To evaluate the concept that genetic factors modulate susceptibility to agents that cause interstitial lung disease, animal models of interstitial lung disease caused by bleomycin or by inhalation of organic particulates (ovalbumin or bovine gamma globulin after specific immunization) were studied in strains of mice with different genetic backgrounds. Because immune processes have been implicated in modulating the susceptibility to agents that cause interstitial lung disease, we also compared congenic, resistant strains (strains with the same background but with different H-2 haplotypes) for their sensitivity to the same agents. In bleomycin-induced disease, the degree of lung disease was different in some of the different strains of mice and, in some strains, was related to H-2 locus genes since all strains with H-2b haplotypes were high responders, whereas most of the strains with H-2a, H-2d, and H-2k haplotypes were low responders. However, some of the strains of mice with the same H-2 haplotype but otherwise different genetic backgrounds had different responses to bleomycin, suggesting that there is also a role for non-H-2 genetic factors in modulating the response to this experimental interstitial lung disease. In the ovalbumin-induced lung disease model, as in bleomycin-induced lung disease, there were different strain susceptibilities: 2 of the 3 strains in the H-2b group were high responders, as was 1 of the 3 strains in the H-2k group. Interestingly, evaluation of the congenic, resistant strains showed that on the same backgrounds the H-2-related genes were able to modulate the degree of lung lesions.(ABSTRACT TRUNCATED AT 250 WORDS)