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  1. Article ; Online: Surfactant protein D regulates caspase-8-mediated cascade of the intrinsic pathway of apoptosis while promoting bleb formation.

    Djiadeu, Pascal / Farmakovski, Nicole / Azzouz, Dhia / Kotra, Lakshmi P / Sweezey, Neil / Palaniyar, Nades

    Molecular immunology

    2017  Volume 92, Page(s) 190–198

    Abstract: Surfactant-associated protein D (SP-D) is a soluble innate immune collectin present on many mucosal surfaces. We recently showed that SP-D suppresses the extrinsic pathway of apoptosis by downregulating caspase-8 activation. However, the effects of SP-D ... ...

    Abstract Surfactant-associated protein D (SP-D) is a soluble innate immune collectin present on many mucosal surfaces. We recently showed that SP-D suppresses the extrinsic pathway of apoptosis by downregulating caspase-8 activation. However, the effects of SP-D on the intrinsic pathway of apoptosis are not clearly understood. In the intrinsic pathway, cytochrome c is released by mitochondria into the cytoplasm. Oxidation of cytochrome c by cytochrome c oxidase activates the apoptosome and caspase-9 cascade. Both caspase-8- and caspase-9-mediated branches are activated in the intrinsic pathway of apoptosis; however, little is known about the relevance of the caspase-8 pathway in this context. Here we studied the effects of SP-D on different branches of the intrinsic pathway of apoptosis using UV-irradiated Jurkat T-cells. We found that SP-D does not inhibit the caspase-9 branch of apoptosis and the relevance of the caspase-8-related branch became apparent when the caspase-9 pathway was inhibited by blocking cytochrome c oxidase. Under these conditions, SP-D reduces the activation of caspase-8, executioner caspase-3 and exposure of phosphatidylserine (PS) on the membranes of dying cells. By contrast, SP-D increases the formation of nuclear and membrane blebs. Inhibition of caspase-8 confirms the effect of SP-D is unique to the caspase-8 pathway. Overall, SP-D suppresses certain aspects of the intrinsic pathway of apoptosis via reduction of caspase-8 activation and PS flipping while at the same time increasing membrane and nuclear bleb formation. This novel regulatory aspect of SP-D could help to regulate intrinsic pathway of apoptosis to promote effective blebbing and breakdown of dying cells.
    MeSH term(s) Apoptosis/immunology ; Caspase 3/immunology ; Caspase 8/immunology ; Caspase 9/immunology ; Cell Membrane Structures/immunology ; Cytochromes c/immunology ; Humans ; Jurkat Cells ; Nuclear Envelope/immunology ; Pulmonary Surfactant-Associated Protein D/immunology ; Signal Transduction/immunology
    Chemical Substances Pulmonary Surfactant-Associated Protein D ; Cytochromes c (9007-43-6) ; CASP3 protein, human (EC 3.4.22.-) ; CASP8 protein, human (EC 3.4.22.-) ; CASP9 protein, human (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-) ; Caspase 8 (EC 3.4.22.-) ; Caspase 9 (EC 3.4.22.-)
    Language English
    Publishing date 2017-11-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 424427-8
    ISSN 1872-9142 ; 0161-5890
    ISSN (online) 1872-9142
    ISSN 0161-5890
    DOI 10.1016/j.molimm.2017.10.016
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: SP-D counteracts GM-CSF-mediated increase of granuloma formation by alveolar macrophages in lysinuric protein intolerance

    Grasemann Hartmut / Dell Sharon / Farmakovski Nicole / Douda David N / Palaniyar Nades

    Orphanet Journal of Rare Diseases, Vol 4, Iss 1, p

    2009  Volume 29

    Abstract: Abstract Background Pulmonary alveolar proteinosis (PAP) is a syndrome with multiple etiologies and is often deadly in lysinuric protein intolerance (LPI). At present, PAP is treated by whole lung lavage or with granulocyte/monocyte colony stimulating ... ...

    Abstract Abstract Background Pulmonary alveolar proteinosis (PAP) is a syndrome with multiple etiologies and is often deadly in lysinuric protein intolerance (LPI). At present, PAP is treated by whole lung lavage or with granulocyte/monocyte colony stimulating factor (GM-CSF); however, the effectiveness of GM-CSF in treating LPI associated PAP is uncertain. We hypothesized that GM-CSF and surfactant protein D (SP-D) would enhance the clearance of proteins and dying cells that are typically present in the airways of PAP lungs. Methods Cells and cell-free supernatant of therapeutic bronchoalveolar lavage fluid (BALF) of a two-year-old patient with LPI were isolated on multiple occasions. Diagnostic BALF samples from an age-matched patient with bronchitis or adult PAP patients were used as controls. SP-D and total protein content of the supernatants were determined by BCA assays and Western blots, respectively. Cholesterol content was determined by a calorimetic assay or Oil Red O staining of cytospin preparations. The cells and surfactant lipids were also analyzed by transmission electron microscopy. Uptake of Alexa-647 conjugated BSA and DiI-labelled apoptotic Jurkat T-cells by BAL cells were studied separately in the presence or absence of SP-D (1 μg/ml) and/or GM-CSF (10 ng/ml), ex vivo . Specimens were analyzed by light and fluorescence microscopy. Results Here we show that large amounts of cholesterol, and large numbers of cholesterol crystals, dying cells, and lipid-laden foamy alveolar macrophages were present in the airways of the LPI patient. Although SP-D is present, its bioavailability is low in the airways. SP-D was partially degraded and entrapped in the unusual surfactant lipid tubules with circular lattice, in vivo . We also show that supplementing SP-D and GM-CSF increases the uptake of protein and dying cells by healthy LPI alveolar macrophages, ex vivo . Serendipitously, we found that these cells spontaneously generated granulomas, ex vivo , and GM-CSF treatment drastically increased the number of granulomas whereas SP-D treatment counteracted the adverse effect of GM-CSF. Conclusions We propose that increased GM-CSF and decreased bioavailability of SP-D may promote granuloma formation in LPI, and GM-CSF may not be suitable for treating PAP in LPI. To improve the lung condition of LPI patients with PAP, it would be useful to explore alternative therapies for increasing dead cell clearance while decreasing cholesterol content in the airways.
    Keywords Medicine ; R
    Subject code 610 ; 616
    Language English
    Publishing date 2009-12-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: SP-D counteracts GM-CSF-mediated increase of granuloma formation by alveolar macrophages in lysinuric protein intolerance.

    Douda, David N / Farmakovski, Nicole / Dell, Sharon / Grasemann, Hartmut / Palaniyar, Nades

    Orphanet journal of rare diseases

    2009  Volume 4, Page(s) 29

    Abstract: Background: Pulmonary alveolar proteinosis (PAP) is a syndrome with multiple etiologies and is often deadly in lysinuric protein intolerance (LPI). At present, PAP is treated by whole lung lavage or with granulocyte/monocyte colony stimulating factor ( ... ...

    Abstract Background: Pulmonary alveolar proteinosis (PAP) is a syndrome with multiple etiologies and is often deadly in lysinuric protein intolerance (LPI). At present, PAP is treated by whole lung lavage or with granulocyte/monocyte colony stimulating factor (GM-CSF); however, the effectiveness of GM-CSF in treating LPI associated PAP is uncertain. We hypothesized that GM-CSF and surfactant protein D (SP-D) would enhance the clearance of proteins and dying cells that are typically present in the airways of PAP lungs.
    Methods: Cells and cell-free supernatant of therapeutic bronchoalveolar lavage fluid (BALF) of a two-year-old patient with LPI were isolated on multiple occasions. Diagnostic BALF samples from an age-matched patient with bronchitis or adult PAP patients were used as controls. SP-D and total protein content of the supernatants were determined by BCA assays and Western blots, respectively. Cholesterol content was determined by a calorimetic assay or Oil Red O staining of cytospin preparations. The cells and surfactant lipids were also analyzed by transmission electron microscopy. Uptake of Alexa-647 conjugated BSA and DiI-labelled apoptotic Jurkat T-cells by BAL cells were studied separately in the presence or absence of SP-D (1 microg/ml) and/or GM-CSF (10 ng/ml), ex vivo. Specimens were analyzed by light and fluorescence microscopy.
    Results: Here we show that large amounts of cholesterol, and large numbers of cholesterol crystals, dying cells, and lipid-laden foamy alveolar macrophages were present in the airways of the LPI patient. Although SP-D is present, its bioavailability is low in the airways. SP-D was partially degraded and entrapped in the unusual surfactant lipid tubules with circular lattice, in vivo. We also show that supplementing SP-D and GM-CSF increases the uptake of protein and dying cells by healthy LPI alveolar macrophages, ex vivo. Serendipitously, we found that these cells spontaneously generated granulomas, ex vivo, and GM-CSF treatment drastically increased the number of granulomas whereas SP-D treatment counteracted the adverse effect of GM-CSF.
    Conclusions: We propose that increased GM-CSF and decreased bioavailability of SP-D may promote granuloma formation in LPI, and GM-CSF may not be suitable for treating PAP in LPI. To improve the lung condition of LPI patients with PAP, it would be useful to explore alternative therapies for increasing dead cell clearance while decreasing cholesterol content in the airways.
    MeSH term(s) Adult ; Amino Acid Metabolism, Inborn Errors/immunology ; Amino Acid Metabolism, Inborn Errors/metabolism ; Amino Acid Metabolism, Inborn Errors/physiopathology ; Amino Acid Metabolism, Inborn Errors/therapy ; Bronchoalveolar Lavage Fluid/chemistry ; Bronchoalveolar Lavage Fluid/cytology ; Child, Preschool ; Cholesterol/metabolism ; Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use ; Granuloma/metabolism ; Humans ; Lung/cytology ; Lung/metabolism ; Lysine/metabolism ; Macrophages, Alveolar/physiology ; Pulmonary Alveolar Proteinosis/immunology ; Pulmonary Alveolar Proteinosis/metabolism ; Pulmonary Alveolar Proteinosis/physiopathology ; Pulmonary Alveolar Proteinosis/therapy ; Pulmonary Alveoli/metabolism ; Pulmonary Alveoli/physiology ; Pulmonary Surfactant-Associated Protein D/metabolism ; Pulmonary Surfactant-Associated Protein D/therapeutic use ; Treatment Outcome
    Chemical Substances Pulmonary Surfactant-Associated Protein D ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1) ; Cholesterol (97C5T2UQ7J) ; Lysine (K3Z4F929H6)
    Language English
    Publishing date 2009-12-23
    Publishing country England
    Document type Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1750-1172
    ISSN (online) 1750-1172
    DOI 10.1186/1750-1172-4-29
    Database MEDical Literature Analysis and Retrieval System OnLINE

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