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Am. J. Respir. Cell Mol. Biol., Vol 16, No. 1, Jan 1997, 91-101.

Apoptosis and expression of Fas/Fas ligand mRNA in bleomycin-induced pulmonary fibrosis in mice

N Hagimoto, K Kuwano, Y Nomoto, R Kunitake and N Hara
Research Institute for Diseases of the Chest, Faculty of Medicine, Kyushu University, Fukuoka, Japan.

The incidence of apoptosis and the expression of Fas antigen (Fas)/Fas ligand (FasL) mRNA in bleomycin-induced pulmonary fibrosis in mice were examined. Male ICR mice were intratracheally instilled with bleomycin (5 U/kg of body weight). The controls were injected with sterile saline. The animals were anesthetized and killed at 1, 6, and 12 h, and 1, 3, 5, 7, 9, and 14 days after bleomycin instillation. We assessed the incidence of apoptosis in lung tissues by DNA fragmentation on agarose gel electrophoresis, terminal deoxynucleotidyl transferase- mediated dUTP biotin nick end-labeling, and electron microscopy. The expression of Fas and FasL mRNA was detected by reverse transcription polymerase chain reaction (RT-PCR). The localization of Fas mRNA was analyzed by in situ hybridization and that of FasL mRNA was analyzed by RT in situ PCR. The results showed that (1) a single instillation of bleomycin leads to the rapid appearance of apoptosis in bronchial and alveolar epithelial cells, which resolves within 1 day, and (2) apoptosis reappears on day 7 and continues for over 14 days after bleomycin instillation. This was accompanied with a progression of fibrosis. Corticosteroid administration completely blocked both apoptosis and fibrosis. The expression of Fas mRNA was upregulated in the alveolar epithelial cells by the bleomycin instillation. FasL mRNA was also upregulated in infiltrating lymphocytes after bleomycin treatment, but not in the control mice. The administration of corticosteroids suppressed the expression of Fas and FasL mRNA as well as apoptosis and fibrosis. Although these results do not show that apoptosis mediated by the Fas/FasL system is directly linked to bleomycin-induced fibrosis, we speculate that excessive apoptosis and the Fas/FasL system play a role in the pathogenesis of bleomycin- induced lung injury.


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Asbestos-induced phosphorylation of epidermal growth factor receptor is linked to c-fos and apoptosis
Am J Physiol Lung Cell Mol Physiol, October 1, 1999; 277(4): L684 - L693.
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Am. J. Pathol.Home page
K. Okudela, T. Ito, H. Mitsui, H. Hayashi, N. Udaka, M. Kanisawa, and H. Kitamura
The Role of p53 in Bleomycin-Induced DNA Damage in the Lung : A Comparative Study with the Small Intestine
Am. J. Pathol., October 1, 1999; 155(4): 1341 - 1351.
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Am. J. Respir. Cell Mol. Bio.Home page
N. Hagimoto, K. Kuwano, M. Kawasaki, M. Yoshimi, Y. Kaneko, R. Kunitake, T. Maeyama, T. Tanaka, and N. Hara
Induction of Interleukin-8 Secretion and Apoptosis in Bronchiolar Epithelial Cells by Fas Ligation
Am. J. Respir. Cell Mol. Biol., September 1, 1999; 21(3): 436 - 445.
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ThoraxHome page
D. W Kamp and S. A Weitzman
The molecular basis of asbestos induced lung injury
Thorax, July 1, 1999; 54(7): 638 - 652.
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Am. J. Respir. Cell Mol. Bio.Home page
A. N. Liu, A. Z. Mohammed, W. R. Rice, D. T. Fiedeldey, J. S. Liebermann, J. A. Whitsett, T. J. Braciale, and R. I. Enelow
Perforin-Independent CD8+ T-Cell-Mediated Cytotoxicity of Alveolar Epithelial Cells Is Preferentially Mediated by Tumor Necrosis Factor-alpha . Relative Insensitivity to Fas Ligand
Am. J. Respir. Cell Mol. Biol., May 1, 1999; 20(5): 849 - 858.
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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
R. Wang, A. Zagariya, O. Ibarra-Sunga, C. Gidea, E. Ang, S. Deshmukh, G. Chaudhary, J. Baraboutis, G. Filippatos, and B. D. Uhal
Angiotensin II induces apoptosis in human and rat alveolar epithelial cells
Am J Physiol Lung Cell Mol Physiol, May 1, 1999; 276(5): L885 - L889.
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Am. J. Respir. Cell Mol. Bio.Home page
L. A. Ortiz, J. Lasky, G. Lungarella, E. Cavarra, P. Martorana, W. A. Banks, J. J. Peschon, H.-L. Schmidts, A. R. Brody, and M. Friedman
Upregulation of the p75 But Not the p55 TNF-alpha Receptor mRNA after Silica and Bleomycin Exposure and Protection from Lung Injury in Double Receptor Knockout Mice
Am. J. Respir. Cell Mol. Biol., April 1, 1999; 20(4): 825 - 833.
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Am. J. Respir. Cell Mol. Bio.Home page
M. Nishikawa, N. Kakemizu, T. Ito, M. Kudo, T. Kaneko, M. Suzuki, N. Udaka, H. Ikeda, and T. Okubo
Superoxide Mediates Cigarette Smoke-Induced Infiltration of Neutrophils into the Airways through Nuclear Factor-kappa B Activation and IL-8 mRNA Expression in Guinea Pigs In Vivo
Am. J. Respir. Cell Mol. Biol., February 1, 1999; 20(2): 189 - 198.
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Am. J. Respir. Cell Mol. Bio.Home page
K. Kuwano, H. Miyazaki, N. Hagimoto, M. Kawasaki, M. Fujita, R. Kunitake, Y. Kaneko, and N. Hara
The Involvement of Fas-Fas Ligand Pathway in Fibrosing Lung Diseases
Am. J. Respir. Cell Mol. Biol., January 1, 1999; 20(1): 53 - 60.
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Am. J. Respir. Cell Mol. Bio.Home page
N. Hussain, F. Wu, L. Zhu, R. S. Thrall, and M. J. Kresch
Neutrophil Apoptosis during the Development and Resolution of Oleic Acid-Induced Acute Lung Injury in the Rat
Am. J. Respir. Cell Mol. Biol., December 1, 1998; 19(6): 867 - 874.
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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
B. D. Uhal, I. Joshi, W. F. Hughes, C. Ramos, A. Pardo, and M. Selman
Alveolar epithelial cell death adjacent to underlying myofibroblasts in advanced fibrotic human lung
Am J Physiol Lung Cell Mol Physiol, December 1, 1998; 275(6): L1192 - L1199.
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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
L. A. Ortiz, K. Moroz, J.-Y. Liu, G. W. Hoyle, T. Hammond, R. F. Hamilton, A. Holian, W. Banks, A. R. Brody, and M. Friedman
Alveolar macrophage apoptosis and TNF-alpha , but not p53, expression correlate with murine response to bleomycin
Am J Physiol Lung Cell Mol Physiol, December 1, 1998; 275(6): L1208 - L1218.
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Am. J. Respir. Cell Mol. Bio.Home page
A. Druilhe, B. Wallaert, A. Tsicopoulos, J.-R. L. e Silva, I. Tillie-Leblond, A.-B. Tonnel, and M. Pretolani
Apoptosis, Proliferation, and Expression of Bcl-2, Fas, and Fas Ligand in Bronchial Biopsies from Asthmatics
Am. J. Respir. Cell Mol. Biol., November 1, 1998; 19(5): 747 - 757.
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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
B. D. Uhal, C. Gidea, R. Bargout, A. Bifero, O. Ibarra-Sunga, M. Papp, K. Flynn, and G. Filippatos
Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism
Am J Physiol Lung Cell Mol Physiol, November 1, 1998; 275(5): L1013 - L1017.
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Am. J. Respir. Cell Mol. Bio.Home page
C. Barazzone, S. Horowitz, Y. R. Donati, I. Rodriguez, and P.-F. Piguet
Oxygen Toxicity in Mouse Lung: Pathways to Cell Death
Am. J. Respir. Cell Mol. Biol., October 1, 1998; 19(4): 573 - 581.
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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
L.-P. Wen, K. Madani, J. A. Fahrni, S. R. Duncan, and G. D. Rosen
Dexamethasone inhibits lung epithelial cell apoptosis induced by IFN-gamma and Fas
Am J Physiol Lung Cell Mol Physiol, November 1, 1997; 273(5): L921 - L929.
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Am. J. Respir. Cell Mol. Bio.Home page
J. L. Goldberg, C. L. Zanella, Y. M. W. Janssen, C. R. Timblin, L. A. Jimenez, P. Vacek, D. J. Taatjes, and B. T. Mossman
Novel Cell Imaging Techniques Show Induction of Apoptosis and Proliferation in Mesothelial Cells by Asbestos
Am. J. Respir. Cell Mol. Biol., September 1, 1997; 17(3): 265 - 271.
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Am. J. Respir. Cell Mol. Bio.Home page
N. Hagimoto, K. Kuwano, H. Miyazaki, R. Kunitake, M. Fujita, M. Kawasaki, Y. Kaneko, and N. Hara
Induction of Apoptosis and Pulmonary Fibrosis in Mice in Response to Ligation of Fas Antigen
Am. J. Respir. Cell Mol. Biol., September 1, 1997; 17(3): 272 - 278.
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Am. J. Respir. Crit. Care Med.Home page
B. T. MOSSMAN and A. CHURG
Mechanisms in the Pathogenesis of Asbestosis and Silicosis
Am. J. Respir. Crit. Care Med., May 1, 1997; 157(5): 1666 - 1680.
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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
L. A. Ortiz, H. C. Champion, J. A. Lasky, F. Gambelli, E. Gozal, G. W. Hoyle, M. B. Beasley, A. L. Hyman, M. Friedman, and P. J. Kadowitz
Enalapril protects mice from pulmonary hypertension by inhibiting TNF-mediated activation of NF-kappa B and AP-1
Am J Physiol Lung Cell Mol Physiol, June 1, 2002; 282(6): L1209 - L1221.
[Abstract] [Full Text] [PDF]




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