RESUMO
Exposure to pathogens throughout a lifetime influences immunity and organ function. Here, we explore how the systemic host-response to bacterial urinary tract infection (UTI) induces tissue-specific alterations to the mammary gland. Utilizing a combination of histological tissue analysis, single cell transcriptomics, and flow cytometry, we identify that mammary tissue from UTI-bearing mice displays collagen deposition, enlarged ductal structures, ductal hyperplasia with atypical epithelial transcriptomes and altered immune composition. Bacterial cells are absent in the mammary tissue and blood of UTI-bearing mice, therefore, alterations to the distal mammary tissue are mediated by the systemic host response to local infection. Furthermore, broad spectrum antibiotic treatment resolves the infection and restores mammary cellular and tissue homeostasis. Systemically, unresolved UTI correlates with increased plasma levels of the metalloproteinase inhibitor, TIMP1, which controls extracellular matrix remodeling and neutrophil function. Treatment of nulliparous and post-lactation UTI-bearing female mice with a TIMP1 neutralizing antibody, restores mammary tissue normal homeostasis, thus providing evidence for a link between the systemic host response during UTI and mammary gland alterations.
Assuntos
Glândulas Mamárias Animais , Infecções Urinárias , Animais , Feminino , Camundongos , Colágeno , Matriz Extracelular/fisiologia , HomeostaseRESUMO
The identification of defectives genes underlying inherited diseases has made it clear that patients with the same genotype can have variable clinical expression. Suggestions proposing that the protein AHSP, a alpha-globin specific chaperone could influence disease severity in patients with beta-thalassemia, an inherited disorder characterized by a quantitative deficiency of beta-globin genes. This article presents a review of the AHSP gene structure, function and expression. A discussion of the AHSP gene acknowledgements is presented with an overview of the possible genetic modifier function of AHSP on beta-thalassemia pathophysiology.
Assuntos
Proteínas Sanguíneas/genética , Regulação da Expressão Gênica , Chaperonas Moleculares/genética , Talassemia beta/genética , Proteínas Sanguíneas/metabolismo , Progressão da Doença , Humanos , Chaperonas Moleculares/metabolismo , Talassemia beta/metabolismo , Talassemia beta/fisiopatologiaRESUMO
A human homologue of Sar1, named Sara2, was shown to be preferentially expressed during erythropoiesis in a culture stimulated by EPO. Previous studies, in yeast, have shown that secretion-associated and Ras-related protein (Sar1p) plays an essential role in protein transport from the endoplasmic reticulum to the Golgi apparatus. Here, we report the molecular analysis of Sara2 in erythroid cell culture. A 1250 bp long cDNA, encoding a 198 amino-acid protein very similar to Sar1 proteins from other organisms, was obtained. Furthermore, we also report a functional study of Sara2 with Real-time quantitative PCR analysis, demonstrating that expression of Sara2 mRNA increases during the initial stages of erythroid differentiation with EPO and that a two-fold increase in expression occurs following the addition of hydroxyurea (HU). In K562 cells, Sara2 mRNA was observed to have a constant expression and the addition of HU also up-regulated the expression in these cells. Our results suggest that Sara2 is an important gene in processes involving proliferation and differentiation and could be valuable for understanding the vesicular transport system during erythropoiesis.
Assuntos
Células Precursoras Eritroides/fisiologia , Eritropoese/fisiologia , Proteínas Monoméricas de Ligação ao GTP/genética , Sequência de Aminoácidos , Técnicas de Cultura de Células , Diferenciação Celular , Clonagem Molecular , Primers do DNA , DNA Complementar , Células Precursoras Eritroides/citologia , Amplificação de Genes , Humanos , Hidroxiureia/farmacologia , Células K562 , Dados de Sequência Molecular , Proteínas Monoméricas de Ligação ao GTP/química , Reação em Cadeia da Polimerase , RNA Mensageiro/genéticaRESUMO
alpha-Hemoglobin stabilizing protein (AHSP) is an abundant, erythroid-specific protein that forms a stable complex with free alpha-hemoglobin but not with beta-hemoglobin or hemoglobin A. As such, AHSP is required for normal erythropoiesis, probably acting by blocking the deleterious effects of free alpha-hemoglobin precipitation. In order to study the levels of expression of the AHSP gene during the different phases of erythropoiesis, we carried out a two-phase liquid culture of erythroid cells and real-time quantitative polymerase chain reaction. Blood from control volunteers was cultured with erythropoietin to stimulate differentiation. The different stages of erythropoiesis were confirmed by morphologic and flow cytometric analysis. The results showed a progressive increase in AHSP gene expression following the expression of alpha-globin gene, during maturation of the red blood cell precursors, confirming the probable important function of this protein during normal erythropoiesis.