RESUMO
Anemia is common in older adults and associated with adverse health outcomes in epidemiological studies. A thorough understanding of the complex pathophysiological mechanisms driving anemia in the elderly is lacking; but inflammation, iron restriction, and impaired erythroid maturation are thought to influence the phenotype. We hypothesized that interleukin-6 contributes to this anemia, given its pro-inflammatory activities, its ability to induce hepcidin antimicrobial peptide, and its negative impact on several tissues in older adults. We tested this hypothesis by comparing changes in indices of inflammation, iron metabolism and erythropoiesis in aged C57BL/6 mice to aged mice with targeted deletions of interleukin-6 or hepcidin antimicrobial peptide. Circulating neutrophil and monocyte numbers and inflammatory cytokines increased with age. Decline in hemoglobin concentration and red blood cell number indicated that C57BL/6, interleukin-6 knockout mice, and hepcidin antimicrobial peptide knockout mice all demonstrated impaired erythropoiesis by 24 months. However, the interleukin-6 knock out genotype and the hepcidin antimicrobial peptide knock out genotype resulted in improved erythropoiesis in aged mice. Increased erythropoietic activity in the spleen suggested that the erythroid compartment was stressed in aged C57BL/6 mice compared to aged interleukin-6 knockout mice. Our data suggest C57BL/6 mice are an appropriate mammalian model for the study of anemia with age. Furthermore, although interleukin-6 and hepcidin antimicrobial peptide are not required, they can participate in the development of anemia in aging mice, and could be targeted, pre-clinically, with existing interventions to determine the feasibility of such agents for the treatment of anemia in older adults.
Assuntos
Envelhecimento/genética , Envelhecimento/metabolismo , Anemia/sangue , Anemia/genética , Hepcidinas/fisiologia , Interleucina-6/fisiologia , Animais , Feminino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Especificidade da EspécieRESUMO
BACKGROUND: We and others have shown previously that over-expression of hepcidin antimicrobial peptide, independently of inflammation, induces several features of anemia of inflammation and chronic disease, including hypoferremia, sequestration of iron stores and iron-restricted erythropoiesis. Because the iron-restricted erythropoiesis evident in hepcidin transgenic mice differs from the normocytic, normochromic anemia most often observed in anemia of inflammation, we tested the hypothesis that chronic inflammation may contribute additional features to anemia of inflammation which continue to impair erythropoiesis following the acute phase of inflammation in which hepcidin is active. DESIGN AND METHODS: We compared erythropoiesis and iron handling in mice with turpentine-induced sterile abscesses with erythropoiesis and iron handling in hepcidin transgenic mice. We compared erythrocyte indices, expression of genes in the hepcidin regulatory pathway, tissue iron distribution, expression of heme and iron transport genes in splenic macrophages, the phenotype of erythroid maturation and chloromethyl dichlorodihydrofluorescein diacetate, acetyl ester fluorescence. RESULTS: Mice with sterile abscesses exhibited an intense, acute inflammatory phase followed by a mild to moderate chronic inflammatory phase. We found that erythrocytes in mice with sterile abscesses were normocytic and normochromic in contrast to those in hepcidin transgenic mice. We also observed that although hypoferremia resolved in the late phases of inflammation, erythropoiesis remained suppressed, with evidence of inefficient maturation of erythroid precursors in the bone marrow of mice with sterile abscesses. Finally, we observed increased oxidative stress in erythroid progenitors and circulating erythrocytes of mice with sterile abscesses which was not evident in hepcidin transgenic mice. CONCLUSIONS: Our results suggest that chronic inflammation inhibits late stages of erythroid production in the turpentine-induced sterile abscess model and induces features of impaired erythropoiesis which are distinct from those in hepcidin transgenic mice.
Assuntos
Peptídeos Catiônicos Antimicrobianos/biossíntese , Células Precursoras Eritroides/metabolismo , Eritropoese , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Doença Crônica , Células Precursoras Eritroides/patologia , Hepcidinas , Inflamação/sangue , Inflamação/induzido quimicamente , Inflamação/genética , Mediadores da Inflamação/sangue , Irritantes/efeitos adversos , Irritantes/farmacologia , Camundongos , Camundongos Transgênicos , Terebintina/efeitos adversos , Terebintina/farmacologiaRESUMO
BACKGROUND: Polyoma virus-associated nephropathy (PVN) is a common cause of renal transplant failure. The risk factors for the development of PVN have not yet been studied in large cohorts of patients for periods of 20 years. METHODS: We collected clinical, renal biopsy and urinary cytology data from all patients with renal transplantations performed at the University Hospital of Basel from 1985 to 2005. All patients with a renal biopsy and urine cytology were included (n = 880). Renal transplants were divided into three groups, according to evidence of polyoma virus (PV) infection (decoy cells in the urine) and biopsy-proven PVN: Renal transplants without evidence of a PV infection (n = 751). Renal transplants with PV reactivation, e.g. decoy cell (DC) found by urinary cytology, but without PVN (n = 90). Renal transplants with PVN (n = 39). RESULTS: The prevalence of biopsy-proven PVN in this cohort of patients was 3.3%. Immunosuppression with mycophenolate and/or tacrolimus, ATGAM, male gender of the recipient and a higher number of transplant rejection episodes were factors significantly associated with PVN development. CONCLUSIONS: The most important risk factors for the development of PVN are acute rejection and ATGAM used as induction therapy as well as tacrolimus and mycophenolate as maintenance therapy. Therefore, we conclude that patients with tacrolimus and mycophenolate maintenance therapy should be carefully monitored for the development of PVN.