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Alveolar Epithelial Cell

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Thomas H Sisson – One of the best experts on this subject based on the ideXlab platform.

  • diverse injury pathways induce Alveolar Epithelial Cell ccl2 12 which promotes lung fibrosis
    American Journal of Respiratory Cell and Molecular Biology, 2020
    Co-Authors: Jibing Yang, Rachel L Zemans, Manisha Agarwal, Song Ling, Seagal Teitztennenbaum, John J Osterholzer, Thomas H Sisson

    Abstract:

    Accumulating evidence suggests that fibrosis is a multiCellular process with contributions from Alveolar Epithelial Cells (AECs), recruited monocytes/macrophages, and fibroblasts. We have previously shown that AEC injury is sufficient to induce fibrosis, but the precise mechanism remains unclear. Several Cell types, including AECs, can produce CCL2 and CCL12, which can promote fibrosis through CCR2 activation. CCR2 signaling is critical for the initiation and progression of pulmonary fibrosis, in part through recruitment of profibrotic bone marrow-derived monocytes. Attempts at inhibiting CCL2 in patients with fibrosis demonstrated a marked upregulation of CCL2 production and no therapeutic response. To better understand the mechanisms involved in CCL2/CCR2 signaling, we generated mice with conditional deletion of CCL12, a murine homolog of human CCL2. Surprisingly, we found that mice with complete deletion of CCL12 had markedly increased concentrations of other CCR2 ligands and were not protected from fibrosis after bleomycin injury. In contrast, mice with lung Epithelial Cell-specific deletion of CCL12 were protected from bleomycin-induced fibrosis and had expression of CCL2 and CCL7 similar to that of control mice treated with bleomycin. Deletion of CCL12 within AECs led to decreased recruitment of exudate macrophages. Finally, injury to murine and human primary AECs resulted in increased production of CCL2 and CCL12, in part through activation of the mTOR pathway. In conclusion, these data suggest that targeting CCL2 may be a viable antifibrotic strategy once the pathways involved in the production and function of CCL2 and other CCR2 ligands are better defined.

  • phosphodiesterase 4 inhibition reduces lung fibrosis following targeted type ii Alveolar Epithelial Cell injury
    Physiological Reports, 2018
    Co-Authors: Thomas H Sisson, Jeffrey C Horowitz, Paul J Christensen, Yo Muraki, Anthony J Dils, Lauren N Chibucos, Natalya Subbotina, Kimio Tohyama, Takanori Matsuo, Marc B Bailie

    Abstract:

    : 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.

  • the vitronectin rgd motif regulates tgf β induced Alveolar Epithelial Cell apoptosis
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2016
    Co-Authors: Amanda K Wheaton, Miranda Velikoff, Manisha Agarwal, Jeffrey C Horowitz, Thomas H Sisson

    Abstract:

    Transforming growth factor-β (TGF-β) is a critical driver of acute lung injury and fibrosis. Injury leads to activation of TGF-β, which regulates changes in the Cellular and matrix makeup of the lung during the repair and fibrosis phase. TGF-β can also initiate Alveolar Epithelial Cell (AEC) apoptosis. Injury leads to destruction of the laminin-rich basement membrane, which is replaced by a provisional matrix composed of arginine-glycine-aspartate (RGD) motif-containing plasma matrix proteins, including vitronectin and fibronectin. To determine the role of specific matrix proteins on TGF-β-induced apoptosis, we studied primary AECs cultured on different matrix conditions and utilized mice with deletion of vitronectin (Vtn−/−) or mice in which the vitronectin RGD motif is mutated to nonintegrin-binding arginine-glycine-glutamate (RGE) (VtnRGE/RGE). We found that AECs cultured on fibronectin and vitronectin or in wild-type mouse serum are resistant to TGF-β-induced apoptosis. In contrast, AECs cultured on l…

Amanda K Wheaton – One of the best experts on this subject based on the ideXlab platform.

  • the vitronectin rgd motif regulates tgf β induced Alveolar Epithelial Cell apoptosis
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2016
    Co-Authors: Amanda K Wheaton, Miranda Velikoff, Manisha Agarwal, Jeffrey C Horowitz, Thomas H Sisson

    Abstract:

    Transforming growth factor-β (TGF-β) is a critical driver of acute lung injury and fibrosis. Injury leads to activation of TGF-β, which regulates changes in the Cellular and matrix makeup of the lung during the repair and fibrosis phase. TGF-β can also initiate Alveolar Epithelial Cell (AEC) apoptosis. Injury leads to destruction of the laminin-rich basement membrane, which is replaced by a provisional matrix composed of arginine-glycine-aspartate (RGD) motif-containing plasma matrix proteins, including vitronectin and fibronectin. To determine the role of specific matrix proteins on TGF-β-induced apoptosis, we studied primary AECs cultured on different matrix conditions and utilized mice with deletion of vitronectin (Vtn−/−) or mice in which the vitronectin RGD motif is mutated to nonintegrin-binding arginine-glycine-glutamate (RGE) (VtnRGE/RGE). We found that AECs cultured on fibronectin and vitronectin or in wild-type mouse serum are resistant to TGF-β-induced apoptosis. In contrast, AECs cultured on l…

  • the vitronectin rgd motif regulates tgf β induced Alveolar Epithelial Cell apoptosis
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2016
    Co-Authors: Amanda K Wheaton, Miranda Velikoff, Manisha Agarwal, Jeffrey C Horowitz, Thomas H Sisson

    Abstract:

    Transforming growth factor-β (TGF-β) is a critical driver of acute lung injury and fibrosis. Injury leads to activation of TGF-β, which regulates changes in the Cellular and matrix makeup of the lu…

Manisha Agarwal – One of the best experts on this subject based on the ideXlab platform.

  • diverse injury pathways induce Alveolar Epithelial Cell ccl2 12 which promotes lung fibrosis
    American Journal of Respiratory Cell and Molecular Biology, 2020
    Co-Authors: Jibing Yang, Rachel L Zemans, Manisha Agarwal, Song Ling, Seagal Teitztennenbaum, John J Osterholzer, Thomas H Sisson

    Abstract:

    Accumulating evidence suggests that fibrosis is a multiCellular process with contributions from Alveolar Epithelial Cells (AECs), recruited monocytes/macrophages, and fibroblasts. We have previously shown that AEC injury is sufficient to induce fibrosis, but the precise mechanism remains unclear. Several Cell types, including AECs, can produce CCL2 and CCL12, which can promote fibrosis through CCR2 activation. CCR2 signaling is critical for the initiation and progression of pulmonary fibrosis, in part through recruitment of profibrotic bone marrow-derived monocytes. Attempts at inhibiting CCL2 in patients with fibrosis demonstrated a marked upregulation of CCL2 production and no therapeutic response. To better understand the mechanisms involved in CCL2/CCR2 signaling, we generated mice with conditional deletion of CCL12, a murine homolog of human CCL2. Surprisingly, we found that mice with complete deletion of CCL12 had markedly increased concentrations of other CCR2 ligands and were not protected from fibrosis after bleomycin injury. In contrast, mice with lung Epithelial Cell-specific deletion of CCL12 were protected from bleomycin-induced fibrosis and had expression of CCL2 and CCL7 similar to that of control mice treated with bleomycin. Deletion of CCL12 within AECs led to decreased recruitment of exudate macrophages. Finally, injury to murine and human primary AECs resulted in increased production of CCL2 and CCL12, in part through activation of the mTOR pathway. In conclusion, these data suggest that targeting CCL2 may be a viable antifibrotic strategy once the pathways involved in the production and function of CCL2 and other CCR2 ligands are better defined.

  • the vitronectin rgd motif regulates tgf β induced Alveolar Epithelial Cell apoptosis
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2016
    Co-Authors: Amanda K Wheaton, Miranda Velikoff, Manisha Agarwal, Jeffrey C Horowitz, Thomas H Sisson

    Abstract:

    Transforming growth factor-β (TGF-β) is a critical driver of acute lung injury and fibrosis. Injury leads to activation of TGF-β, which regulates changes in the Cellular and matrix makeup of the lung during the repair and fibrosis phase. TGF-β can also initiate Alveolar Epithelial Cell (AEC) apoptosis. Injury leads to destruction of the laminin-rich basement membrane, which is replaced by a provisional matrix composed of arginine-glycine-aspartate (RGD) motif-containing plasma matrix proteins, including vitronectin and fibronectin. To determine the role of specific matrix proteins on TGF-β-induced apoptosis, we studied primary AECs cultured on different matrix conditions and utilized mice with deletion of vitronectin (Vtn−/−) or mice in which the vitronectin RGD motif is mutated to nonintegrin-binding arginine-glycine-glutamate (RGE) (VtnRGE/RGE). We found that AECs cultured on fibronectin and vitronectin or in wild-type mouse serum are resistant to TGF-β-induced apoptosis. In contrast, AECs cultured on l…

  • the vitronectin rgd motif regulates tgf β induced Alveolar Epithelial Cell apoptosis
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2016
    Co-Authors: Amanda K Wheaton, Miranda Velikoff, Manisha Agarwal, Jeffrey C Horowitz, Thomas H Sisson

    Abstract:

    Transforming growth factor-β (TGF-β) is a critical driver of acute lung injury and fibrosis. Injury leads to activation of TGF-β, which regulates changes in the Cellular and matrix makeup of the lu…