Increased sensitivity to toluene diisocyanate (TDI) in airways previously exposed to low doses of TDI.
Repeated airway exposures to toluene diisocyanate (TDI) may cause sensitization and asthma. This study has examined the acute inflammatory response to TDI in guinea-pig tracheobronchial airways, the development of increased sensitivity to TDI and the effects of xanthines and a glucocorticoid on these responses to TDI. A restricted surface area of the tracheobronchial mucosa of Ketalar-Xylazin anaesthetized guinea-pigs was exposed to TDI, dissolved in olive oil, by means of 1 min infusions through an oral catheter. The TDI-induced inflammatory process was quantified by determination of airway luminal entry of plasma. Already 3 nl (approximately 20 pmol) of TDI produced a significant and sustained exudation response (P less than 0.001 to P less than 0.01, 5 and 17 hr after exposure). Pretreatment with intravenous enprofylline (25 mumol/kg) intraperitoneally or 26 mumol/kg by tracheal superfusion) was without effect. Two repeated exposures to TDI 3 nl (on days 1 and 8) made the animals hyperresponsive to TDI so that on day 15 a previously subthreshold dose of TDI (0.3 nl) produced significant exudation both at 5 and 17 hr after exposure (P less than 0.001 to P less than 0.01). Similarly, two repeated dermal exposures to a large dose of TDI (20 microliters) lowered the threshold for tracheal provocation with TDI. Budesonide (2.6 mumol/kg orally) given daily during the topical airway 'sensitization' regimen (days 1-14) significantly reduced the response to the subsequent 0.3 nl challenge dose of TDI (P less than 0.05). The effects of daily treatments with either theophylline (100 mumol/kg) or enprofylline (50 mumol/kg) were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)
Erjefält
I
I
Department of Pharmacology 1, ASTRA DRACO, Lund, Sweden.
Persson
C G
CG
D000279:Administration, Cutaneous; D000287:Administration, Topical; D000818:Animals; D019819:Budesonide; D006168:Guinea Pigs; D007249:Inflammation; D007442:Intubation, Intratracheal; D008297:Male; D011282:Pregnenediones / Q000627:therapeutic use; D012130:Respiratory Hypersensitivity / Q000139:chemically induced* / Q000188:drug therapy; D013806:Theophylline / Q000627:therapeutic use; D014051:Toluene 2,4-Diisocyanate / Q000008:administration & dosage / Q000633:toxicity*; D014970:Xanthines / Q000627:therapeutic use
D011282:Pregnenediones; D014970:Xanthines; D014051:Toluene 2,4-Diisocyanate; D019819:Budesonide; D013806:Theophylline; C034347:enprofylline