Onset and progression of pathological lesions in transforming growth factor-beta 1-deficient mice.
Null-mutant (knockout) mice were obtained through disruption of the sixth exon of the endogenous transforming growth factor-beta 1 allele in murine embryonic stem cells via homologous recombination. Mice lacking transforming growth factor-beta 1 (mutants) were born grossly indistinguishable from wild-type littermates. With time, mutant mice exhibited a wasting phenotype that manifested itself in severe weight loss and dishevelled appearance (between 15 and 36 days of age). Examination of these moribund mice histologically revealed that transforming growth factor-beta 1-deficient mice exhibit a moderate to severe, multifocal, organ-dependent, mixed inflammatory cell response adversely affecting the heart, stomach, diaphragm, liver, lung, salivary gland, and pancreas. Because of the known multifunctional nature of transforming growth factor-beta 1 on the control of growth and differentiation of many different cell types, it is important to determine the degree to which the inflammatory response interacts with or masks other deficiencies that are present. To this end, we 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 age) and compared them with the histology seen in wild-type normal animals. 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 examined. Moderate to severe inflammation was not present until the mice were 10 to 14 days old. In the older animals, there was a slight increase in the severity of the inflammatory lesions as the mice aged.
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, OH 45267-0529.
G P
GP
Boivin
B A
BA
O'Toole
I E
IE
Orsmby
R J
RJ
Diebold
M J
MJ
Eis
T
T
Doetschman
A B
AB
Kier
D000818:Animals; D001483:Base Sequence; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005838:Genotype; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016212:Transforming Growth Factor beta / Q000235:genetics*; D015430:Weight Gain
D016212:Transforming Growth Factor beta