Genetic susceptibility to irritant-induced acute lung injury in mice

Recent studies suggest that genetic variability can influence irritant-indu ced lung injury and inflammation. To begin identifying genes controlling su sceptibility to inhaled irritants, seven inbred mouse strains were continuo usly exposed to nickel sulfate (NiSO4), polytetrafluoroethylene, or ozone ( O-3), and survival time was recorded. The A/J (A) mouse strain was sensitiv e, the C3H/He (C3) strain was intermediate, and the C57BL/6 (B6) strain was resistant to NiSO4-induced acute lung injury. The B6AF(1) offspring were a lso resistant. The strain sensitivity pattern for NiSO4 exposure was simila r to that of polytetrafluoroethylene or ozone (O3). Pulmonary pathology was comparable for A and B6 mice. In the A strain, 15 mu g/m(3) of NiSO4 produ ced 20% mortality. The strain sensitivity patterns for lavage fluid protein s (B6. C3. A) and neutrophils (A greater than or equal to B6. C3) differed from those for acute lung injury. This phenotype discordance suggests that these traits are not causally linked (i.e., controlled by independent array s of genes). As in acute lung injury, B6C3F(1) offspring exhibited phenotyp es (lavage fluid proteins and neutrophils) resembling those of the resistan t parental strain. Agreement of acute lung injury strain sensitivity patter ns among irritants suggested a common mechanism, possibly oxidative stress, and offspring resistance suggested that sensitivity is inherited as a rece ssive trait.