Airway administration of Escherichia coli endotoxin to mice induces glucocorticosteroid-resistant bronchoconstriction and vasopermeation

The effects of the administration of Escherichia coli endotoxin (lipopolysa ccharide, LPS) into the airways of C57B1/6 mice were studied. Neutrophil se questration in the lungs and their enrichment, together with tumor necrosis factor (TNF)-alpha, in bronchoalveolar lavage fluid (BALF) were associated with bronchoconstriction and bronchopulmonary hyperreactivity (BHR) to met hacholine and alveolocapillary dysfunction. Granulocyte depletion by the my elotoxic drug vinblastine failed to modify TNF-alpha production and prevent ed LPS-induced neutrophil recruitment to lungs and BALF, bronchoconstrictio n, and BHR. Neutrophils were again sequestered in the lungs when LPS was ad ministered 4 to 5 d after vinblastine, whereas inhibition of their passage to BALF persisted. Under those conditions, bronchoconstriction and BHR by L PS also recovered, showing that these functional effects are independent fr om BALF neutrophil enrichment but require lung sequestration. Administratio n of granulocyte colony-stimulating factor after vinblastine counteracted i ts effects and allowed the recovery of lung neutrophil sequestration by LPS and a partial recovery of bronchoconstriction under conditions where neutr ophils still failed to migrate to BALF. Dexamethasone (the phosphate salt a nd its free base) suppressed LPS-induced TNF-alpha generation in BALF and i ts neutrophil enrichment, whereas neutrophil lung sequestration, bronchocon striction, BHR, and alveolocapillary dysfunction were marginally reduced an d only so at tow doses of dexamethasone, higher doses being inactive or agg ravating. In situ neutrophil activation could account for LPS-induced bronc hoconstriction and BHR, both of which are refractory to steroids and appear to be mediated by unrelated mechanisms, which may be relevant for acute re spiratory distress syndrome, a condition for which LPS administration is us ed as a model.