EVIDENCE FOR 2 PATTERNS OF INHERITANCE OF SENSITIVITY TO INDUCTION OFLUNG FIBROSIS IN MICE BY RADIATION, ONE OF WHICH INVOLVES 2 GENES

We showed previously that autosomal recessive determinants control the development of pulmonary fibrosis in mice during the early and late p hases after irradiation. The extent of fibrosis was inversely correlat ed with the intrinsic lung activity of both plasminogen activator (PLA ) and angiotensin-converting enzyme (ACE). To test these observations further, two groups of mice were given a dose of 15 Gy to the thorax: offspring of a backcross between C57L/J (''fibrosing mice'') and the F -1 of CBA/J (''non-fibrosing in the early phase'') x C57L/J, and addit ional F-1 individuals of CBA/J x C57L/J. Mice were euthanized upon dev eloping a substantial respiratory deficiency (50% reduction in carbon monoxide uptake) during the early phase (14-25 weeks postirradiation). Seventeen mice from the backcross were heavily fibrosed, 38 were clas sed as intermediate, and 15 contained no fibrosis. No evidence of sex linkage was seen. These data strongly support our earlier conclusions and suggest that two autosomal genes which function additively determi ne the extent of the principal type of fibrosis in these strains. As n o indication of a bimodal distribution of lung PLA or ACE activity was obtained, it is unlikely that one of the genes controls the level of either enzyme. The F-1 mice unexpectedly showed small amounts of an un usual type of fibrosis which was not associated with hyaline material or fibrin deposits, in contrast to all previous reports of fibrosis du ring the early phase in mice. Similar, fibrin-free fibrosis was found during the early phase in mast cell-deficient WBB6F(1)/J mice (and the ir normal siblings). In the F-1 mice this unusual fibrosis appears to be regulated independently by two additional genes, one of which is se x-linked. (C) 1996 by Radiation Research Society