Hydroxyurea inhibits airway hyperresponsiveness in guinea pigs by a granulocyte-independent mechanism.
Exposure of guinea pigs to toluene diisocyanate (TDI) causes an increase in airway responsiveness to inhaled acetylcholine. This increased airway responsiveness is temporally associated with an increase in polymorphonuclear leukocytes (PMN) in the tracheal wall. To determine whether PMN play a mechanistic role in this increase in acetylcholine responsiveness, we studied the effects of PMN depletion on this response with 2 different cytotoxic drugs, hydroxyurea and cyclophosphamide. Airway responsiveness was measured in untreated, hydroxyurea-treated, or cyclophosphamide-treated animals while they breathed spontaneously or during mechanical ventilation through a tracheostomy. In untreated animals, exposure to TDI caused a significant increase in airway responsiveness to acetylcholine for both spontaneously breathing and anesthetized and ventilated animals. This TDI-induced increase in airway responsiveness was associated with a significant influx of PMN into both the extravascular and intravascular trachea. Treatment with hydroxyurea, to reduce PMN counts in the bloodstream to less than 200/mm3, inhibited both the TDI-induced increase in airway responsiveness and the TDI-induced influx of PMN into the trachea of both spontaneously breathing and mechanically ventilated animals. In mechanically ventilated animals, treatment with cyclophosphamide, until PMN counts in the bloodstream were less than 200/mm3, also inhibited the influx of PMN into the trachea but did not inhibit the TDI-induced increase in airway responsiveness. These results suggest that PMN are not necessary for the TDI-induced increase in airway responsiveness and that hydroxyurea inhibits this effect by a mechanism other than PMN depletion.
D000109:Acetylcholine / Q000494:pharmacology; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology; D006098:Granulocytes / Q000187:drug effects* / Q000502:physiology; D006168:Guinea Pigs; D006918:Hydroxyurea / Q000494:pharmacology*; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D012119:Respiration / Q000187:drug effects; D012121:Respiration, Artificial; D014051:Toluene 2,4-Diisocyanate / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
D014051:Toluene 2,4-Diisocyanate; D003520:Cyclophosphamide; D000109:Acetylcholine; D006918:Hydroxyurea