Endotoxin‐induced hyperreactivity of the guinea‐pig isolated trachea coincides with decreased prostaglandin E₂ production by the epithelial layer

Abstract

Pretreatment of guinea‐pigs with endotoxin (1 mg kg −1 b.w., i.p., 4 days before the experiments) results in respiratory airway hyperreactivity in vitro . Dose‐response curves with either arecoline or histamine on isolated tracheae from these animals display increased maximal contractions, and decreased EC 50 values. Tracheae denuded of epithelium respond with a similar hyperreactivity to histamine as observed in preparations from endotoxin pretreated animals. Removal of the epithelial layer of tracheae from endotoxin pretreated guinea‐pigs did not additionally affect the histamine dose‐response curve. The cyclo‐oxygenase inhibitor indomethacin (10 μ m ) induces histamine hyperreactivity which is equal in intact and epithelium‐denuded tracheae from saline or endotoxin pretreated guinea‐pigs. Similar results are obtained with the combined lipoxygenase/cyclo‐oxygenase inhibitor nordihydroguaiaretic acid (10 μ m ). Histamine (0.1 m m ) induces an increase in prostaglandin E 2 (PGE 2 ) formation by the tracheal spiral in vitro , which is reduced by 34% by endotoxin pretreatment, and by about 60% following epithelium removal irrespective of endotoxin pretreatment. Arachidonic acid (AA, 22 μ m ) stimulation of the guinea‐pig trachea in vitro induces a relaxation, and an increase in PGE 2 production. In preparations lacking the epithelium, AA induces a contraction which coincides with a 60% reduced increase in PGE 2 formation. These effects are not altered by endotoxin pretreatment. It is concluded that the endotoxin‐induced respiratory airway hyperreactivity may be caused by a disturbed ability of epithelial cells to synthesize PGE 2 . The decreased formation of this prostaglandin is rather the consequence of a diminished liberation of AA from the phospholipid stores than a dysfunction of the cyclo‐oxygenase enzyme.