Systemic administration of endotoxin induces bronchopulmonary hyperreactivity dissociated from TNF-alpha formation and neutrophil sequestration into the murine lungs.
Bronchopulmonary hyperreactivity (BHR), an increased responsiveness to nonspecific bronchoconstrictor agents, is a well-known characteristic of bronchial asthma. It has been recently suggested that the severity of this disease is related to the endotoxin content of house dust. In the present report, it is shown that the i.p. administration of bacterial LPS to mice is followed by a marked early dose-dependent BHR in response to methacholine. The microscopic examination showed no ultrastructural lesions of the lungs or of the airways, but a marked neutrophil accumulation in the capillaries, as confirmed by an increase of the lung content in the neutrophil enzyme marker myeloperoxidase. In parallel, high levels of TNF-alpha were found in plasma as well as its transcripts in the lung tissues. Using immunologic (anti-TNF-alpha and anti-granulocyte Abs), and pharmacologic (dexamethasone and vinblastine) tools, it is demonstrated that BHR is apparently neither related to the presence of neutrophils in the pulmonary microvasculature nor to the synthesis of TNF-alpha.
Lefort
J
J
Unité de Pharmacologie Cellulaire, Unité Associée IP/Institut National de la Santé et de la Recherche Médicale 485, Paris, France.
Singer
M
M
Leduc
D
D
Renesto
P
P
Nahori
M A
MA
Huerre
M
M
Créminon
C
C
Chignard
M
M
Vargaftig
B B
BB
D000336:Aerosols; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000097:blood / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D005786:Gene Expression Regulation / Q000276:immunology; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000187:drug effects
D000336:Aerosols; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride