Bleomycin-Induced Lung Injury

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Thomas R Ulich - One of the best experts on this subject based on the ideXlab platform.

  • Keratinocyte Growth Factor Decreases Pulmonary Edema, Transforming Growth Factor-Beta and Platelet-Derived Growth Factor-BB Expression, and Alveolar Type II Cell Loss in Bleomycin-Induced Lung Injury
    Inflammation, 1998
    Co-Authors: Eunhee S Yi, Moses Salgado, Scott T. Williams, Eliezer Masliah, Thomas R Ulich
    Abstract:

    Keratinocyte growth factor (KGF), a potent growth factor for type II pneumocytes and Clara cells, has been shown to prevent the end-stage pulmonary fibrosis and mortality in a rat model of Bleomycin-Induced Lung Injury. In this study, protective effects of KGF were explored during the earlier course of Bleomycin-Induced Lung Injury by studying protein exudation in alveolar edema fluids, pulmonary expression of transforming growth factor-beta (TGFβ) and platelet-derived growth factor-BB (PDGF-BB), and changes in type II pneumocytes and Clara cells after i.t. (intratracheal) bleomycin injection following KGF- or saline-pretreatment in rats. Total protein in bronchoalveolar lavage (BAL) fluids after bleomycin Injury from KGF-pretreated rats was significantly lower than the levels in saline-pretreated rats. TGFβ protein in BAL fluids which peaked at day 3 after i.t. bleomycin in saline-pretreated Lungs was not significantly increased at any time points in KGF-pretreated rats. PDGF-BB protein in whole Lung tissues of KGF-pretreated rats also remained near normal throughout the course after i.t. bleomycin, in contrast to the significant increase in saline-pretreated rats. Numbers of type II pneumocytes and Clara cells in KGF-pretreated Lungs after a high dose of bleomycin were close to the normal in intact Lungs. At the same dose of bleomycin Injury, type II pneumocytes in saline-pretreated Lungs were markedly decreased, while the number of Clara cells in these rats was relatively preserved as the pre-Injury level. In conclusion, KGF prevents Bleomycin-Induced end-stage pulmonary Injury and mortality probably at least partly by decreasing protein-rich pulmonary edema, protein expression of fibrogenic cytokines TGFβ and PDGF-BB, and type II cell loss during the course of Lung Injury.

  • keratinocyte growth factor ameliorates radiation and bleomycin induced Lung Injury and mortality
    American Journal of Pathology, 1996
    Co-Authors: Eunhee S Yi, Scott Williams, Denise M Malicki, Elaine M Chin, John E Tarpley, Thomas R Ulich
    Abstract:

    Keratinocyte growth factor (KGF) is a growth factor for type II pneumocytes. Type II pneumocyte hyperplasia, a common reaction to Lung Injury, has been postulated to play an important role in Lung repair. The potential protective effect of KGF was therefore studied in rat models of radiation- and Bleomycin-Induced Lung Injury. Intratracheal instillation of KGF (5 mg/kg) 72 and 48 hours before 18 Gy of bilateral thoracic irradiation did not significantly improve survival, although histology showed less pneumonitis and fibrosis in KGF-pretreated as compared with control-irradiated rats. Intratracheal pretreatment with KGF in rats receiving intratracheal bleomycin (2.5 U) improved survival at 3 weeks to 100% (20/20 rats) from 40% (8/20 rats) in controls. All KGF-pretreated rats receiving bleomycin were well at 3 weeks and without histological evidence of pulmonary fibrosis whereas the 8 surviving control rats exhibited severe respiratory distress. Finally, in the most lethal challenge to the Lung, rats pretreated with intratracheal KGF or saline were challenged with a combination of bleomycin (1.5 U) and bilateral thoracic irradiation (18 Gy). KGF-pretreated rats did not begin to die or show signs of respiratory distress until 7 weeks, whereas all saline-pretreated control rats receiving radiation and bleomycin died within approximately 4 weeks with severe respiratory distress and weight loss. In conclusion, radiation- and Bleomycin-Induced pulmonary Injury and respiratory death are ameliorated by KGF pretreatment, suggesting a protective role for KGF-induced type II pneumocyte proliferation in Lung Injury.

Eunhee S Yi - One of the best experts on this subject based on the ideXlab platform.

  • Keratinocyte Growth Factor Decreases Pulmonary Edema, Transforming Growth Factor-Beta and Platelet-Derived Growth Factor-BB Expression, and Alveolar Type II Cell Loss in Bleomycin-Induced Lung Injury
    Inflammation, 1998
    Co-Authors: Eunhee S Yi, Moses Salgado, Scott T. Williams, Eliezer Masliah, Thomas R Ulich
    Abstract:

    Keratinocyte growth factor (KGF), a potent growth factor for type II pneumocytes and Clara cells, has been shown to prevent the end-stage pulmonary fibrosis and mortality in a rat model of Bleomycin-Induced Lung Injury. In this study, protective effects of KGF were explored during the earlier course of Bleomycin-Induced Lung Injury by studying protein exudation in alveolar edema fluids, pulmonary expression of transforming growth factor-beta (TGFβ) and platelet-derived growth factor-BB (PDGF-BB), and changes in type II pneumocytes and Clara cells after i.t. (intratracheal) bleomycin injection following KGF- or saline-pretreatment in rats. Total protein in bronchoalveolar lavage (BAL) fluids after bleomycin Injury from KGF-pretreated rats was significantly lower than the levels in saline-pretreated rats. TGFβ protein in BAL fluids which peaked at day 3 after i.t. bleomycin in saline-pretreated Lungs was not significantly increased at any time points in KGF-pretreated rats. PDGF-BB protein in whole Lung tissues of KGF-pretreated rats also remained near normal throughout the course after i.t. bleomycin, in contrast to the significant increase in saline-pretreated rats. Numbers of type II pneumocytes and Clara cells in KGF-pretreated Lungs after a high dose of bleomycin were close to the normal in intact Lungs. At the same dose of bleomycin Injury, type II pneumocytes in saline-pretreated Lungs were markedly decreased, while the number of Clara cells in these rats was relatively preserved as the pre-Injury level. In conclusion, KGF prevents Bleomycin-Induced end-stage pulmonary Injury and mortality probably at least partly by decreasing protein-rich pulmonary edema, protein expression of fibrogenic cytokines TGFβ and PDGF-BB, and type II cell loss during the course of Lung Injury.

  • keratinocyte growth factor ameliorates radiation and bleomycin induced Lung Injury and mortality
    American Journal of Pathology, 1996
    Co-Authors: Eunhee S Yi, Scott Williams, Denise M Malicki, Elaine M Chin, John E Tarpley, Thomas R Ulich
    Abstract:

    Keratinocyte growth factor (KGF) is a growth factor for type II pneumocytes. Type II pneumocyte hyperplasia, a common reaction to Lung Injury, has been postulated to play an important role in Lung repair. The potential protective effect of KGF was therefore studied in rat models of radiation- and Bleomycin-Induced Lung Injury. Intratracheal instillation of KGF (5 mg/kg) 72 and 48 hours before 18 Gy of bilateral thoracic irradiation did not significantly improve survival, although histology showed less pneumonitis and fibrosis in KGF-pretreated as compared with control-irradiated rats. Intratracheal pretreatment with KGF in rats receiving intratracheal bleomycin (2.5 U) improved survival at 3 weeks to 100% (20/20 rats) from 40% (8/20 rats) in controls. All KGF-pretreated rats receiving bleomycin were well at 3 weeks and without histological evidence of pulmonary fibrosis whereas the 8 surviving control rats exhibited severe respiratory distress. Finally, in the most lethal challenge to the Lung, rats pretreated with intratracheal KGF or saline were challenged with a combination of bleomycin (1.5 U) and bilateral thoracic irradiation (18 Gy). KGF-pretreated rats did not begin to die or show signs of respiratory distress until 7 weeks, whereas all saline-pretreated control rats receiving radiation and bleomycin died within approximately 4 weeks with severe respiratory distress and weight loss. In conclusion, radiation- and Bleomycin-Induced pulmonary Injury and respiratory death are ameliorated by KGF pretreatment, suggesting a protective role for KGF-induced type II pneumocyte proliferation in Lung Injury.

Raphael Breuer - One of the best experts on this subject based on the ideXlab platform.

  • The effect of enoxaparin on Bleomycin-Induced Lung Injury in mice.
    Experimental Lung Research, 2009
    Co-Authors: Uri Laxer, Ronald H. Goldstein, Reuven Or, Izidore S. Lossos, Thomas G. Christensen, S. Gillis, Raphael Breuer
    Abstract:

    We have evaluated the effect of enoxaparin, a potent antithrombotic drug, on bleomycin (Bleo) induced pulmonary inflammation in mice. Pulmonary Injury was induced by a single intratracheal (IT) instillation of Bleo. Four groups of female C57BL/6 mice, each received one of four treatments: (1) IT Bleo and daily intraperitoneal (IP) injections of enoxaparin (EN) starting one day before IT instillation of Bleo (Bleo-EN); (2) IT Bleo and IP injections of saline (Bleo-Sal); (3) IT saline and IP enoxaparin (Sal-EN); (4) IT saline and IP saline (Sal-Sal). Animals were sacrificed 14 days after IT treatment. Lung Injury was evaluated by analysis of bronchoalveolar lavage fluid and histologically by an overall semiquantitative index of Lung Injury and a quantitative image analysis assessing alveolar wall area fraction and fibrosis fraction. Treatment of mice with enoxaparin did not ameliorate Bleo induced Lung Injury. Our study does not establish a critical role of procoagulant activity in the evolution of Bleo-ind...

  • Lymphokines in Bleomycin-Induced Lung Injury in bleomycin-sensitive C57BL/6 and -resistant BALB/c mice.
    Experimental Lung Research, 2009
    Co-Authors: Reuven Or, Michael J. Segel, Miriam Shriki, Gabriel Izbicki, Raphael Breuer
    Abstract:

    To study the pattern of lymphokines in Bleomycin-Induced Lung Injury, T cells were isolated from Lung interstitial tissue (LIL), peribronchial lymphatic tissue (PBLT), and bronchoalveolar lavage (BAL) fluid of bleomycin-"sensitive" C57Bl/6 and bleomycin-''resistant'' BALB/c mice at 3, 6, and 14 days following intratracheal instillation of bleomycin or saline. After 48 hours in culture, conditioned media were collected and assayed with specific enzyme-linked immunosorbent assay (ELISA) for interferon (IFN)-, interleukin (IL)-2, IL-4 and IL-5. In bleomycin-treated C57B1/6 mice, IFN- production was increased up to 20-fold at 3 and 6 days in LIL, and at 3 days in PBLT lymphocytes. IL-4 production was slightly decreased in LIL and PBLT lymphocytes at 14 days. IL-2 and IL-5 were not changed by bleomycin. In BALB/c mice, IFN- production was increased 5-fold at 14 days, and IL-2 production at 6 days, in LIL but not PBLT. IL-4 and IL-5 were not significantly changed. The increase in IFN- may play a role in the pat...

  • Bleomycin initiates apoptosis of Lung epithelial cells by ROS but not by Fas/FasL pathway.
    American Journal of Physiology-lung Cellular and Molecular Physiology, 2005
    Co-Authors: Shulamit B. Wallach-dayan, Gabriel Izbicki, Pazit Y. Cohen, Regina Gerstl-golan, Alan Fine, Raphael Breuer
    Abstract:

    Epithelial cells are considered to be a main target of Bleomycin-Induced Lung Injury, which leads to fibrosis in vivo. We studied the characteristics of in vitro Bleomycin-Induced apoptosis in a mo...

  • Halofuginone does not reduce fibrosis in Bleomycin-Induced Lung Injury
    Life Sciences, 2002
    Co-Authors: Anat Tzurel, Michael J. Segel, Ronald H. Goldstein, Reuven Or, Raphael Breuer
    Abstract:

    Abstract Halofuginone, a coccidiostatic alkaloid, has anti-fibrotic properties, and may be useful as a therapeutic agent in Lung fibrosis. To test this hypothesis we investigated the effect of halofuginone on Bleomycin-Induced Lung fibrosis in Sprague–Dawley rats. Treatment groups included: (1) a single intratracheal (IT) instillation of 1.2U bleomycin, and intraperitoneal (IP) injection of halofuginone (0.5 mg/dose), every other day; (2) IT 1.2U bleomycin and IP distilled water (D.W.), every other day; (3) IT 0.8U bleomycin and daily IP halofuginone (0.5 mg/dose); (4) IT 0.8U bleomycin and daily IP D.W.; (5) IT saline and IP halofuginone, every other day; (6) IT saline and daily IP D.W.; (7) IT 0.625U bleomycin and oral halofuginone (10 mg/kg rodent lab chow); (8) IT 0.625U bleomycin and standard lab chow. Animals were studied 14 days after IT instillation. Lung Injury was evaluated by total and differential cell count in bronchoalveolar lavage fluid, by a semi-quantitative morphological index of Lung Injury, and by biochemical analysis of Lung hydroxyproline content. Overt signs of Lung Injury were apparent in bleomycin-treated rats by all measures. These changes were not affected by treatment with halofuginone, irrespective of the treatment regimen used. This study does not support the use of halofuginone to prevent or ameliorate Lung fibrosis.

  • The effect of suramin on Bleomycin-Induced Lung Injury.
    Life Sciences, 2000
    Co-Authors: Izidore S. Lossos, Ronald H. Goldstein, Reuven Or, Gabriel Izbicki, Raphael Breuer
    Abstract:

    Abstract Since transforming growth factor β (TGF-β) is presumed to play a role in Lung fibrosis, we evaluated the effect of suramin (Sur), a substance with an anti-TGF-β effect, in vivo on bleomycin (Bleo)-induced pulmonary Injury in mice and in vitro on human Lung fibroblasts. Four groups of C57BL/6 mice each received one of four treatments: (1) intratracheal (IT) instillation of Bleo and intraperitoneal (IP) injections of Sur, every other day, starting one day before IT instillation of Bleo (Bleo-Sur); (2) IT Bleo and IP injections of saline (Bleo-Sal); (3) IT saline and IP Sur (Sal-Sur); and (4) IT and IP saline (Sal-Sal). Animals were sacrificed 14 days after IT treatment. Lung Injury was evaluated by analysis of bronchoalveolar lavage (BAL) fluid, histologically by the semiquantitative morphological index, and biochemically by analysis of Lung hydroxyproline content. In vitro , Sur did not affect TGF-β induced increase of α 1 (I) collagen mRNA in human Lung fibroblasts. In vivo treatment of mice with Sur did not affect Bleo-induced Lung Injury. These results indicate that despite its potential anti TGF-β and lymphocytotoxic effects, Sur is not a therapeutic candidate drug for rescue of Lung fibrosis.

Yannick Crémillieux - One of the best experts on this subject based on the ideXlab platform.

  • MR imaging, targeting and characterization of pulmonary fibrosis using intra-tracheal administration of gadolinium-based nanoparticles
    Contrast Media and Molecular Imaging, 2016
    Co-Authors: Nawal Tassali, Andrea Bianchi, François Lux, Gérard Raffard, Stephane Sanchez, Olivier Tillement, Yannick Crémillieux
    Abstract:

    Idiopathic pulmonary fibrosis is a devastating disease. Animal models are critical to develop new diagnostic approaches. We investigate here whether the application of an ultra-short echo time MRI sequence combined with the intra-tracheal administration of Gd-based nanoparticles can help to visualize and characterize pulmonary fibrosis in mice. 21 mice were imaged. Treated mice were administered bleomycin. MRI was used for longitudinal detection of Bleomycin-Induced Lung Injury from Day 1 up to Day 60. On Day 30, all mice received nanoparticles and MR images were acquired. A signal enhancement of 120% and 50% in fibrotic lesions and healthy tissues respectively was obtained. A twofold increase of contrast-to-noise ratio between fibrotic and healthy tissue was also observed, leading to a more accurate delineation of the extent of fibrosis. The elimination time constant of the nanoparticles was 54% higher in fibrotic lesions. Bleomycin-Induced Lung Injury can be monitored using MRI. Intra-tracheal administration of Gd-based nanoparticles enabled us to enhance fibrotic tissue in Lungs but also to extract imaging biomarkers that quantify elimination and diffusion of contrast agents and can characterize fibrotic tissue. The added value of MRI associated with pulmonary administration of contrast agents is key to better understand the Lung fibrotic process and monitor drug response in pre-clinical studies, which will be valuable for transla-tional applications.

Steven L. Kunkel - One of the best experts on this subject based on the ideXlab platform.

  • production and function of murine macrophage inflammatory protein 1 alpha in bleomycin induced Lung Injury
    Journal of Immunology, 1994
    Co-Authors: Robert E Smith, Robert M. Strieter, Marie D. Burdick, Sem H Phan, Nicholas W Lukacs, Gary B Huffnagle, Carol A Wilke, Pamela M Lincoln, Holly L Evanoff, Steven L. Kunkel
    Abstract:

    We investigated the role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in Bleomycin-Induced Lung Injury, a model of interstitial Lung disease. Bleomycin stimulates a T cell-dependent pulmonary inflammatory response characterized by an increase in leukocyte infiltration, fibroblast proliferation, and collagen synthesis. Intratracheal challenge of CBA/J mice with bleomycin resulted in a significant time-dependent increase in MIP-1 alpha protein levels both in whole-Lung homogenates and bronchoalveolar lavage fluid. The kinetics of MIP-1 alpha expression were biphasic, with the first peak occurring at 2 days postinstillation and the second peak at 16 days. These levels of Ag expression temporally correlated with the accumulation of granulocytes, lymphocytes, and mononuclear phagocytes in the Lung. In addition, immunohistochemical staining identified alveolar macrophages and bronchial epithelial cells as the primary cellular sources of MIP-1 alpha production. Interestingly, passive immunization of bleomycin-challenged mice with anti-MIP-1 alpha Abs significantly reduced pulmonary mononuclear phagocyte accumulation and fibrosis. These experiments establish that MIP-1 alpha protein is expressed in the Lungs of bleomycin-treated mice and provide evidence that MIP-1 alpha promotes leukocyte accumulation and activation. Furthermore, these findings support the notion that leukocyte accumulation and activation are linked to fibrosis.