Am. J. Respir. Cell Mol. Biol., Volume 24, Number 3, March, 2001 345-351

Airway Administration of Escherichia coli Endotoxin to Mice Induces Glucocorticosteroid-Resistant Bronchoconstriction and Vasopermeation

Jean Lefort, Laurence Motreff, and B. Boris Vargaftig

Unité de Pharmacologie Cellulaire, Institut Pasteur, Paris, France

The effects of the administration of Escherichia coli endotoxin (lipopolysaccharide, LPS) into the airways of C57Bl/6 mice were studied. Neutrophil sequestration in the lungs and their enrichment, together with tumor necrosis factor (TNF)-, in bronchoalveolar lavage fluid (BALF) were associated with bronchoconstriction and bronchopulmonary hyperreactivity (BHR) to methacholine and alveolocapillary dysfunction. Granulocyte depletion by the myelotoxic drug vinblastine failed to modify TNF- production and prevented LPS-induced neutrophil recruitment to lungs and BALF, bronchoconstriction, and BHR. Neutrophils were again sequestered in the lungs when LPS was administered 4 to 5 d after vinblastine, whereas inhibition of their passage to BALF persisted. Under those conditions, bronchoconstriction and BHR by LPS also recovered, showing that these functional effects are independent from BALF neutrophil enrichment but require lung sequestration. Administration of granulocyte colony-stimulating factor after vinblastine counteracted its effects and allowed the recovery of lung neutrophil sequestration by LPS and a partial recovery of bronchoconstriction under conditions where neutrophils still failed to migrate to BALF. Dexamethasone (the phosphate salt and its free base) suppressed LPS-induced TNF- generation in BALF and its neutrophil enrichment, whereas neutrophil lung sequestration, bronchoconstriction, BHR, and alveolocapillary dysfunction were marginally reduced and only so at low doses of dexamethasone, higher doses being inactive or aggravating. In situ neutrophil activation could account for LPS-induced bronchoconstriction and BHR, both of which are refractory to steroids and appear to be mediated by unrelated mechanisms, which may be relevant for acute respiratory distress syndrome, a condition for which LPS administration is used as a model.

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