Oxidized α1-antitrypsin stimulates the release of monocyte chemotactic protein-1 from lung epithelial cells: potential role in emphysema

α1-Antitrypsin (AT) is a major elastase inhibitor within the lung. Oxidation of critical methionine residues in AT generates oxidized AT (Ox-AT), which has a greatly diminished ability to inhibit neutrophil elastase. This process may contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD) by creating a functional deficiency of AT permitting lung destruction. We show here that Ox-AT promotes release of human monocyte chemoattractant protein-1 (MCP-1) and IL-8 from human lung type epithelial cells (A549) and normal human bronchial epithelial (NHBE) cells. Native, cleaved, polymeric AT and secretory leukoproteinase inhibitor (SLPI) and oxidized conformations of cleaved, polymeric AT and SLPI did not have any significant effect on MCP-1 and IL-8 secretion. These findings were supported by the fact that instillation of Ox-AT into murine lungs resulted in an increase in JE (mouse MCP-1) and increased macrophage numbers in the bronchoalveolar lavage fluid. The effect of Ox-AT was dependent on NF-κB and activator protein-1 (AP-1)/JNK. These findings have important implications. They demonstrate that the oxidation of methionines in AT by oxidants released by cigarette smoke or inflammatory cells not only reduces the antielastase lung protection, but also converts AT into a proinflammatory stimulus. Ox-AT generated in the airway interacts directly with epithelial cells to release chemokines IL-8 and MCP-1, which in turn attracts macrophages and neutrophils into the airways. The release of oxidants by these inflammatory cells could oxidize AT, perpetuating the cycle and potentially contributing to the pathogenesis of COPD. Furthermore, these data demonstrate that molecules such as oxidants, antiproteinases, and chemokines, rather than act independently, are likely to interact to cause emphysema.

[1]  John D. Johnson,et al.  Neonatal lung neutrophils and elastase/proteinase inhibitor imbalance. , 2015, The American review of respiratory disease.

[2]  T. Haas,et al.  JNK as a positive regulator of angiogenic potential in endothelial cells , 2008, Cell biology international.

[3]  D. Postma,et al.  Nitrogen Dioxide Exposure Attenuates Cigarette Smoke-Induced Cytokine Production in Mice , 2008, Inhalation toxicology.

[4]  G. Joos,et al.  Cigarette Smoke-Induced Pulmonary Inflammation and Emphysema Are Attenuated in CCR6-Deficient Mice1 , 2006, The Journal of Immunology.

[5]  P. Barnes,et al.  Chemokine receptors as therapeutic targets in chronic obstructive pulmonary disease. , 2006, Trends in pharmacological sciences.

[6]  T. Flotte,et al.  α-1 Antitrypsin Inhibits Caspase-3 Activity, Preventing Lung Endothelial Cell Apoptosis , 2006 .

[7]  M. Hollenberg,et al.  Proteinase-activated receptor-1 mediates elastase-induced apoptosis of human lung epithelial cells. , 2005, American journal of respiratory cell and molecular biology.

[8]  D. Lomas,et al.  Polymers of Z alpha1-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo. , 2005, The American journal of pathology.

[9]  Tomoko Betsuyaku,et al.  Chemokines in bronchiolar epithelium in the development of chronic obstructive pulmonary disease. , 2004, American journal of respiratory cell and molecular biology.

[10]  Xiaomin Wang,et al.  Leukocyte elastase induces epithelial apoptosis: role of mitochondial permeability changes and Akt. , 2004, American journal of physiology. Gastrointestinal and liver physiology.

[11]  P. Paré,et al.  The nature of small-airway obstruction in chronic obstructive pulmonary disease. , 2004, The New England journal of medicine.

[12]  I. Adcock,et al.  Effect of smoking on MAP kinase-induced modulation of IL‐8 in human alveolar macrophages , 2004, European Respiratory Journal.

[13]  N. McElvaney,et al.  Z alpha1-antitrypsin polymerizes in the lung and acts as a neutrophil chemoattractant. , 2004, Chest.

[14]  U. Pastorino,et al.  Primary human alveolar type II epithelial cell chemokine release: effects of cigarette smoke and neutrophil elastase. , 2004, American journal of respiratory cell and molecular biology.

[15]  R. Pauwels,et al.  Chronic obstructive pulmonary disease: molecular and cellularmechanisms , 2003, European Respiratory Journal.

[16]  L. Kunz-Schughart,et al.  Expression and Release of Interleukin-8 by Human Bronchial Epithelial Cells from Patients with Chronic Obstructive Pulmonary Disease, Smokers, and Never-Smokers , 2003, Respiration.

[17]  D. Perlmutter Liver injury in alpha1-antitrypsin deficiency: an aggregated protein induces mitochondrial injury. , 2002, The Journal of clinical investigation.

[18]  D. Lomas,et al.  Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. , 2002, The Journal of clinical investigation.

[19]  T. Betsuyaku,et al.  Increased levels of interleukin-8 in BAL fluid from smokers susceptible to pulmonary emphysema , 2002, Thorax.

[20]  S. Lindgren,et al.  Human monocyte activation by cleaved form of alpha-1-antitrypsin involvement of the phagocytic pathway. , 2001, European journal of biochemistry.

[21]  J. Whisstock,et al.  The Serpins Are an Expanding Superfamily of Structurally Similar but Functionally Diverse Proteins , 2001, The Journal of Biological Chemistry.

[22]  P. Paré,et al.  Amplification of inflammation in emphysema and its association with latent adenoviral infection. , 2001, American journal of respiratory and critical care medicine.

[23]  K. Chung,et al.  Cytokines in chronic obstructive pulmonary disease , 2001, European Respiratory Journal.

[24]  P. Barnes Cytokine modulators as novel therapies for airway disease , 2001, European Respiratory Journal.

[25]  M. Wu,et al.  Inhibitor of nuclear factor-kappaB induction by cAMP antagonizes interleukin-1-induced human macrophage-colony-stimulating-factor expression. , 2001, The Biochemical journal.

[26]  S. Lindgren,et al.  Effects of Noninhibitory α-1-Antitrypsin on Primary Human Monocyte Activation in Vitro , 2001 .

[27]  R. Chambers,et al.  Alpha‐1‐antitrypsin stimulates fibroblast proliferation and procollagen production and activates classical MAP kinase signalling pathways , 2001, Journal of cellular physiology.

[28]  Randy J. Read,et al.  Structure of a serpin–protease complex shows inhibition by deformation , 2000, Nature.

[29]  P. Vandenabeele,et al.  Functional Protection by Acute Phase Proteins &agr;1-Acid Glycoprotein and &agr;1-Antitrypsin Against Ischemia/Reperfusion Injury by Preventing Apoptosis and Inflammation , 2000, Circulation.

[30]  J. Moss,et al.  Oxidation of either methionine 351 or methionine 358 in alpha 1-antitrypsin causes loss of anti-neutrophil elastase activity. , 2000, The Journal of biological chemistry.

[31]  R. Stockley,et al.  Airways inflammation in chronic bronchitis: the effects of smoking and alpha1-antitrypsin deficiency. , 2000, The European respiratory journal.

[32]  S. Janciauskiene,et al.  Activation of Primary Human Monocytes by the Oxidized Form of α1-Antitrypsin* , 2000, The Journal of Biological Chemistry.

[33]  R. Stockley,et al.  Evidence for excessive bronchial inflammation during an acute exacerbation of chronic obstructive pulmonary disease in patients with alpha(1)-antitrypsin deficiency (PiZ). , 1999, American journal of respiratory and critical care medicine.

[34]  D. Lomas,et al.  Heteropolymerization of S, I, and Z α1-antitrypsin and liver cirrhosis , 1999 .

[35]  D. Mattey,et al.  Oxidation of alpha1-proteinase inhibitor by the myeloperoxidase-hydrogen peroxidase system promotes binding to immunoglobulin A. , 1999, Biochemical and biophysical research communications.

[36]  W. MacNee,et al.  Neutrophil chemokines in bronchoalveolar lavage fluid and leukocyte-conditioned medium from nonsmokers and smokers. , 1998, The European respiratory journal.

[37]  D. Lomas,et al.  Lung polymers in Z alpha1-antitrypsin deficiency-related emphysema. , 1998, American journal of respiratory cell and molecular biology.

[38]  W. Vogel,et al.  The acute-phase protein α1-antitrypsin inhibits transferrin-receptor binding and proliferation of human skin fibroblasts , 1998 .

[39]  M. Karin,et al.  Regulation and function of the JNK subgroup of MAP kinases. , 1997, Biochimica et biophysica acta.

[40]  W. Fiers,et al.  Alpha 1-acid glycoprotein and alpha 1-antitrypsin inhibit TNF-induced but not anti-Fas-induced apoptosis of hepatocytes in mice. , 1997, Journal of immunology.

[41]  E. Zandi,et al.  AP-1 function and regulation. , 1997, Current opinion in cell biology.

[42]  P. Gettins,et al.  Major proteinase movement upon stable serpin-proteinase complex formation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[43]  R. Kettritz,et al.  Apoptosis of endothelial cells induced by the neutrophil serine proteases proteinase 3 and elastase. , 1996, The American journal of pathology.

[44]  R. Crystal,et al.  Systemic deficiency of glutathione in cystic fibrosis. , 1993, Journal of applied physiology.

[45]  R. Senior,et al.  The serpin-enzyme complex (SEC) receptor mediates the neutrophil chemotactic effect of alpha-1 antitrypsin-elastase complexes and amyloid-beta peptide. , 1992, The Journal of clinical investigation.

[46]  D. Lomas,et al.  The mechanism of Z alpha 1-antitrypsin accumulation in the liver. , 1992, Nature.

[47]  R. Crystal,et al.  Aerosol α1 -antitrypsin treatment for cystic fibrosis , 1991, The Lancet.

[48]  R. Crystal,et al.  Molecular basis of alpha-1-antitrypsin deficiency. , 1988, The American journal of medicine.

[49]  G. K. Scott,et al.  Modulation of cell proliferation by protein proteinase inhibitors. A new analytical approach. , 1988, Biological chemistry Hoppe-Seyler.

[50]  R. Senior,et al.  The inhibitory complex of human alpha 1-proteinase inhibitor and human leukocyte elastase is a neutrophil chemoattractant , 1988, The Journal of experimental medicine.

[51]  S. Weiss,et al.  Oxidative regulation of neutrophil elastase-alpha-1-proteinase inhibitor interactions. , 1986, The Journal of clinical investigation.

[52]  J. Carlson,et al.  Risk of cirrhosis and primary liver cancer in alpha 1-antitrypsin deficiency. , 1986, The New England journal of medicine.

[53]  R. Senior,et al.  Determination of oxidized alpha-1-proteinase inhibitor in serum. , 1982, The Journal of laboratory and clinical medicine.

[54]  J. Hoidal,et al.  Potential mechanism of emphysema: alpha 1-proteinase inhibitor recovered from lungs of cigarette smokers contains oxidized methionine and has decreased elastase inhibitory capacity. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[55]  R. Spragg,et al.  Studies on the pathogenesis of the adult respiratory distress syndrome. , 1982, The Journal of clinical investigation.

[56]  J. Travis,et al.  Isolation and properties of oxidized alpha-1-proteinase inhibitor from human rheumatoid synovial fluid. , 1980, Biochemical and biophysical research communications.

[57]  J. Travis,et al.  Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin. , 1980, The Journal of biological chemistry.

[58]  R. Crystal,et al.  Cigarette smoking induces functional antiprotease deficiency in the lower respiratory tract of humans. , 1979, Science.

[59]  D. Johnson,et al.  The oxidative inactivation of human alpha-1-proteinase inhibitor. Further evidence for methionine at the reactive center. , 1979, The Journal of biological chemistry.

[60]  W. Krivit,et al.  Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder. , 1969, The Journal of laboratory and clinical medicine.

[61]  P. Gross,et al.  EXPERIMENTAL LUNG CANCER IN HAMSTERS. REPETITIVE INTRATRACHEAL APPLICATIONS OF TWO CARCINOGENIC HYDROCARBONS. , 1965, Archives of environmental health.

[62]  B. Balbi,et al.  Increased MCP-1 and MIP-1b in bronchoalveolar lavage fluid of chronic bronchitics , 1999 .

[63]  J. Travis,et al.  Kinetic and chemical evidence for the inability of oxidized alpha 1-proteinase inhibitor to protect lung elastin from elastolytic degradation. , 1984, Hoppe-Seyler's Zeitschrift fur physiologische Chemie.

[64]  C. Laurell,et al.  The Electrophoretic α;1-Globulin Pattern of Serum in α;1-Antitrypsin Deficiency , 1963 .