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Sem H Phan - One of the best experts on this subject based on the ideXlab platform.

  • bone marrow cd11c cell derived amphiregulin promotes Pulmonary Fibrosis
    Journal of Immunology, 2016
    Co-Authors: Lin Ding, Tianju Liu, Taku Nakashima, Matthew Ullenbruch, Francina Gonzalez De Los Santos, Sem H Phan
    Abstract:

    Amphiregulin (AREG), an epidermal growth factor receptor ligand, is implicated in tissue repair and Fibrosis, but its cellular source and role in regeneration versus Fibrosis remain unclear. In this study, we hypothesize that AREG induced in bone marrow-derived CD11c(+) cells is essential for Pulmonary Fibrosis. Thus, the objectives were to evaluate the importance and role of AREG in Pulmonary Fibrosis, identify the cellular source of AREG induction, and analyze its regulation of fibroblast function and activation. The results showed that lung AREG expression was significantly induced in Bleomycin-Induced Pulmonary Fibrosis. AREG deficiency in knockout mice significantly diminished Pulmonary Fibrosis. Analysis of AREG expression in major lung cell types revealed induction in fibrotic lungs predominantly occurred in CD11c(+) cells. Moreover, depletion of bone marrow-derived CD11c(+) cells suppressed both induction of lung AREG expression and Pulmonary Fibrosis. Conversely, adoptive transfer of bone marrow-derived CD11c(+) cells from bleomycin-treated donor mice exacerbated Pulmonary Fibrosis, but not if the donor cells were made AREG deficient prior to transfer. CD11c(+) cell-conditioned media or coculture stimulated fibroblast proliferation, activation, and myofibroblast differentiation in an AREG-dependent manner. Furthermore, recombinant AREG induced telomerase reverse transcriptase, which appeared to be essential for the proliferative effect. Finally, AREG significantly enhanced fibroblast motility, which was associated with increased expression of α6 integrin. These findings suggested that induced AREG specifically in recruited bone marrow-derived CD11c(+) cells promoted Bleomycin-Induced Pulmonary Fibrosis by activation of fibroblast telomerase reverse transcriptase-dependent proliferation, motility, and indirectly, myofibroblast differentiation.

  • endothelial mesenchymal transition in bleomycin induced Pulmonary Fibrosis
    American Journal of Respiratory Cell and Molecular Biology, 2010
    Co-Authors: Naozumi Hashimoto, Sem H Phan, Kazuyoshi Imaizumi, Masaki Matsuo, Harunori Nakashima, Tsutomu Kawabe, Kaoru Shimokata, Yoshinori Hasegawa
    Abstract:

    The pathological hallmark lesions in idiopathic Pulmonary Fibrosis are the fibroblastic foci, in which fibroblasts are thought to be involved in the tissue remodeling, matrix deposition, and cross-talk with alveolar epithelium. Recent evidence indicates that some fibroblasts in Fibrosis may be derived from bone marrow progenitors as well as from epithelial cells through epithelial–mesenchymal transition. To evaluate whether endothelial cells could represent an additional source for fibroblasts, Bleomycin-Induced lung Fibrosis was established in Tie2-Cre/CAG-CAT-LacZ double-transgenic mice, in which LacZ was stably expressed in pan-endothelial cells. Combined X-gal staining and immunocytochemical staining for type I collagen and α-smooth muscle actin revealed the presence of X-gal–positive cells in lung fibroblast cultures from bleomycin-treated mice. To explore the underlying mechanisms, by which loss of endothelial-specific markers and gain of mesenchymal phenotypes could be involved in microvascular end...

  • lung fibroblast alpha smooth muscle actin expression and contractile phenotype in bleomycin induced Pulmonary Fibrosis
    American Journal of Pathology, 1996
    Co-Authors: Hong Yu Zhang, Mehrnaz Gharaeekermani, Kai Zhang, Soverin Karmiol, Sem H Phan
    Abstract:

    The emergence of the myofibroblast phenotype (characterized by alpha-smooth muscle actin expression) in wound healing and in tissues undergoing Fibrosis is thought to be responsible for the increased contractility of the affected tissues. In Bleomycin-Induced Pulmonary Fibrosis, the myofibroblast is also responsible for the observed increase in collagen gene expression. To evaluate further these phenotypic changes in lung fibroblasts, contractile and other phenotypic properties of fibroblasts isolated from lungs of rats with Bleomycin-Induced Fibrosis were compared with those of normal rats using in vitro models. Pulmonary Fibrosis was induced in rats by endotracheal injection on day 0, and 7 and 14 days later the animals were sacrificed and lung fibroblasts isolated. Using immunofluorescence, < 10% of fibroblasts from control animals express alpha-smooth muscle actin when cultured as a monolayer. In contrast, 19% and 21% of cells from day 7 and day 14 bleomycin-treated animals, respectively, expressed this actin and with greater intensity than in control lung cells. This increase in actin expression was associated with enhanced contractility when evaluated using a three-dimensional cell culture model consisting of fibroblast-populated collagen gels. This enhanced contractility was abolished by treatment with antibody to transforming growth factor-beta (TGF-beta), whereas exogenous TGF-beta 1 and serum-stimulated contraction of control lung fibroblasts. TGF-beta 1 gene expression was greater in cells from bleomycin-treated animals than those from control lungs. These results show that cells with the myofibroblast phenotype are more abundant in fibrotic lung, and that these cells possess greater contractile capacity in vitro at least partly by virtue of their enhanced endogenous TGF-beta 1 gene expression.

Akinori Arimura - One of the best experts on this subject based on the ideXlab platform.

  • antifibrotic action of pirfenidone and prednisolone different effects on Pulmonary cytokines and growth factors in bleomycin induced murine Pulmonary Fibrosis
    European Journal of Pharmacology, 2008
    Co-Authors: Hisashi Oku, Toshikatsu Shimizu, Tomoji Kawabata, Morio Nagira, Ichiro Hikita, Azumi Ueyama, Shuuichi Matsushima, Mikinori Torii, Akinori Arimura
    Abstract:

    Pirfenidone, a broad-spectrum antifibrotic agent, is known to have efficacy in certain fibrotic disease models, and is under clinical trials in patients with idiopathic Pulmonary Fibrosis. We investigated the antifibrotic effect of pirfenidone, and its regulatory effect on various Pulmonary cytokines, in Bleomycin-Induced lung Fibrosis in mice at the protein level, using prednisolone as a reference agent. Pirfenidone attenuated the Bleomycin-Induced Pulmonary Fibrosis at a minimum effective dose of 30 mg/kg/day t.i.d. from the analysis of lung hydroxyproline content. Both pirfenidone (30, 100 mg/kg/day t.i.d) and prednisolone (3, 15 mg/kg/day q.d.) suppressed lung inflammatory edema; however, prednisolone failed to suppress Pulmonary Fibrosis, which was significantly suppressed only by pirfenidone. Both pirfenidone and prednisolone suppressed the increase in lung interleukin (IL)-1beta, IL-6, IL-12p40 and monocyte chemoattractant protein (MCP)-1 levels induced by bleomycin. On the other hand, pirfenidone prevented the Bleomycin-Induced decrease in lung interferon (IFN)-gamma levels, while prednisolone had no such effect. Furthermore, pirfenidone suppressed elevation of lung basic-fibroblast growth factor (bFGF) and transforming growth factor (TGF)-beta1 levels, but prednisolone had no such effect. The increases in lung stroma cell derived factor (SDF)-1alpha and IL-18 were also suppressed. These findings suggest that pirfenidone exerts its antifibrotic effect through regulation of lung IFN-gamma, bFGF and TGF-beta1 levels during the development of Bleomycin-Induced Pulmonary Fibrosis in mice. The effect on SDF-1alpha and IL-18 levels may also be related to the antifibrotic effects of pirfenidone.

  • antifibrotic action of pirfenidone and prednisolone different effects on Pulmonary cytokines and growth factors in bleomycin induced murine Pulmonary Fibrosis
    European Journal of Pharmacology, 2008
    Co-Authors: Toshikatsu Shimizu, Tomoji Kawabata, Morio Nagira, Ichiro Hikita, Azumi Ueyama, Shuuichi Matsushima, Mikinori Torii, Akinori Arimura
    Abstract:

    Abstract Pirfenidone, a broad-spectrum antifibrotic agent, is known to have efficacy in certain fibrotic disease models, and is under clinical trials in patients with idiopathic Pulmonary Fibrosis. We investigated the antifibrotic effect of pirfenidone, and its regulatory effect on various Pulmonary cytokines, in Bleomycin-Induced lung Fibrosis in mice at the protein level, using prednisolone as a reference agent. Pirfenidone attenuated the Bleomycin-Induced Pulmonary Fibrosis at a minimum effective dose of 30 mg/kg/day t.i.d. from the analysis of lung hydroxyproline content. Both pirfenidone (30, 100 mg/kg/day t.i.d) and prednisolone (3, 15 mg/kg/day q.d.) suppressed lung inflammatory edema; however, prednisolone failed to suppress Pulmonary Fibrosis, which was significantly suppressed only by pirfenidone. Both pirfenidone and prednisolone suppressed the increase in lung interleukin (IL)-1β, IL-6, IL-12p40 and monocyte chemoattractant protein (MCP)-1 levels induced by bleomycin. On the other hand, pirfenidone prevented the Bleomycin-Induced decrease in lung interferon (IFN)-γ levels, while prednisolone had no such effect. Furthermore, pirfenidone suppressed elevation of lung basic-fibroblast growth factor (bFGF) and transforming growth factor (TGF)-β1 levels, but prednisolone had no such effect. The increases in lung stroma cell derived factor (SDF)-1α and IL-18 were also suppressed. These findings suggest that pirfenidone exerts its antifibrotic effect through regulation of lung IFN-γ, bFGF and TGF-β1 levels during the development of Bleomycin-Induced Pulmonary Fibrosis in mice. The effect on SDF-1α and IL-18 levels may also be related to the antifibrotic effects of pirfenidone.

Y Kapanci - One of the best experts on this subject based on the ideXlab platform.

  • rat alveolar myofibroblasts acquire alpha smooth muscle actin expression during bleomycin induced Pulmonary Fibrosis
    American Journal of Pathology, 1993
    Co-Authors: S L Vyalov, Giulio Gabbiani, Y Kapanci
    Abstract:

    The majority of fibroblasts in alveolar septa are characterized by the presence of cytoplasmic bundles of microfilaments that contain cytoplasmic actin isoforms; these cells have been named contractile interstitial cells or V-type myofibroblasts. In the rat, they express desmin as intermediate filament protein. In this study, we explored the possibility that modulation and replication of such septal fibroblasts result in the appearance of alpha-smooth muscle (alpha-SM) actin-positive myofibroblasts, typical of lung Fibrosis. Experimental Pulmonary Fibrosis was produced by a unique intratracheal instillation of bleomycin to 28 rats. Eight additional rats used as controls received the equivalent volume of saline. Paraffin and frozen sections of lungs were examined at days 1, 3, 5 and 7 after treatment. Microfilaments and intermediate filaments were stained using antibodies against total actin, alpha-SM actin, desmin, vimentin, keratin, and SM myosin. Electron microscopic labeling of desmin and alpha-SM actin using immunogold technique was done on Lowicryl K4M resin-embedded specimens. alpha-SM actin appeared in desmin-positive alveolar fibroblasts as early as 24 hours after intratracheal bleomycin instillation; the modulation of alpha-SM actin in these cells was preceded by a lymphomonocytic infiltration of alveolar septa. Twenty-four hours to 3 days after bleomycin administration, a proliferation of alveolar myofibroblasts occurred. Fibrosis with laying down of collagen fibers took place after the above mentioned cellular modifications. Our results support the view that septal fibroblastic cells can modulate into typical alpha-SM actin-containing myofibroblasts during experimental Bleomycin-Induced Pulmonary Fibrosis. In such a modulation a possible role of cytokines, particularly of transforming growth factor-beta, is considered.

Hong Yu Zhang - One of the best experts on this subject based on the ideXlab platform.

  • lung fibroblast alpha smooth muscle actin expression and contractile phenotype in bleomycin induced Pulmonary Fibrosis
    American Journal of Pathology, 1996
    Co-Authors: Hong Yu Zhang, Mehrnaz Gharaeekermani, Kai Zhang, Soverin Karmiol, Sem H Phan
    Abstract:

    The emergence of the myofibroblast phenotype (characterized by alpha-smooth muscle actin expression) in wound healing and in tissues undergoing Fibrosis is thought to be responsible for the increased contractility of the affected tissues. In Bleomycin-Induced Pulmonary Fibrosis, the myofibroblast is also responsible for the observed increase in collagen gene expression. To evaluate further these phenotypic changes in lung fibroblasts, contractile and other phenotypic properties of fibroblasts isolated from lungs of rats with Bleomycin-Induced Fibrosis were compared with those of normal rats using in vitro models. Pulmonary Fibrosis was induced in rats by endotracheal injection on day 0, and 7 and 14 days later the animals were sacrificed and lung fibroblasts isolated. Using immunofluorescence, < 10% of fibroblasts from control animals express alpha-smooth muscle actin when cultured as a monolayer. In contrast, 19% and 21% of cells from day 7 and day 14 bleomycin-treated animals, respectively, expressed this actin and with greater intensity than in control lung cells. This increase in actin expression was associated with enhanced contractility when evaluated using a three-dimensional cell culture model consisting of fibroblast-populated collagen gels. This enhanced contractility was abolished by treatment with antibody to transforming growth factor-beta (TGF-beta), whereas exogenous TGF-beta 1 and serum-stimulated contraction of control lung fibroblasts. TGF-beta 1 gene expression was greater in cells from bleomycin-treated animals than those from control lungs. These results show that cells with the myofibroblast phenotype are more abundant in fibrotic lung, and that these cells possess greater contractile capacity in vitro at least partly by virtue of their enhanced endogenous TGF-beta 1 gene expression.

Geoffrey J. Laurent - One of the best experts on this subject based on the ideXlab platform.

  • Mice lacking neutrophil elastase are resistant to Bleomycin-Induced Pulmonary Fibrosis.
    The American Journal of Pathology, 2007
    Co-Authors: Felix Chua, Steven D Shapiro, Sarah E. Dunsmore, Peter H. Clingen, Steven E. Mutsaers, Anthony W. Segal, Jürgen Roes, Geoffrey J. Laurent
    Abstract:

    Neutrophil elastase is a serine protease stored in the azurophilic granules of leukocytes. It has been implicated in the pathology of several lung diseases and is generally presumed to contribute to the tissue destruction and extracellular matrix damage associated with these conditions. To delineate the role of neutrophil elastase in Pulmonary inflammation and Fibrosis, neutrophil elastase-null mice were intratracheally instilled with bleomycin. In neutrophil elastase-null mice, biochemical and morphological characteristics of Pulmonary Fibrosis were attenuated for at least 60 days after bleomycin administration despite a typical response to bleomycin as evidenced by assessment of indices of DNA and cell damage. Neutrophil burden of bleomycin-treated wild-type and neutrophil elastase-null mice was comparable, and marked neutrophilic alveolitis was manifest in bleomycin-treated neutrophil elastase-null mice. An absence of immunostaining for active transforming growth factor (TGF)-β in lung tissue from bleomycin-treated neutrophil elastase-null mice suggested a defect in TGF-β activation, which was confirmed by biochemical assessment of TGF-β levels in bronchoalveolar lavage fluid and lung tissue. These data point to novel and unexpected fibrogenic consequences of neutrophil elastase activity in the inflamed lung.

  • cyclooxygenase 2 deficiency results in a loss of the anti proliferative response to transforming growth factor β in human fibrotic lung fibroblasts and promotes bleomycin induced Pulmonary Fibrosis in mice
    American Journal of Pathology, 2001
    Co-Authors: Carmel B Keerthisingam, Geoffrey J. Laurent, Gisli R Jenkins, N K Harrison, Norma A Hernandezrodriguez, Helen Booth, Stephen L Hart, Martyn Foster, Robin J Mcanulty
    Abstract:

    Prostaglandin E 2 (PGE 2 ) inhibits fibroblast proliferation and collagen production. Its synthesis by fibroblasts is induced by profibrotic mediators including transforming growth factor (TGF)-β 1 . However, in patients with Pulmonary Fibrosis, PGE 2 levels are decreased. In this study we examined the effect of TGF-β 1 on PGE 2 synthesis, proliferation, collagen production, and cyclooxygenase (COX) mRNA levels in fibroblasts derived from fibrotic and nonfibrotic human lung. In addition, we examined the effect of Bleomycin-Induced Pulmonary Fibrosis in COX-2-deficient mice. We demonstrate that basal and TGF-β 1 -induced PGE 2 synthesis is limited in fibroblasts from fibrotic lung. Functionally, this correlates with a loss of the anti-proliferative response to TGF-β 1 . This failure to induce PGE 2 synthesis is because of an inability to up-regulate COX-2 mRNA levels in these fibroblasts. Furthermore, mice deficient in COX-2 exhibit an enhanced response to bleomycin. We conclude that a decreased capacity to up-regulate COX-2 expression and COX-2-derived PGE 2 synthesis in the presence of increasing levels of profibrotic mediators such as TGF-β 1 may lead to unopposed fibroblast proliferation and collagen synthesis and contribute to the pathogenesis of Pulmonary Fibrosis.