ONSET AND PROGRESSION OF PATHOLOGICAL LESIONS IN TRANSFORMING GROWTH FACTOR-BETA-1-DEFICIENT MICE

Null-mutant (knockout) mice were obtained through disruption of the si xth exon of the endogenous transforming growth factor-beta 1 allele in murine embryonic stem cells via homologous recombination, Mice lackin g transforming growth factor-beta 1 (mutants) were born grossly indist inguishable from wild-type littermates, With time, mutant mice exhibit ed a wasting phenotype that manifested itself in severe weight loss an d dishevelled appearance (between 15 and 36 days of age), Examination of these moribund mice histologically revealed that transforming growt h factor-beta 1-deficient mice exhibit a moderate to severe, multifoca l, organ-dependent, mixed inflammatory cell response adversely affecti ng the heart, stomach, diaphragm, liver, lung, salivary gland, and pan creas, Because of the known multifunctional nature of transforming gro wth factor-beta 1 on the control of growth and differentiation of many different cell types, it is important to determine the degree to whic h the inflammatory response interacts with or masks other deficiencies that are present, To this end, toe examined the extent and nature of the inflammatory, lesions in different ages of neonatal knockout mice (5, 7, 10, and 14 days of age) and older moribund mice (>15 days of ag e) and compared them with the histology seen in wild-type normal anima ls. Mild inflammatory infiltrates were first observed in 5-day mutant mice in the heart, by day 7 in the lung, salivary gland, and pancreas, and by day 14 inflammatory lesions were found in almost all organs ex amined. Moderate to severe inflammation was not present until the mice were 10 to 14 days old. In the older animals, there was a slight incr ease in the severity of the inflammatory lesions as the mice aged.