Epithelial autotoxicity of nitric oxide: role in the respiratory cytopathology of pertussis.
Bordetella pertussis releases a specific peptidoglycan fragment known as tracheal cytotoxin (TCT) that reproduces the respiratory epithelial cytopathology of whooping cough (pertussis). In vitro, TCT inhibits DNA synthesis in hamster trachea epithelial cells and causes specific destruction of ciliated cells in explants of human and hamster respiratory epithelium. We have recently demonstrated that TCT triggers production of intracellular interleukin 1 by respiratory epithelial cells, and this cytokine may act as an intermediate signal in the generation of TCT toxicity. Here we report the identification of a subsequent critical step in this pathway: induction of nitric oxide synthesis in the respiratory epithelium. The toxic effects of nitric oxide are consistent with spectroscopic evidence of the formation of iron-dinitrosyl-dithiolate complexes in TCT-treated cells. Aconitase, with its iron-sulfur center, is one expected target of nitric oxide, and TCT inhibited 80% of the activity of this enzyme in respiratory epithelial cells. The deleterious effects of TCT and interleukin 1 were dramatically attenuated by the nitric oxide synthase inhibitors NG-monomethyl-L-arginine and aminoguanidine. These results indicate that nitric oxide mediates the toxicity of TCT for the respiratory epithelium, thus implicating a central role for nitric oxide in the pathogenesis of pertussis.
Heiss
L N
LN
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110.
Lancaster
J R
JR
Corbett
J A
JA
Goldman
W E
WE
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis; D000818:Animals; D001886:Bordetella pertussis / Q000472:pathogenicity; D002478:Cells, Cultured; D006224:Cricetinae; D004790:Enzyme Induction; D004848:Epithelium / Q000187:drug effects; D006020:Glycopeptides / Q000633:toxicity; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000633:toxicity*; D019001:Nitric Oxide Synthase; D010457:Peptidoglycan / Q000633:toxicity*; D014132:Trachea / Q000166:cytology / Q000187:drug effects*; D010566:Virulence Factors, Bordetella / Q000633:toxicity*
D006020:Glycopeptides; D010457:Peptidoglycan; D010566:Virulence Factors, Bordetella; C059708:tracheal cytotoxin, Bordetella pertussis; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases