Differential susceptibility to ozone-induced airways hyperreactivity in inbred strains of mice.

Individuals with heightened airways reactivity, such as asthmatics, may be at risk to inflammatory effects of oxidant air pollutants. In the inbred mouse, significant interstrain variation in airways reactivity to acelycholine (ACh) and differential susceptibility to ozone (O3)-induced airways inflammation has been described previously. This study used these murine models to test hypotheses that (1) O3-induced hyperreactivity to ACh is a function of inherent baseline ACh reactivity, and (2) susceptibility to O3-induced inflammation is associated with O3-induced hyperreactivity. Strains (15-25 g, 6-8 weeks) with HYPERREACTIVE (DBA/2J, AKR/J, A/J), HYPOREACTIVE (C3H/HeJ, C57BL/6J, SJL/H), or INTERMEDIATE (129/J) phenotypes for ACh reactivity were exposed for 3 h to 2.0 ppm O3 or air (control). ACh reactivity (25 and 50 micrograms/kg, IV) was assessed 0 and 24 h after exposure. Relative to air controls, mean airways responses to 25 and 50 micrograms/kg ACh 24 h post-O3 increased significantly in the HYPERREACTIVE A/J strain (p < .05). Among HYPOREACTIVE strains, O3 significantly (p < .05) increased the response to 50 micrograms/kg ACh in C57BL/6J and SJL/J strains 24 h postexposure. A/J, C57BL/6J, and SJL/J mice are susceptible to O3-induced lung injury. O3 did not alter ACh reactivity in the other strains. O3 also did not affect airways reactivity to methacholine or carbachol, observations consistent with the hypothesis that O3-induced hyperreactivity to ACh may be due, in part, to O3 effects on cholinesterase function. Treatment of C57BL/6J and A/J mice with an immunosuppressant (cyclophosphamide) or an anti-PMN antibody significantly (p < .05) attenuated circulating and infiltrating polymorphonuclear leukocytes (PMNs), but did not affect O3-induced hyperreactivity. Therefore, O3-induced ACh hyperreactivity was not a function of baseline reactivity, but correlated with susceptibility to acute O3-induced airways injury and inflammation. Pharmacologic studies suggest that although PMNs were associated with O3-induced hyperreactivity, these cells were not the cause of the effect, and that these two events are not codependent.