understanding of pulmonary fibrotic events. More research is needed to understand the interplay between ACE2, pulmonary fibrosis, and susceptibility to coronavirus infection

Relationship between Autophagy and Ventilator-induced Diaphragmatic Dysfunction

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LSC - 2017 - Targeting glucose metabolism in experimental lung injury and fibrosis

peer reviewedIntroduction:Akin to many cancers, enhanced18F-FDG-PET signal has been associated with fibrotic lesions in pulmonary fibrosis. In tumors, elevated glucose uptake is indicative of a metabolic switch to aerobic glycolysis (AG), critical to fuel biosynthetic demand. De novo expression of the low-activity isoform of the ‘glycolytic gatekeeper’ pyruvate kinase, PKM2, is a key driver of AG and pharmacological modulation of PKM2 is known to attenuate tumor proliferation and tumorigenesis.Aim:We hypothesised that the fibroproliferative response to bleomycin lung injury is characterised by metabolic reprogramming driving an enhanced glucose requirement of cells in the injured lesions. We investigated glucose uptake and modulation of the glycolytic marker PKM2 in the bleomycin mouse model.Methods&Results:Autoradiography of18F-FDG uptake in cryofrozen lung sections at day 28 post-bleomycin showed a significant ›50% increase in18F-FDG uptake in bleomycin-challenged compared to uninjured lungs. The regions of highest18F-FDG uptake corresponded to dense fibrotic regions. Immunohistochemistry revealed that PKM2 was localised to multiple cell types in fibrotic lung lesions, including a-SMA-positive myofibroblasts. A small molecule activator of PKM2, TEPP-46, achieved a significant ~50% increase in PKM2 activity in the bleomycin-injured lung. However, chronic TEPP-46 administration from day 5 post-injury had no significant effect on lung fibrosis quantified by microCt at day 28.Conclusions:We show that glucose uptake is significantly increased in fibrotic lung lesions. Although fibrotic lesions express PKM2, increasing the activity of this isoform was not sufficient to influence progression of fibrosis in bleomycin lung injur

Mechanical ventilation triggers abnormal mitochondrial dynamics and morphology in the diaphragm

International audienceThe diaphragm is a unique skeletal muscle designed to be rhythmically active throughout life, such that its sustained inactivation by the medical intervention of mechanical ventilation (MV) represents an unanticipated physiological state in evolutionary terms. Within a short period after initiating MV, the diaphragm develops muscle atrophy, damage, and diminished strength, and many of these features appear to arise from mitochondrial dysfunction. Notably, in response to metabolic perturbations, mitochondria fuse, divide, and interact with neighboring organelles to remodel their shape and functional properties-a process collectively known as mitochondrial dynamics. Using a quantitative electron microscopy approach, here we show that diaphragm contractile inactivity induced by 6 h of MV in mice leads to fragmentation of intermyofibrillar (IMF) but not subsarcolemmal (SS) mitochondria. Furthermore, physical interactions between adjacent organellar membranes were less abundant in IMF mitochondria during MV. The profusion proteins Mfn2 and OPA1 were unchanged, whereas abundance and activation status of the profission protein Drp1 were increased in the diaphragm following MV. Overall, our results suggest that mitochondrial morphological abnormalities characterized by excessive fission-fragmentation represent early events during MV, which could potentially contribute to the rapid onset of mitochondrial dysfunction, maladaptive signaling, and associated contractile dysfunction of the diaphragm