Enalapril protects mice from pulmonary hypertension by inhibiting TNF-mediated activation of NF-kappaB and AP-1.

The present study was undertaken to investigate the effects of treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril in a mouse model of pulmonary hypertension induced by bleomycin. Bleomycin-induced lung injury in mice is mediated by enhanced tumor necrosis factor-alpha (TNF) expression in the lung, which determines the murine strain sensitivity to bleomycin, and murine strains are sensitive (C57BL/6) or resistant (BALB/c). Bleomycin induced significant pulmonary hypertension in C57BL/6, but not in BALB/c, mice; average pulmonary arterial pressure (PAP) was 26.4 +/- 2.5 mmHg (P < 0.05) vs. 15.2 +/- 3 mmHg, respectively. Bleomycin treatment induced activation of nuclear factor (NF)-kappaB and activator protein (AP)-1 and enhanced collagen and TNF mRNA expression in the lung of C57BL/6 but not in BALB/c mice. Double TNF receptor-deficient mice (in a C57BL/6 background) that do not activate NF-kappaB or AP-1 in response to bleomycin did not develop bleomycin-induced pulmonary hypertension (PAP 14 +/- 3 mmHg). Treatment of C57BL/6 mice with enalapril significantly (P < 0.05) inhibited the development of pulmonary hypertension after bleomycin exposure. Enalapril treatment inhibited NF-kappaB and AP-1 activation, the enhanced TNF and collagen mRNA expression, and the deposition of collagen in bleomycin-exposed C57BL/6 mice. These results suggest that ACE inhibitor treatment decreases lung injury and the development of pulmonary hypertension in bleomycin-treated mice.

[1]  M. Fujita,et al.  Overexpression of tumor necrosis factor-alpha produces an increase in lung volumes and pulmonary hypertension. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[2]  M. Selman,et al.  Tumor necrosis factor receptor deficiency alters matrix metalloproteinase 13/tissue inhibitor of metalloproteinase 1 expression in murine silicosis. , 2001, American journal of respiratory and critical care medicine.

[3]  J. Tamaoki,et al.  The Fas/Fas-ligand system is not required for bleomycin-induced pulmonary fibrosis in mice. , 2000, American journal of respiratory and critical care medicine.

[4]  Y. Ishii,et al.  Aerosolized administration of N-acetylcysteine attenuates lung fibrosis induced by bleomycin in mice. , 2000, American journal of respiratory and critical care medicine.

[5]  G. Laurent,et al.  Angiotensin II is mitogenic for human lung fibroblasts via activation of the type 1 receptor. , 2000, American journal of respiratory and critical care medicine.

[6]  S. Shimohama,et al.  Mechanisms of antiapoptotic effects of estrogens in nigral dopaminergic neurons , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[7]  Y. Wang,et al.  Taurine and niacin block lung injury and fibrosis by down-regulating bleomycin-induced activation of transcription nuclear factor-kappaB in mice. , 2000, The Journal of pharmacology and experimental therapeutics.

[8]  B. Uhal,et al.  Apoptosis of lung epithelial cells in response to TNF-alpha requires angiotensin II generation de novo. , 2000, Journal of cellular physiology.

[9]  H. Champion,et al.  A novel right-heart catheterization technique for in vivo measurement of vascular responses in lungs of intact mice. , 2000, American journal of physiology. Heart and circulatory physiology.

[10]  J. Markham,et al.  Pulmonary angiotensin-converting enzyme (ACE) binding and inhibition in humans. A positron emission tomography study. , 2000, American journal of respiratory and critical care medicine.

[11]  R. Harris.  Potential mechanisms and physiologic actions of intracellular angiotensin II. , 1999, The American journal of the medical sciences.

[12]  B. Uhal,et al.  Fas-induced apoptosis of alveolar epithelial cells requires ANG II generation and receptor interaction. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[13]  W. Banks,et al.  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. , 1999, American journal of respiratory cell and molecular biology.

[14]  Quan Zhao,et al.  Mitogen-activated Protein Kinase/ERK Kinase Kinases 2 and 3 Activate Nuclear Factor-κB through IκB Kinase-α and IκB Kinase-β* , 1999, The Journal of Biological Chemistry.

[15]  M. Yacoub,et al.  Angiotensin II activates MAPK and stimulates growth of human pulmonary artery smooth muscle via AT 1 receptors , 1999 .

[16]  M. Selman,et al.  Human lung myofibroblast-derived inducers of alveolar epithelial apoptosis identified as angiotensin peptides. , 1999, The American journal of physiology.

[17]  J. Egido,et al.  ACE inhibitor quinapril reduces the arterial expression of NF-kappaB-dependent proinflammatory factors but not of collagen I in a rabbit model of atherosclerosis. , 1998, The American journal of pathology.

[18]  T. Hammond,et al.  Alveolar macrophage apoptosis and TNF-alpha, but not p53, expression correlate with murine response to bleomycin. , 1998, The American journal of physiology.

[19]  W. F. Hughes,et al.  Alveolar epithelial cell death adjacent to underlying myofibroblasts in advanced fibrotic human lung. , 1998, American journal of physiology. Lung cellular and molecular physiology.

[20]  W. Banks,et al.  Expression of TNF and the necessity of TNF receptors in bleomycin-induced lung injury in mice. , 1998, Experimental lung research.

[21]  G. Filippatos,et al.  Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism. , 1998, The American journal of physiology.

[22]  K. Forsyth,et al.  Shedding of L-selectin and PECAM-1 and upregulation of Mac-1 and ICAM-1 on neutrophils in RSV bronchiolitis. , 1998, American journal of physiology. Lung cellular and molecular physiology.

[23]  F. Graham,et al.  Transfer of tumor necrosis factor-alpha to rat lung induces severe pulmonary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor-beta1 and myofibroblasts. , 1998, The American journal of pathology.

[24]  D. Schuster,et al.  Angiotensin-converting enzyme inhibition delays pulmonary vascular neointimal formation. , 1998, American journal of respiratory and critical care medicine.

[25]  H. Kawakatsu,et al.  Calcium-dependent Epidermal Growth Factor Receptor Transactivation Mediates the Angiotensin II-induced Mitogen-activated Protein Kinase Activation in Vascular Smooth Muscle Cells* , 1998, The Journal of Biological Chemistry.

[26]  H. Nakano,et al.  Differential regulation of IκB kinase α and β by two upstream kinases, NF-κB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1 , 1998 .

[27]  C. Ware,et al.  TNF receptor-deficient mice reveal divergent roles for p55 and p75 in several models of inflammation. , 1998, Journal of immunology.

[28]  H. Yang,et al.  Kinetic alterations of angiotensin-II and nitric oxide in radiation pulmonary fibrosis. , 1998, Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer.

[29]  M. Karin,et al.  JNK or IKK, AP-1 or NF-kappaB, which are the targets for MEK kinase 1 action? , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[30]  T. Hammond,et al.  Alveolar macrophage apoptosis and TNF-α, but not p53, expression correlate with murine response to bleomycin. , 1998, American journal of physiology. Lung cellular and molecular physiology.

[31]  Y. Mori,et al.  Angiotensin type 2 receptors are reexpressed by cardiac fibroblasts from failing myopathic hamster hearts and inhibit cell growth and fibrillar collagen metabolism. , 1997, Circulation.

[32]  Matthias Mann,et al.  IKK-1 and IKK-2: Cytokine-Activated IκB Kinases Essential for NF-κB Activation , 1997 .

[33]  E. Zandi,et al.  The IκB Kinase Complex (IKK) Contains Two Kinase Subunits, IKKα and IKKβ, Necessary for IκB Phosphorylation and NF-κB Activation , 1997, Cell.

[34]  K. Kuwano,et al.  Induction of apoptosis and pulmonary fibrosis in mice in response to ligation of Fas antigen. , 1997, American journal of respiratory cell and molecular biology.

[35]  M. Gillespie,et al.  Lung angiotensin receptor binding characteristics during the development of monocrotaline-induced pulmonary hypertension. , 1997, Biochemical pharmacology.

[36]  Hong Yang,et al.  Involvement of MAP Kinase in Angiotensin II-Induced Phosphorylation and Intracellular Targeting of Neuronal AT1 Receptors , 1997, The Journal of Neuroscience.

[37]  K. Kuwano,et al.  Apoptosis and expression of Fas/Fas ligand mRNA in bleomycin-induced pulmonary fibrosis in mice. , 1997, American journal of respiratory cell and molecular biology.

[38]  R. Strieter,et al.  C-C chemokines: novel mediators of the profibrotic inflammatory response to bleomycin challenge. , 1996, American journal of respiratory cell and molecular biology.

[39]  S. Eguchi,et al.  Angiotensin II type 2 receptor inhibits cell proliferation and activates tyrosine phosphatase. , 1996, Hypertension.

[40]  L. Moons,et al.  Inhibition of tissue angiotensin-converting enzyme with quinapril reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling. , 1996, Circulation.

[41]  W. Parks,et al.  Angiotensin converting enzyme expression in primary pulmonary hypertension. , 1996, American journal of respiratory and critical care medicine.

[42]  M. Horiuchi,et al.  Angiotensin II type 2 receptor mediates programmed cell death. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[43]  M. Selman,et al.  Fibroblasts isolated after fibrotic lung injury induce apoptosis of alveolar epithelial cells in vitro. , 1995, The American journal of physiology.

[44]  W. Fiers,et al.  Two tumour necrosis factor receptors: structure and function. , 1995, Trends in cell biology.

[45]  N. Morrell,et al.  Angiotensin converting enzyme expression is increased in small pulmonary arteries of rats with hypoxia-induced pulmonary hypertension. , 1995, The Journal of clinical investigation.

[46]  T. Hunter,et al.  Transcriptional control by protein phosphorylation: signal transmission from the cell surface to the nucleus , 1995, Current Biology.

[47]  D. Hyde,et al.  Amelioration of bleomycin-induced lung fibrosis in hamsters by dietary supplementation with taurine and niacin: biochemical mechanisms. , 1994, Environmental health perspectives.

[48]  C. Vesin,et al.  Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice. , 1994, The European respiratory journal.

[49]  P. Baeuerle,et al.  Function and activation of NF-kappa B in the immune system. , 1994, Annual review of immunology.

[50]  E. Vuorio,et al.  Specific hybridization probes for mouse type I, II, III and IX collagen mRNAs. , 1991, Biochimica et biophysica acta.

[51]  W. Martin,et al.  Bronchoalveolar lavage fluid angiotensin-converting enzyme in interstitial lung diseases. , 1990, The American review of respiratory disease.

[52]  P. Vassalli,et al.  Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis , 1989, The Journal of experimental medicine.

[53]  J. Lazo,et al.  High dose continuous infusion of bleomycin in mice: a new model for drug-induced pulmonary fibrosis. , 1987, The Journal of pharmacology and experimental therapeutics.

[54]  K. Kurppa,et al.  Angiotensin-converting enzyme and lysozyme in silicosis and asbestosis. , 1978, Scandinavian journal of respiratory diseases.

[55]  J. Lieberman.  Elevation of serum angiotensin-converting-enzyme (ACE) level in sarcoidosis. , 1975, The American journal of medicine.

[56]  K. Kivirikko,et al.  Modifications of a specific assay for hydroxyproline in urine. , 1967, Analytical biochemistry.