RESUMO
OBJECTIVE: To investigate the mechanisms responsible for the testicular abnormalities and infertility of previously generated male protein C inhibitor (PCI)-deficient mice. DESIGN: Determination of the localization of PCI in the reproductive organs of wild-type males. Generation of double knockout mice lacking the protease inhibitor PCI and one plasminogen activator, either urokinase (uPA) or tissue plasminogen activator (tPA), both of which are PCI-target proteases. SETTING: Animal research and histologic analysis. ANIMAL(S): Male mice of desired genotype. INTERVENTION(S): Fertility testing of double knockout mice. MAIN OUTCOME MEASURE(S): Infertility of PCI(-/-)uPA(-/-) and PCI(-/-)tPA(-/-) double knockout mice. RESULT(S): In the testes of wild-type males PCI was detected in spermatocytes of prophase I, as well as in late spermatids and mature spermatozoa, but absent from somatic cells. All PCI(-/-) uPA(-/-) and PCI(-/-) tPA(-/-) male mice were infertile and histologic analysis of testis showed similar alterations as previously described for PCI(-/-) mice. CONCLUSION(S): The abnormal spermatogenesis of PCI (plasminogen activator inhibitor-3)-deficient mice cannot be rescued by single plasminogen activator knockout.
Assuntos
Fertilidade , Inibidor da Proteína C/análise , Inibidor da Proteína C/genética , Espermatogênese , Testículo/química , Animais , Diferenciação Celular/genética , Feminino , Fertilidade/genética , Infertilidade Masculina/genética , Infertilidade Masculina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Inibidor da Proteína C/deficiência , Espermatogênese/genética , Testículo/citologia , Testículo/metabolismoRESUMO
Protein C inhibitor (PCI) is a nonspecific, heparin-binding serpin (serine protease inhibitor) that inactivates many plasmatic and extravascular serine proteases by forming stable 1:1 complexes. Proteases inhibited by PCI include the anticoagulant activated protein C, the plasminogen activator urokinase, and the sperm protease acrosin. In humans PCI circulates as a plasma protein but is also present at high concentrations in organs of the male reproductive tract. The biological role of PCI has not been defined so far. However, the colocalization of high concentrations of PCI together with several of its target proteases in the male reproductive tract suggests a role of PCI in reproduction. We generated mice lacking PCI by homologous recombination. Here we show that PCI(-/-) mice are apparently healthy but that males of this genotype are infertile. Infertility was apparently caused by abnormal spermatogenesis due to destruction of the Sertoli cell barrier, perhaps due to unopposed proteolytic activity. The resulting sperm are malformed and are morphologically similar to abnormal sperm seen in some cases of human male infertility. This animal model might therefore be useful for analyzing the molecular bases of these human conditions.
Assuntos
Deleção de Genes , Infertilidade Masculina , Inibidor da Proteína C/genética , Inibidor da Proteína C/metabolismo , Espermatogênese , Animais , Modelos Animais de Doenças , Feminino , Fertilização , Fertilização in vitro , Marcação de Genes , Histocitoquímica , Masculino , Camundongos , Camundongos Knockout , Microscopia Eletrônica , Oligopeptídeos/metabolismo , Ovário , Inibidor da Proteína C/deficiência , RNA Mensageiro/análise , RNA Mensageiro/genética , Serina Endopeptidases/metabolismo , Espermatozoides/metabolismo , Espermatozoides/patologia , Testículo/enzimologia , Testículo/metabolismo , Testículo/patologiaRESUMO
The incidence of malignant lymphoma cases in constantly growing. Therefore it is worth-while to consider its presence even in cases where the symptoms do not give a clear indication of the disease. Two cases with angiooema being rare and not carachteristic signs for malignant lymphoma are reported. The authors discuss the supposed paraneoplastic patomechanism in malignant lymphoma, i.e. the possible role of C' 1 inhibition. In the view at the cases discussed the authors propose to consider the possible diagnosis of malignant lymphoma if unexplained angiooedema is present.