DIFFERENTIAL SUSCEPTIBILITY TO OZONE-INDUCED AIRWAYS HYPERREACTIVITY IN INBRED STRAINS OF MICE

Individuals with heightened airways reactivity, such as asthmatics, ma y be at risk to inflammatory effects of oxidant air pollutants. In the inbred mouse, significant interstrain variation in airways reactivity to acetylcholine (ACh) and differential susceptibility to ozone (O-3) -induced airways inflammation has been described previously. This stud y used these murine models to test hypotheses that (1) O-3-induced hyp erreactivity to ACh is a function of inherent baseline ACh reactivity, and (2) susceptibility to O-3-induced inflammation is associated with O-3-induced hyperreactivity. Strains (15-25 g, 6-8 weeks) with HYPERR EACTIVE (DBA/2J, AKR/J, A/J), HYPOREACTIVE (C3H/HeJ, C57BL/6J, SJL/J), or INTERMEDIATE (129/J) phenotypes for ACh reactivity were exposed fo r 3 h to 2.0 ppm O-3 or air (control). ACh reactivity (25 and 50 mu g/ kg, IV) was assessed 0 and 24 h after exposure. Relative to air contro ls, mean airways responses to 25 and 50 mu g/kg ACh 24 h post-O-3 incr eased significantly in the HYPERREACTIVE A/J strain (p < .05). Among H YPOREACTIVE strains, O-3 significantly (p < .05) increased the respons e to 50 mu g/kg ACh in C57BL/6J and SJL/J strains 24 h postexposure. A /J, C57BL/6J, and SJL/J mice are susceptible to O-3-induced lung injur y. O-3 did not alter ACh reactivity in the other strains. O-3 also did not affect airways reactivity to methacholine or carbachol, observati ons consistent with the hypothesis that O-3-induced hyperreactivity to ACh may be due, in part, to O-3 effects on cholinesterase function. T reatment of C57BL/6J and A/J mice with an immunosuppressant (cyclophos phamide) or an anti-PMN antibody significantly (p < .05) attenuated ci rculating and infiltrating polymorphonuclear leukocytes (PMNs), but di d not affect O-3-induced hyperreactivity. Therefore, O-3-induced ACh h yperreactivity was not a function of baseline reactivity, but correlat ed with susceptibility to acute O-3-induced airways injury and inflamm ation. Pharmacologic studies suggest that although PMNs were associate d with O-3-induced hyperreactivity, these cells were not the cause of the effect, and that these two events are not codependent.