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The mitochondria in lung fibrosis: friend or foe?

  • Elizabeth S. Malsin
    Affiliations
    Department of Medicine, Division of Pulmonary & Critical Care Medicine, Jesse Brown VA Medical Center and Northwestern University Feinberg School of Medicine, Chicago, Illinois
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  • David W. Kamp
    Correspondence
    Reprint requests: David W. Kamp, Northwestern University Feinberg School of Medicine, Pulmonary and Critical Care Medicine, McGaw M-330, 240 E. Huron St., Chicago, IL 60611-3010.
    Affiliations
    Department of Medicine, Division of Pulmonary & Critical Care Medicine, Jesse Brown VA Medical Center and Northwestern University Feinberg School of Medicine, Chicago, Illinois
    Search for articles by this author
      Idiopathic pulmonary fibrosis (IPF) and other forms of lung fibrosis are age-associated diseases with increased deposition of mesenchymal collagen that promotes respiratory malfunction and eventual death from respiratory failure. Our understanding of the pathobiology underlying pulmonary fibrosis is incomplete and current therapies available to slow or treat lung fibrosis are limited. Evidence reviewed herein demonstrates key involvement of mitochondrial dysfunction in diverse pulmonary cell populations, including alveolar epithelial cells (AEC), fibroblasts, and macrophages and/or immune cells that collectively advances the development of pulmonary fibrosis. The mitochondria have an important role in regulating whether fibrogenic stimuli results in the return of normal healthy function ("friend") or the development of pulmonary fibrosis ("foe"). In particular, we summarize the evidence suggesting that AEC mitochondrial dysfunction is important in mediating lung fibrosis signaling via mechanisms involving imbalances in the levels of reactive oxygen species, endoplasmic reticulum stress response, mitophagy, apoptosis and/or senescence, and inflammatory signaling. Further, we review the emerging evidence suggesting that dysfunctional mitochondria in AECs and other cell types play crucial roles in modulating nearly all aspects of the 9 hallmarks of aging in the context of pulmonary fibrosis as well as some novel molecular pathways that have recently been identified. Finally, we discuss the potential translational aspects of these studies as well as the key knowledge gaps necessary for better informing our understanding of the pathobiology of the mitochondria in mediating pulmonary fibrosis. We reason that targeting deficient mitochondria-derived pathways may provide innovative future treatment strategies that are urgently needed for lung fibrosis.
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