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Anna Serranomollar - One of the best experts on this subject based on the ideXlab platform.
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induced pluripotent stem cell derived Lung alveolar epithelial type ii cells reduce damage in bleomycin induced Lung Fibrosis
Stem Cell Research & Therapy, 2020Co-Authors: Belen Alvarezpalomo, Luis Ignacio Sanchezlopez, Yuben Moodley, Michael J Edel, Anna SerranomollarAbstract:Background Idiopathic pulmonary Fibrosis is a chronic, progressive, and severe disease with a limited response to currently available therapies. Epithelial cell injury and failure of appropriate healing or regeneration are central to the pathogenesis of idiopathic pulmonary Fibrosis. The purpose of this study is to investigate whether intratracheal transplantation of alveolar type II-like cells differentiated from induced pluripotent stem cells can stop and reverse the fibrotic process in an experimental model of bleomycin-induced Lung Fibrosis in rats. Methods Human induced pluripotent stem cells were differentiated to alveolar type II-like cells and characterized. Lung Fibrosis was induced in rats by a single intratracheal instillation of bleomycin. Animals were transplanted with human induced pluripotent stem cells differentiated to alveolar type II-like cells at a dose of 3 × 106 cells/animal 15 days after endotracheal bleomycin instillation when the animal Lungs were already fibrotic. Animals were sacrificed 21 days after the induction of Lung Fibrosis. Lung Fibrosis was assessed by hydroxiprolin content, histologic studies, and the expression of transforming growth factor-β and α-smooth muscle actin. Results Cell transplantation of alveolar type II-like cells differentiated from induced pluripotent stem cells can significantly reduce pulmonary Fibrosis and improve Lung alveolar structure, once Fibrosis has already formed. This is associated with the inhibition of transforming growth factor-β and α-smooth muscle actin in the damaged rat Lung tissue. Conclusion To our knowledge, this is the first data to demonstrate that at the fibrotic stage of the disease, intratracheal transplantation of human induced pluripotent differentiated to alveolar type II-like cells halts and reverses Fibrosis.
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alveolar type ii cell transplantation restores pulmonary surfactant protein levels in Lung Fibrosis
Journal of Heart and Lung Transplantation, 2014Co-Authors: Raquel Guillamatprats, Gemma Gayjordi, Antoni Xaubet, Victor I Peinado, Anna SerranomollarAbstract:Background Alveolar Type II cell transplantation has been proposed as a cell therapy for the treatment of idiopathic pulmonary Fibrosis. Its long-term benefits include repair of Lung Fibrosis, but its success partly depends on the restoration of Lung homeostasis. Our aim was to evaluate surfactant protein restoration after alveolar Type II cell transplantation in an experimental model of bleomycin-induced Lung Fibrosis in rats. Methods Lung Fibrosis was induced by intratracheal instillation of bleomycin. Alveolar Type II cells were obtained from healthy animals and transplanted 14 days after bleomycin was administered. Furthermore, one group transplanted with alveolar macrophages and another group treated with surfactant were established to evaluate the specificity of the alveolar Type II cell transplantation. The animals were euthanized at 21 days after bleomycin instillation. Lung Fibrosis was confirmed by a histologic study and an evaluation of the hydroxyproline content. Changes in surfactant proteins were evaluated by mRNA expression, Western blot and immunofluorescence studies. Results The group with alveolar Type II cell transplantation was the only one to show a reduction in the degree of Lung Fibrosis and a complete recovery to normal levels of surfactant proteins. Conclusion One of the mechanisms involved in the beneficial effect of alveolar Type II cell transplantation is restoration of Lung surfactant protein levels, which is required for proper respiratory function.
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intratracheal transplantation of alveolar type ii cells reverses bleomycin induced Lung Fibrosis
American Journal of Respiratory and Critical Care Medicine, 2007Co-Authors: Anna Serranomollar, Gemma Gayjordi, Antoni Xaubet, Maria Nacher, Daniel Closa, O BulbenaAbstract:Rationale: Transplantation of stem cells has been proposed as a strategy for repair of Lung Fibrosis. Nevertheless, many studies have yielded controversial results that currently limit the potential use of these cells as an efficient treatment. Alveolar type II cells are the progenitor cells of the pulmonary epithelium and usually proliferate after epithelial cell injury. During Lung Fibrosis, however, the altered regeneration process leads to uncontrolled fibroblast proliferation.Objectives: To investigate whether intratracheal transplantation of isolated alveolar type II cells can halt and reverse the fibrotic process in an experimental model of bleomycin-induced Lung Fibrosis in rats.Methods: Lung Fibrosis was induced in syngeneic female Lewis rats by a single intratracheal instillation of bleomycin (2.5 U/kg). Animals were transplanted with alveolar type II cells from male animals at a dose of 2.5 × 106 cells per animal 3, 7, and 15 days after endotracheal bleomycin instillation. Animals were killed 2...
Michael J Edel - One of the best experts on this subject based on the ideXlab platform.
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induced pluripotent stem cell derived Lung alveolar epithelial type ii cells reduce damage in bleomycin induced Lung Fibrosis
Stem Cell Research & Therapy, 2020Co-Authors: Belen Alvarezpalomo, Luis Ignacio Sanchezlopez, Yuben Moodley, Michael J Edel, Anna SerranomollarAbstract:Background Idiopathic pulmonary Fibrosis is a chronic, progressive, and severe disease with a limited response to currently available therapies. Epithelial cell injury and failure of appropriate healing or regeneration are central to the pathogenesis of idiopathic pulmonary Fibrosis. The purpose of this study is to investigate whether intratracheal transplantation of alveolar type II-like cells differentiated from induced pluripotent stem cells can stop and reverse the fibrotic process in an experimental model of bleomycin-induced Lung Fibrosis in rats. Methods Human induced pluripotent stem cells were differentiated to alveolar type II-like cells and characterized. Lung Fibrosis was induced in rats by a single intratracheal instillation of bleomycin. Animals were transplanted with human induced pluripotent stem cells differentiated to alveolar type II-like cells at a dose of 3 × 106 cells/animal 15 days after endotracheal bleomycin instillation when the animal Lungs were already fibrotic. Animals were sacrificed 21 days after the induction of Lung Fibrosis. Lung Fibrosis was assessed by hydroxiprolin content, histologic studies, and the expression of transforming growth factor-β and α-smooth muscle actin. Results Cell transplantation of alveolar type II-like cells differentiated from induced pluripotent stem cells can significantly reduce pulmonary Fibrosis and improve Lung alveolar structure, once Fibrosis has already formed. This is associated with the inhibition of transforming growth factor-β and α-smooth muscle actin in the damaged rat Lung tissue. Conclusion To our knowledge, this is the first data to demonstrate that at the fibrotic stage of the disease, intratracheal transplantation of human induced pluripotent differentiated to alveolar type II-like cells halts and reverses Fibrosis.
Thomas H Sisson - One of the best experts on this subject based on the ideXlab platform.
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efferocytosis of apoptotic alveolar epithelial cells is sufficient to initiate Lung Fibrosis
Cell Death and Disease, 2018Co-Authors: Megan R Dotson, Patrick B Bradley, Natalia Subbotina, Jibing Yang, John J Osterholzer, Manisha Agarwal, Thomas H SissonAbstract:Type II alveolar epithelial cell (AEC) apoptosis is a prominent feature of fibrotic Lung diseases and animal models of pulmonary Fibrosis. While there is growing recognition of the importance of AEC injury and apoptosis as a causal factor in Fibrosis, the underlying mechanisms that link these processes remain unknown. We have previously shown that targeting the type II alveolar epithelium for injury by repetitively administering diphtheria toxin to transgenic mice expressing the diphtheria toxin receptor off of the surfactant protein C promoter (SPC-DTR) develop Lung Fibrosis, confirming that AEC injury is sufficient to cause Fibrosis. In the present study, we find that SPC-DTR mice develop increased activation of caspase 3/7 after initiation of diphtheria toxin treatment consistent with apoptosis within AECs. We also find evidence of efferocytosis, the uptake of apoptotic cells, by alveolar macrophages in this model. To determine the importance of efferocytosis in Lung Fibrosis, we treated cultured alveolar macrophages with apoptotic type II AECs and found that the uptake induced pro-fibrotic gene expression. We also found that the repetitive intrapulmonary administration of apoptotic type II AEC or MLE-12 cells induces Lung Fibrosis. Finally, mice lacking a key efferocytosis receptor, CD36, developed attenuated Fibrosis in response to apoptotic MLE-12 cells. Collectively, these studies support a novel mechanism linking AEC apoptosis with macrophage pro-fibrotic activation via efferocytosis and reveal previously unrecognized therapeutic targets.
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phosphodiesterase 4 inhibition reduces Lung Fibrosis following targeted type ii alveolar epithelial cell injury
Physiological Reports, 2018Co-Authors: Thomas H Sisson, Paul J Christensen, Yo Muraki, Anthony J Dils, Lauren N Chibucos, Natalya Subbotina, Jeffrey C. Horowitz, Kimio Tohyama, Takanori Matsuo, Marc B BailieAbstract:: Fibrosis of the Lung constitutes a major clinical challenge and novel therapies are required to alleviate the associated morbidity and mortality. Investigating the antifibrotic efficacy of drugs that are already in clinical practice offers an efficient strategy to identify new therapies. The phosphodiesterase 4 (PDE4) inhibitors, approved for the treatment of chronic obstructive pulmonary disease, harbor therapeutic potential for pulmonary Fibrosis by augmenting the activity of endogenous antifibrotic mediators that signal through cyclic AMP. In this study, we tested the efficacy of several PDE4 inhibitors including a novel compound (Compound 1) in a murine model of Lung Fibrosis that results from a targeted type II alveolar epithelial cell injury. We also compared the antifibrotic activity of PDE4 inhibition to the two therapies that are FDA-approved for idiopathic pulmonary Fibrosis (pirfenidone and nintedanib). We found that both preventative (day 0-21) and therapeutic (day 11-21) dosing regimens of the PDE4 inhibitors significantly ameliorated the weight loss and Lung collagen accumulation that are the sequelae of targeted epithelial cell damage. In a therapeutic protocol, the reduction in Lung Fibrosis with PDE4 inhibitor administration was equivalent to pirfenidone and nintedanib. Treatment with this class of drugs also resulted in a decrease in plasma surfactant protein D concentration, a reduction in the plasma levels of several chemokines implicated in Lung Fibrosis, and an in vitro inhibition of fibroblast profibrotic gene expression. These results motivate further investigation of PDE4 inhibition as a treatment for patients with fibrotic Lung disease.
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Dataset for: Phosphodiesterase 4 Inhibition Reduces Lung Fibrosis Following Targeted Type II Alveolar Epithelial Cell Injury
2018Co-Authors: Thomas H Sisson, Paul J Christensen, Yo Muraki, Anthony J Dils, Lauren N Chibucos, Natalya Subbotina, Jeffrey C. Horowitz, Kimio Tohyama, Takanori Matsuo, Marc B BailieAbstract:Fibrosis of the Lung constitutes a major clinical challenge and novel therapies are required to alleviate the associated morbidity and mortality. Investigating the anti-fibrotic efficacy of drugs that are already in clinical practice offers an efficient strategy to identify new therapies. The phosphodiesterase 4 (PDE4) inhibitors, approved for the treatment of chronic obstructive pulmonary disease, harbor therapeutic potential for pulmonary Fibrosis by augmenting the activity of endogenous anti-fibrotic mediators that signal through cyclic AMP. In the present study, we tested the efficacy of several PDE4 inhibitors including a novel compound (Compound 1) in a murine model of Lung Fibrosis that results from a targeted type II alveolar epithelial cell injury. We also compared the anti-fibrotic activity of PDE4 inhibition to the two therapies that are FDA-approved for idiopathic pulmonary Fibrosis (pirfenidone and nintedanib). We found that both preventative (day 0-21) and therapeutic (day 11-21) dosing regimens of the PDE4 inhibitors significantly ameliorated the weight loss and Lung collagen accumulation that are the sequelae of targeted epithelial cell damage. In a therapeutic protocol, the reduction in Lung Fibrosis with PDE4 inhibitor administration was equivalent to pirfenidone and nintedanib. Treatment with this class of drugs also resulted in a decrease in plasma surfactant protein D concentration, a reduction in the plasma levels of several chemokines implicated in Lung Fibrosis, and an in vitro inhibition of fibroblast pro-fibrotic gene expression. These results motivate further investigation of PDE4 inhibition as a treatment for patients with fibrotic Lung disease
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inhibition of myocardin related transcription factor serum response factor signaling decreases Lung Fibrosis and promotes mesenchymal cell apoptosis
American Journal of Pathology, 2015Co-Authors: Thomas H Sisson, Lauren N Chibucos, Natalya Subbotina, Yong Zhou, Iyabode O Ajayi, Amos E Dodi, Eva S Rodansky, Venkateshwar G Keshamouni, Eric S White, Peter D R HigginsAbstract:Myofibroblasts are crucial to the pathogenesis of tissue Fibrosis. Their formation of stress fibers results in the release of myocardin-related transcription factor (MRTF), a transcriptional coactivator of serum response factor (SRF). MRTF-A (Mkl1)-deficient mice are protected from Lung Fibrosis. We hypothesized that the SRF/MRTF pathway inhibitor CCG-203971 would modulate myofibroblast function in vitro and limit Lung Fibrosis in vivo. Normal and idiopathic pulmonary Fibrosis Lung fibroblasts were treated with/without CCG-203971 (N-[4-chlorophenyl]-1-[3-(2-furanyl)benzoyl]-3-piperidine carboxamide) and/or Fas-activating antibody in the presence/absence of transforming growth factor (TGF)-β1, and apoptosis was assessed. In vivo studies examined the effect of therapeutically administered CCG-203971 on Lung Fibrosis in two distinct murine models of Fibrosis induced by bleomycin or targeted type II alveolar epithelial injury. In vitro, CCG-203971 prevented nuclear localization of MRTF-A; increased the apoptotic susceptibility of normal and idiopathic pulmonary Fibrosis fibroblasts; blocked TGF-β1–induced myofibroblast differentiation; and inhibited TGF-β1–induced expression of fibronectin, X-linked inhibitor of apoptosis, and plasminogen activator inhibitor-1. TGF-β1 did not protect fibroblasts or myofibroblasts from apoptosis in the presence of CCG-203971. In vivo, CCG-203971 significantly reduced Lung collagen content in both murine models while decreasing alveolar plasminogen activator inhibitor-1 and promoting myofibroblast apoptosis. These data support a central role of the SRF/MRTF pathway in the pathobiology of Lung Fibrosis and suggest that its inhibition can help resolve Lung Fibrosis by promoting fibroblast apoptosis.
Paul Cheresh - One of the best experts on this subject based on the ideXlab platform.
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mitochondrial 8 oxoguanine dna glycosylase mitigates alveolar epithelial cell pink1 deficiency mitochondrial dna damage apoptosis and Lung Fibrosis
American Journal of Physiology-lung Cellular and Molecular Physiology, 2020Co-Authors: Paul Cheresh, Renea P Jablonski, Lyudmila I Rachek, Raul Piseauxaillon, Mark J Ciesielski, Cara J. Gottardi, Anjana V. Yeldandi, Karen M. Ridge, Annie Pardo, Moisés SelmanAbstract:Alveolar epithelial cell (AEC) apoptosis, arising from mitochondrial dysfunction and mitophagy defects, is important in mediating idiopathic pulmonary Fibrosis (IPF). Our group established a role for the mitochondrial (mt) DNA base excision repair enzyme, 8-oxoguanine-DNA glycosylase 1 (mtOGG1), in preventing oxidant-induced AEC mtDNA damage and apoptosis and showed that OGG1-deficient mice have increased Lung Fibrosis. Herein, we determined whether mice overexpressing the mtOGG1 transgene (mtOgg1tg) are protected against Lung Fibrosis and whether AEC mtOGG1 preservation of mtDNA integrity mitigates phosphatase and tensin homolog-induced putative kinase 1 (PINK1) deficiency and apoptosis. Compared with wild type (WT), mtOgg1tg mice have diminished asbestos- and bleomycin-induced pulmonary Fibrosis that was accompanied by reduced Lung and AEC mtDNA damage and apoptosis. Asbestos and H2O2 promote the MLE-12 cell PINK1 deficiency, as assessed by reductions in the expression of PINK1 mRNA and mitochondrial protein expression. Compared with WT, Pink1-knockout (Pink1-KO) mice are more susceptible to asbestos-induced Lung Fibrosis and have increased Lung and alveolar type II (AT2) cell mtDNA damage and apoptosis. AT2 cells from Pink1-KO mice and PINK1-silenced (siRNA) MLE-12 cells have increased mtDNA damage that is augmented by oxidative stress. Interestingly, mtOGG1 overexpression attenuates oxidant-induced MLE-12 cell mtDNA damage and apoptosis despite PINK1 silencing. mtDNA damage is increased in the Lungs of patients with IPF as compared with controls. Collectively, these findings suggest that mtOGG1 maintenance of AEC mtDNA is crucial for preventing PINK1 deficiency that promotes apoptosis and Lung Fibrosis. Given the key role of AEC apoptosis in pulmonary Fibrosis, strategies aimed at preserving AT2 cell mtDNA integrity may be an innovative target.
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sirt3 deficiency promotes Lung Fibrosis by augmenting alveolar epithelial cell mitochondrial dna damage and apoptosis
The FASEB Journal, 2017Co-Authors: R Jablonski, Paul Cheresh, Anjana V. Yeldandi, Annie Pardo, Luisa Moralesnebreda, Yuan Cheng, Seok Jo Kim, David Williams, Sangeeta Bhorade, Moisés SelmanAbstract:Alveolar epithelial cell (AEC) mitochondrial dysfunction and apoptosis are important in idiopathic pulmonary Fibrosis and asbestosis. Sirtuin 3 (SIRT3) detoxifies mitochondrial reactive oxygen species, in part, by deacetylating manganese superoxide dismutase (MnSOD) and mitochondrial 8-oxoguanine DNA glycosylase. We reasoned that SIRT3 deficiency occurs in fibrotic Lungs and thereby augments AEC mtDNA damage and apoptosis. Human Lungs were assessed by using immunohistochemistry for SIRT3 activity via acetylated MnSODK68 Murine AEC SIRT3 and cleaved caspase-9 (CC-9) expression were assayed by immunoblotting with or without SIRT3 enforced expression or silencing. mtDNA damage was measured by using quantitative PCR and apoptosis via ELISA. Pulmonary Fibrosis after asbestos or bleomycin exposure was evaluated in 129SJ/wild-type and SIRT3-knockout mice (Sirt3-/- ) by using Fibrosis scoring and Lung collagen levels. Idiopathic pulmonary Fibrosis Lung alveolar type II cells have increased MnSODK68 acetylation compared with controls. Asbestos and H2O2 diminished AEC SIRT3 protein expression and increased mitochondrial protein acetylation, including MnSODK68 SIRT3 enforced expression reduced oxidant-induced AEC OGG1K338/341 acetylation, mtDNA damage, and apoptosis, whereas SIRT3 silencing promoted these effects. Asbestos- or bleomycin-induced Lung Fibrosis, AEC mtDNA damage, and apoptosis in wild-type mice were amplified in Sirt3-/- animals. These data suggest a novel role for SIRT3 deficiency in mediating AEC mtDNA damage, apoptosis, and Lung Fibrosis.-Jablonski, R. P., Kim, S.-J., Cheresh, P., Williams, D. B., Morales-Nebreda, L., Cheng, Y., Yeldandi, A., Bhorade, S., Pardo, A., Selman, M., Ridge, K., Gius, D., Budinger, G. R. S., Kamp, D. W. SIRT3 deficiency promotes Lung Fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis.
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mitochondrial catalase overexpressed transgenic mice are protected against Lung Fibrosis in part via preventing alveolar epithelial cell mitochondrial dna damage
Free Radical Biology and Medicine, 2016Co-Authors: Paul Cheresh, Renea P Jablonski, Erin Hogan, Raul Piseaux, Michael C Hart, Anjana V. Yeldandi, Karen M. Ridge, Luisa Moralesnebreda, Yuan Cheng, Navdeep S. ChandelAbstract:Abstract Rationale Alveolar epithelial cell (AEC) injury and mitochondrial dysfunction are important in the development of Lung Fibrosis. Our group has shown that in the asbestos exposed Lung, the generation of mitochondrial reactive oxygen species (ROS) in AEC mediate mitochondrial DNA (mtDNA) damage and apoptosis which are necessary for Lung Fibrosis. These data suggest that mitochondrial-targeted antioxidants should ameliorate asbestos-induced Lung. Objective To determine whether transgenic mice that express mitochondrial-targeted catalase ( MCAT) have reduced Lung Fibrosis following exposure to asbestos or bleomycin and, if so, whether this occurs in association with reduced AEC mtDNA damage and apoptosis. Methods Crocidolite asbestos (100 µg/50 µL), TiO 2 (negative control), bleomycin (0.025 units/50 µL), or PBS was instilled intratracheally in 8–10 week-old wild-type (WT - C57Bl/6 J) or MCAT mice. The Lungs were harvested at 21 d. Lung Fibrosis was quantified by collagen levels (Sircol) and Lung Fibrosis scores. AEC apoptosis was assessed by cleaved caspase-3 (CC-3)/Surfactant protein C (SFTPC) immunohistochemistry (IHC) and semi-quantitative analysis. AEC (primary AT2 cells from WT and MCAT mice and MLE-12 cells) mtDNA damage was assessed by a quantitative PCR-based assay, apoptosis was assessed by DNA fragmentation, and ROS production was assessed by a Mito-Sox assay. Results Compared to WT, crocidolite-exposed MCAT mice exhibit reduced pulmonary Fibrosis as measured by Lung collagen levels and Lung Fibrosis score. The protective effects in MCAT mice were accompanied by reduced AEC mtDNA damage and apoptosis. Similar findings were noted following bleomycin exposure. Euk-134, a mitochondrial SOD/catalase mimetic, attenuated MLE-12 cell DNA damage and apoptosis. Finally, compared to WT, asbestos-induced MCAT AT2 cell ROS production was reduced. Conclusions Our finding that MCAT mice have reduced pulmonary Fibrosis, AEC mtDNA damage and apoptosis following exposure to asbestos or bleomycin suggests an important role for AEC mitochondrial H 2 O 2 -induced mtDNA damage in promoting Lung Fibrosis. We reason that strategies aimed at limiting AEC mtDNA damage arising from excess mitochondrial H 2 O 2 production may be a novel therapeutic target for mitigating pulmonary Fibrosis.
Moisés Selman - One of the best experts on this subject based on the ideXlab platform.
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mitochondrial 8 oxoguanine dna glycosylase mitigates alveolar epithelial cell pink1 deficiency mitochondrial dna damage apoptosis and Lung Fibrosis
American Journal of Physiology-lung Cellular and Molecular Physiology, 2020Co-Authors: Paul Cheresh, Renea P Jablonski, Lyudmila I Rachek, Raul Piseauxaillon, Mark J Ciesielski, Cara J. Gottardi, Anjana V. Yeldandi, Karen M. Ridge, Annie Pardo, Moisés SelmanAbstract:Alveolar epithelial cell (AEC) apoptosis, arising from mitochondrial dysfunction and mitophagy defects, is important in mediating idiopathic pulmonary Fibrosis (IPF). Our group established a role for the mitochondrial (mt) DNA base excision repair enzyme, 8-oxoguanine-DNA glycosylase 1 (mtOGG1), in preventing oxidant-induced AEC mtDNA damage and apoptosis and showed that OGG1-deficient mice have increased Lung Fibrosis. Herein, we determined whether mice overexpressing the mtOGG1 transgene (mtOgg1tg) are protected against Lung Fibrosis and whether AEC mtOGG1 preservation of mtDNA integrity mitigates phosphatase and tensin homolog-induced putative kinase 1 (PINK1) deficiency and apoptosis. Compared with wild type (WT), mtOgg1tg mice have diminished asbestos- and bleomycin-induced pulmonary Fibrosis that was accompanied by reduced Lung and AEC mtDNA damage and apoptosis. Asbestos and H2O2 promote the MLE-12 cell PINK1 deficiency, as assessed by reductions in the expression of PINK1 mRNA and mitochondrial protein expression. Compared with WT, Pink1-knockout (Pink1-KO) mice are more susceptible to asbestos-induced Lung Fibrosis and have increased Lung and alveolar type II (AT2) cell mtDNA damage and apoptosis. AT2 cells from Pink1-KO mice and PINK1-silenced (siRNA) MLE-12 cells have increased mtDNA damage that is augmented by oxidative stress. Interestingly, mtOGG1 overexpression attenuates oxidant-induced MLE-12 cell mtDNA damage and apoptosis despite PINK1 silencing. mtDNA damage is increased in the Lungs of patients with IPF as compared with controls. Collectively, these findings suggest that mtOGG1 maintenance of AEC mtDNA is crucial for preventing PINK1 deficiency that promotes apoptosis and Lung Fibrosis. Given the key role of AEC apoptosis in pulmonary Fibrosis, strategies aimed at preserving AT2 cell mtDNA integrity may be an innovative target.
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sirt3 deficiency promotes Lung Fibrosis by augmenting alveolar epithelial cell mitochondrial dna damage and apoptosis
The FASEB Journal, 2017Co-Authors: R Jablonski, Paul Cheresh, Anjana V. Yeldandi, Annie Pardo, Luisa Moralesnebreda, Yuan Cheng, Seok Jo Kim, David Williams, Sangeeta Bhorade, Moisés SelmanAbstract:Alveolar epithelial cell (AEC) mitochondrial dysfunction and apoptosis are important in idiopathic pulmonary Fibrosis and asbestosis. Sirtuin 3 (SIRT3) detoxifies mitochondrial reactive oxygen species, in part, by deacetylating manganese superoxide dismutase (MnSOD) and mitochondrial 8-oxoguanine DNA glycosylase. We reasoned that SIRT3 deficiency occurs in fibrotic Lungs and thereby augments AEC mtDNA damage and apoptosis. Human Lungs were assessed by using immunohistochemistry for SIRT3 activity via acetylated MnSODK68 Murine AEC SIRT3 and cleaved caspase-9 (CC-9) expression were assayed by immunoblotting with or without SIRT3 enforced expression or silencing. mtDNA damage was measured by using quantitative PCR and apoptosis via ELISA. Pulmonary Fibrosis after asbestos or bleomycin exposure was evaluated in 129SJ/wild-type and SIRT3-knockout mice (Sirt3-/- ) by using Fibrosis scoring and Lung collagen levels. Idiopathic pulmonary Fibrosis Lung alveolar type II cells have increased MnSODK68 acetylation compared with controls. Asbestos and H2O2 diminished AEC SIRT3 protein expression and increased mitochondrial protein acetylation, including MnSODK68 SIRT3 enforced expression reduced oxidant-induced AEC OGG1K338/341 acetylation, mtDNA damage, and apoptosis, whereas SIRT3 silencing promoted these effects. Asbestos- or bleomycin-induced Lung Fibrosis, AEC mtDNA damage, and apoptosis in wild-type mice were amplified in Sirt3-/- animals. These data suggest a novel role for SIRT3 deficiency in mediating AEC mtDNA damage, apoptosis, and Lung Fibrosis.-Jablonski, R. P., Kim, S.-J., Cheresh, P., Williams, D. B., Morales-Nebreda, L., Cheng, Y., Yeldandi, A., Bhorade, S., Pardo, A., Selman, M., Ridge, K., Gius, D., Budinger, G. R. S., Kamp, D. W. SIRT3 deficiency promotes Lung Fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis.
