Approximately 200,000 people in the United States develop acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) annually. Despite research driven advances in therapy, 30%-40% of these patients will die. ALI and ARDS often manifest as a part of an inflammatory process characterized by acute failure of the alveolar-capillary membrane, which allows an exudate of plasma to flood the alveolar space. Influenza is the leading cause of death from an infectious cause in the United States and is an important cause of ARDS. Current influenza therapies inhibit viral proteins to prevent either replication or spreading of the virus while other strategies target host anti-viral responses However, the high genetic variability of the influenza virus results in variants that escape strain-specific adaptive immune responses or that are resistant to antiviral agents. Thus, targeting host cells proteins rather than viral proteins might prove to be a more effective strategy. Metabolism is an understudied area in acute lung injury and because viral metabolism requires highly conserved host proteins rather than viral proteins, targeting metabolic enzymes might provide a novel and effective strategy to prevent influenza-induced lung injury. We conducted a large scale metabolomics screen in primary human lung epithelial cells following infection with influenza A virus. These preliminary data indicate that influenza virus infection within hours causes the activation of catabolic pathways in the host cell reminiscent of autophagy and the upregulation of the glucose-dependent hexosamine biosynthetic pathway to generate the sialic acid N-acetylneuraminate?a metabolite required for efficient virus entry and exit from host lung epithelial cells. Furthermore, mice harboring 50% decrease in their maximal mitochondrial function recover quicker from influenza virus induced injury suggesting a causal role for changes in mitochondrial metabolism in regulating alveolar epithelial repair. The goal of this grant is to mechanistically determine the changes in metabolic pathways in epithelial cells that are essential for influenza virus induced lung injury. We propose three aims which will test whether (1) the glucose dependent hexosamine biosynthetic pathway is essential for influenza A virus production in lung epithelial cells; (2) autophagy within lungs epithelial cells is necessary for lung injury; (3) decreasing maximal mitochondrial capacity in lung epithelial cells accelerates recovery from lung injury.
To date, the NHLBI ARDS network has identified only a single therapy that has favorably impacted survival in patients with ARDS. Thus, it is imperative to develop new therapeutic strategies. If our hypothesis that specific changes in metabolism play a causal role in the development of and recovery from lung injury then drugs targeting metabolism might be provide novel and effective therapies for these patients.
| Sala, Marc A; Balderas-Martínez, Yalbi Itzel; Buendía-Roldan, Ivette et al. (2018) Inflammatory pathways are upregulated in the nasal epithelium in patients with idiopathic pulmonary fibrosis. Respir Res 19:233 |
| Mehta, Manan M; Weinberg, Samuel E; Steinert, Elizabeth M et al. (2018) Hexokinase 2 is dispensable for T cell-dependent immunity. Cancer Metab 6:10 |
| Brazee, Patricia L; Dada, Laura A (2018) Splice Wars: The Role of MLCK Isoforms in Ventilation-induced Lung Injury. Am J Respir Cell Mol Biol 58:549-550 |
| Koch, Clarissa M; Chiu, Stephen F; Akbarpour, Mahzad et al. (2018) A Beginner's Guide to Analysis of RNA Sequencing Data. Am J Respir Cell Mol Biol 59:145-157 |
| Dela Cruz, Charles S; Wunderink, Richard G; Christiani, David C et al. (2018) Future Research Directions in Pneumonia. NHLBI Working Group Report. Am J Respir Crit Care Med 198:256-263 |
| Kong, Hyewon; Chandel, Navdeep S (2018) Regulation of redox balance in cancer and T cells. J Biol Chem 293:7499-7507 |
| Hsiao, Hsi-Min; Fernandez, Ramiro; Tanaka, Satona et al. (2018) Spleen-derived classical monocytes mediate lung ischemia-reperfusion injury through IL-1?. J Clin Invest 128:2833-2847 |
| Wang, Zheng; Divanyan, Alex; Jourd'heuil, Frances L et al. (2018) Vimentin expression is required for the development of EMT-related renal fibrosis following unilateral ureteral obstruction in mice. Am J Physiol Renal Physiol 315:F769-F780 |
| Lu, Ziyan; Casalino-Matsuda, S Marina; Nair, Aisha et al. (2018) A role for heat shock factor 1 in hypercapnia-induced inhibition of inflammatory cytokine expression. FASEB J 32:3614-3622 |
| Amarelle, Luciano; Lecuona, Emilia (2018) A Nonhospitable Host: Targeting Cellular Factors as an Antiviral Strategy for Respiratory Viruses. Am J Respir Cell Mol Biol 59:666-667 |
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