RESUMEN
Infection-induced hemolysis results in intravascular hemolysis, which releases hemoglobin (Hb) into the tissues. Free Hb exhibits cytotoxic, oxidative, and pro-inflammatory effects, leading to systemic inflammation, vascular constriction dysfunction, thrombosis, and proliferative vascular lesions. Currently, the impact of intravascular hemolysis on the middle kidney in fish is unclear. Here, the injection of phenylhydrazine (PHZ) was used to establish a persistent hemolysis model in grass carp. The determination results revealed that the PHZ-induced hemolysis caused conspicuous tissue damage in the kidneys of grass carp, increased the levels of Cr in the serum and the expression indicators of kidney injury-related genes in the middle kidney. Prussian blue staining indicated that PHZ-induced hemolysis significantly increased the deposition of iron ions in the kidneys of grass carp, and activated the expression levels of iron metabolism-related genes. The results of oxidative damage-related experiments indicate that under PHZ treatment, the activity of middle kidney cells decreases, and the production of oxidative damage markers malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) increases, simultaneously inhibiting the activity of antioxidant enzymes and upregulating the transcription levels of antioxidant enzyme-related genes. Additionally, the analysis of inflammatory factors revealed a significant upregulation of genes associated with inflammation induced by PHZ-induced hemolysis. The transcriptome analysis was performed to further explore the molecular regulatory effects of hemolysis on tissues, the analysis revealed the treatment of PHZ activated various of programmed cell death (PCD) pathways, including ferroptosis, apoptosis, and autophagy. In summary, this study found that sustained hemolysis in fish results in Hb and iron ion deposition in middle kidney, promoting oxidative damage, ultimately inducing various forms of PCD.
Asunto(s)
Carpas , Enfermedades de los Peces , Hemólisis , Animales , Carpas/inmunología , Enfermedades de los Peces/inmunología , Fenilhidrazinas/efectos adversos , Fenilhidrazinas/toxicidad , Enfermedades Renales/veterinaria , Enfermedades Renales/etiología , Enfermedades Renales/inmunología , Riñón/inmunología , Riñón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacosRESUMEN
Background: Hemolytic anemia (HA) is a serious health condition resulting from reduced erythrocytes' average life span. Echinochrome (Ech) is a dark-red pigment found in shells and spines of sea urchins. Aim: Studying the potential therapeutic effect of Ech on phenylhydrazine (PHZ)-induced HA in rats. Methods: Eighteen rats were divided into three groups (n = 6): the control group, the phenylhydrazine-induced HA group and the Ech group, injected intraperitoneally with PHZ and supplemented with oral Ech daily for 6 days. Results: Ech resulted in a considerable increase in RBCs, WBCs, and platelets counts, hemoglobin, reduced glutathione, catalase, and glutathione-S-transferase levels, and a significant decrease in aspartate & alanine aminotransferases, alkaline phosphatase, gamma-glutamyl transferase, bilirubin, creatinine, urea, urate, malondialdehyde & nitric oxide levels in anemic rats. Histopathological examination of liver and kidney tissue samples showed marked improvement. Conclusion: Ech ameliorated phenylhydrazine-induced HA with a hepatorenal protective effect owing to its anti-inflammatory and antioxidant properties.
Asunto(s)
Anemia Hemolítica , Estrés Oxidativo , Ratas , Animales , Antioxidantes/farmacología , Anemia Hemolítica/inducido químicamente , gamma-Glutamiltransferasa/farmacología , Glutatión Transferasa/efectos adversos , Fenilhidrazinas/efectos adversosRESUMEN
NEW FINDINGS: What is the central question of this study? Can an anaemic state modify adiposity and metabolic parameters in hypothalamic obese rats? What is the main finding and its importance? Hypothalamic obese rats do not display iron deficiency. However, the pharmacological induction of anaemia in hypothalamic obese rats resulted in reduced adiposity, characterized by a decrease in subcutaneous white and brown adipose tissue depots. These findings suggest that iron imbalance in obesity may elevate lipolysis. ABSTRACT: Iron imbalance is frequent in obesity. Herein, we evaluated the impact of anaemia induced by phenylhydrazine on adiposity and metabolic state of hypothalamic obese rats. Hypothalamic obesity was induced by high doses of monosodium glutamate (MSG; 4 g/kg) administered to neonatal male rats (n = 20). Controls (CTL; non-obese rats) received equimolar saline (n = 20). Rats were weaned at 21 days of life. At 70 days, half of the rats received three intraperitoneal doses of phenylhydrazine (PHZ; 40 mg/kg/dose) or saline solution. Body weight and food intake were followed for 4 weeks after PHZ administration. At 92 days, rats were killed and blood was collected for microcapillary haematocrit (Hct) analysis and plasma quantification of glucose, triglycerides, total cholesterol and iron levels. The liver, the spleen, and the white (WAT) and brown (BAT) adipose tissues were excised, weighed and used for histology. MSG-treated rats developed obesity, hypertriglyceridaemia and insulin resistance, compared to CTL rats, without changes in iron levels and Hct. PHZ administration reduced plasma iron levels and promoted similar tissue injuries in the spleen and liver from MSG and CTL rats. However, in MSG-treated rats, PHZ decreased fasting glucose levels and Hct, as well as diminishing the subcutaneous WAT and BAT mass. Although MSG-obesity does not affect plasma iron levels and Hct by itself, PHZ-induced anaemia associated with obesity induces a marked drop in subcutaneous WAT and BAT mass, suggesting that iron imbalance may lead to increased lipolytic responses in obese rats, compared to lean rats.
Asunto(s)
Tejido Adiposo Pardo , Anemia , Tejido Adiposo/metabolismo , Tejido Adiposo Pardo/metabolismo , Anemia/inducido químicamente , Anemia/metabolismo , Animales , Glucosa/metabolismo , Hierro , Masculino , Obesidad/metabolismo , Fenilhidrazinas/efectos adversos , Fenilhidrazinas/metabolismo , Ratas , Glutamato de SodioRESUMEN
OBJECTIVES: Anemia is a direct or indirect consequence of oxidative stress via free radicals on erythrocytes and subsequently on other tissues like liver. Ficus glumosa constitute a rich pharmacologically compound that can prevent or repair oxidative damage. Therefore, this study seeks to evaluate the effect of F. glumosa on phenylhydrazine-induced hemolytic anemia and hepatic damage in rats. METHODS: Twenty-four (24) albino Wistar rats were assigned to four (4) experimental groups (n=6) as follows: Group I (non-anemic control) and Group 2 (anemic control) received normal saline, while Group III and IV (test groups) 200 and 400 mg/kg of aqueous leaf extract of F. glumosa (ALEFG), respectively. All the groups were treated orally (via a cannula) for seven consecutive days. Intraperitoneal (IP) injection of phenylhydrazine (PHZ) at 40 mg/kg for two consecutive days induced hemolytic anemia in group II to IV before treatment. Rats of all groups were anaesthetized and sacrificed 24 h after the last treatment. Blood and liver samples were collected for some hematological indices, liver function test, antioxidant parameter and histological analysis. RESULTS: The LD50 of ALEFG was assessed orally in rats and found to be above 5,000 mg/kg body weight. Significant (p<0.05) decreases in the level of red blood cell (RBC), hemoglobin (HGB) concentrations and packed cell volume (PCV) by 50% after 2 days of PHZ induction, were attenuated by more than 50% after 7 days administration of ALEFG at 200 and 400 mg/kg. The percentage change in body weight increased significantly (p<0.05) after 7 days post PHZ-induced anemia, but those that received oral administration of ALEFG (at 200 and 400 mg/kg) for 7 days increased significantly (p<0.05) by more than 2%, dose-dependently compared to anemic untreated group. Increased level of serum ALT, AST, ALP and GGT in PHZ-induced anemic animals, were significantly (p<0.05) attenuated in the groups that received oral administration of ALEFG (at 200 and 400 mg/kg) for 7 days. Decreased level of catalase (CAT) and superoxide dismutase (SOD) activities with concomitant increase in malondialdehyde (MDA) content from PHZ-induced untreated group, were significantly (p<0.05) mitigated in the rats that received oral administration of ALEFG (at 200 and 400 mg/kg) for 7 days. Histopathological analysis showed that ALEFG could remarkably though not completely mitigated PHZ-induced hepatic damage. CONCLUSIONS: Our data suggests that the leaves of F. glumosa contain important antioxidant(s) that could effectively reduce hemolytic anemia and hepatic damage, especially during phenylhydrazine-induced toxicity.
Asunto(s)
Anemia Hemolítica , Ficus , Anemia Hemolítica/inducido químicamente , Anemia Hemolítica/tratamiento farmacológico , Anemia Hemolítica/prevención & control , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Peso Corporal , Catalasa , Hemoglobinas , Malondialdehído , Estrés Oxidativo , Fenilhidrazinas/efectos adversos , Extractos Vegetales/efectos adversos , Ratas , Ratas Wistar , Solución Salina/efectos adversos , Superóxido DismutasaRESUMEN
Clearance of red blood cells and hemoproteins is a key metabolic function of macrophages during hemolytic disorders and following tissue injury. Through this archetypical phagocytic function, heme is detoxified and iron is recycled to support erythropoiesis. Reciprocal interaction of heme metabolism and inflammatory macrophage functions may modify disease outcomes in a broad range of clinical conditions. We hypothesized that acute hemolysis and heme induce acute anti-inflammatory signals in liver macrophages. Using a macrophage-driven model of sterile liver inflammation, we showed that phenylhydrazine (PHZ)-mediated acute erythrophagocytosis blocked the anti-CD40 antibody-induced pathway of macrophage activation. This process attenuated the inflammatory cytokine release syndrome and necrotizing hepatitis induced by anti-CD40 antibody treatment of mice. We further established that administration of heme-albumin complexes specifically delivered heme to liver macrophages and replicated the anti-inflammatory effect of hemolysis. The anti-inflammatory heme-signal was induced in macrophages by an increased intracellular concentration of the porphyrin independently of iron. Overall, our work suggests that induction of heme-signaling strongly suppresses inflammatory macrophage function, providing protection against sterile liver inflammation.
Asunto(s)
Anticuerpos/inmunología , Antígenos CD40/antagonistas & inhibidores , Antígenos CD40/inmunología , Hemólisis/inmunología , Hepatitis/etiología , Albúminas/metabolismo , Animales , Anticuerpos/efectos adversos , Biopsia , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Eritrocitos/patología , Perfilación de la Expresión Génica , Hemo/metabolismo , Hepatitis/metabolismo , Hepatitis/patología , Hierro/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Noqueados , Fenilhidrazinas/efectos adversos , Porfirinas/metabolismo , Unión ProteicaRESUMEN
Bone marrow steady-state erythropoiesis maintains erythroid homeostasis throughout life. This process constantly generates new erythrocytes to replace the senescent erythrocytes that are removed by macrophages in the spleen. In contrast, anemic or hypoxic stress induces a physiological response designed to increase oxygen delivery to the tissues. Stress erythropoiesis is a key component of this response. It is best understood in mice where it is extramedullary occurring in the adult spleen and liver and in the fetal liver during development. Stress erythropoiesis utilizes progenitor cells and signals that are distinct from bone marrow steady-state erythropoiesis. Because of that observation many genes may play a role in stress erythropoiesis despite having no effect on steady-state erythropoiesis. In this chapter, we will discuss in vivo and in vitro techniques to study stress erythropoiesis in mice and how the in vitro culture system can be extended to study human stress erythropoiesis.
Asunto(s)
Eritropoyesis , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Estrés Fisiológico , Anemia Hemolítica/sangre , Anemia Hemolítica/etiología , Animales , Biomarcadores , Trasplante de Médula Ósea , Diferenciación Celular , Ensayo de Unidades Formadoras de Colonias , Células Precursoras Eritroides/citología , Células Precursoras Eritroides/metabolismo , Eritropoyesis/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Inmunofenotipificación , Ratones , Fenilhidrazinas/efectos adversos , Fenilhidrazinas/farmacologíaRESUMEN
BACKGROUND AND AIM: Prevalence of colonic diverticulosis is increasing worldwide with age, and up to 25% of patients who have colonic diverticulosis might experience diverticulitis. However, a definitive approach of preventing recurrent diverticulitis remains unknown. 5-aminosalicylic acid (5-ASA) agents are anti-inflammatory agents and have been used to prevent recurrent diverticulitis, and there have been some randomized clinical trials (RCTs). However, the efficacy results for secondary prevention in uncomplicated diverticulitis differed across studies. Our aim was to clarify the efficacy and safety of 5-ASA agents in the prevention of recurrent diverticulitis. METHODS: We searched MEDLINE, EMBASE, Web of Science, and the Cochrane library with no language restrictions. Two reviewers independently assessed and selected RCTs. The data were pooled using a random effect model and were presented in the pooled risk ratio (RR) and 95% confidence interval (CI). Cochrane's Q and I-squared statistics were used to assess heterogeneity. The protocol was registered at PROSPERO. RESULTS: Seven articles with eight RCTs from 329 potentially relevant articles were included. 5-ASA agents were not superior to controls in preventing recurrent diverticulitis (RR 0.86, 95% CI 0.63 to 1.17, I2 = 60%) and the incidence of adverse events was not different between 5-ASA agents and controls (RR 0.97, 95% CI 0.84 to 1.11, I2 = 45%). However, some included studies were few in number of participants and substantial risk of bias. CONCLUSIONS: 5-aminosalicylic acid agents were not associated with prevention of recurrent diverticulitis.
Asunto(s)
Antiinflamatorios/administración & dosificación , Bases de Datos Bibliográficas , Diverticulitis/prevención & control , Mesalamina/administración & dosificación , Prevención Secundaria , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ácidos Aminosalicílicos/administración & dosificación , Ácidos Aminosalicílicos/efectos adversos , Antiinflamatorios/efectos adversos , Femenino , Humanos , Masculino , Mesalamina/efectos adversos , Persona de Mediana Edad , Fenilhidrazinas/administración & dosificación , Fenilhidrazinas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Recurrencia , Sulfasalazina/administración & dosificación , Sulfasalazina/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
Induction of hyperbilirubinemia in experimental rabbits by phenylhydrazine was optimized in terms of dose, dose interval and number of doses using response surface methodology. Central Composite Design was employed using five levels for each of the three input variables. Degree of hyperbilirubinemia was measured in terms of bilirubin level in serum of animals. A dose dependent significant elevation (P<0.05) of total serum bilirubin level was observed which was optimized by using eight factorial, six axial and six central points as suggested by experimental design. Optimum levels of phenylhydrazine dose, total number of doses and a dose interval to achieve maximum elevation (4.06 mg/dl-1) of total serum bilirubin were found to be 11.56 mg/kg-1 body weight, 8 and 24.65 h, respectively. The induction procedure was validated by performing five replicate experiments on a group of five animals which showed 3.56 ± 0.47 mg/kg-1 body weight elevation in total serum bilirubin level.
Asunto(s)
Hemolíticos/efectos adversos , Hiperbilirrubinemia/inducido químicamente , Fenilhidrazinas/efectos adversos , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Hiperbilirrubinemia/sangre , Masculino , Conejos , Distribución Aleatoria , Ácido Ursodesoxicólico/efectos adversosRESUMEN
Phenylhydrazine (PHZ) treatment is generally used to enhance parasitemia in infected mice models. Transient reticulocytosis is commonly observed in iron-deficient anemic hosts after treatment with iron supplementation, and is also associated with short-term hemolysis caused by PHZ treatment. In this study, we investigated the relationship between reticulocytosis and cerebral malaria (CM) in a murine model induced by PHZ administration before Plasmodium berghei ANKA (PbA) infection. Mortality and parasitemia were checked daily. Pro-inflammatory cytokines and IL-10 were quantified by ELISA. The expression of CXCL9, CXCL10, CCL5, and CXCR3 mRNAs was determined by real-time PCR. Brain sequestration of CD4(+) and CD8(+) T cells and populations of splenic Th1 CD4(+) T cells, dendritic cells (DCs), CD11b(+) Gr1(+) cells, and regulatory T cells (Tregs) were assessed by FACS. PHZ administration dramatically increased parasitemia from day 3 to day 5 post infection (p.i.) compared with the untreated control infected mice group; also, CM developed at day 5 p.i., compared with day 7 p.i. in untreated control infected mice, as well as significantly decreased blood-brain barrier function (P < 0.001). PHZ administration during PbA infection significantly increased the expression of CXCL9 (P <0.05) and VCAM-1 (P <0.001) in the brain, increased the expression of CXCL10, CCL5 and CXCR3, and significantly increased the recruitment of CD4(+) and CD8(+) T cells (P <0.001 and P <0.01, respectively) as well as CD11b(+) Gr1(+) cells to the brain. In addition, PHZ administration significantly increased the numbers of IL-12-secreting DCs at days 3 and 5 p.i. compared to those of untreated control infected mice (P <0.001 and P <0.01, respectively). Consequently, the activation of CD4(+) T cells, especially the expansion of the Th1 subset (P <0.05), was significantly and dramatically enhanced and was accompanied by marked increases in the production of protein and/or mRNA of the Th1-type pro-inflammatory mediators, IFN-γ and TNF-α (P <0.01 for both for protein; P <0.05 for TNF-α mRNA). Our results suggest that, compared to healthy individuals, people suffering from reticulocytosis may be more susceptible to severe malaria infection in malaria endemic areas. This has implications for the most appropriate selection of treatment, which may also cause reticulocytosis in patients living in such areas.
Asunto(s)
Malaria Cerebral/inducido químicamente , Oxidantes/efectos adversos , Parasitemia/inducido químicamente , Fenilhidrazinas/efectos adversos , Plasmodium berghei/efectos de los fármacos , Reticulocitosis/efectos de los fármacos , Animales , Barrera Hematoencefálica/metabolismo , Recuento de Eritrocitos , Índices de Eritrocitos , Femenino , Hemoglobinas/análisis , Inyecciones Intraperitoneales , Ratones , Ratones Endogámicos C57BL , Plasmodium berghei/patogenicidad , Distribución Aleatoria , Receptores CCR5/genética , Receptores CCR5/metabolismo , Receptores CXCR3/genética , Receptores CXCR3/metabolismo , Reticulocitos/citología , Reticulocitos/efectos de los fármacos , Reticulocitosis/inmunología , Bazo/citología , Bazo/inmunología , Linfocitos T/efectos de los fármacos , Regulación hacia ArribaRESUMEN
Ulcerative colitis (UC) is an idiopathic chronic inflammatory disorder that affects the colonic mucosa. One class among the drugs used for its treatment is the 5-aminosalicylates (5-ASAs). While highly efficacious in treating mild-to-moderate UC, 5-ASAs are associated with rare but potentially life-threatening side effects such as pericarditis, myocarditis and pneumonitis. These adverse events appear to be caused by a hypersensitivity reaction and resolve after cessation of 5-ASA drugs. This article presents a case report of febrile pleuropericarditis in a UC patient treated with balsalazide, and provides a thorough literature review of the rare side effects of 5-ASAs, their incidence, clinical presentation, differential diagnosis and treatment. In conclusion, the clinicians should be aware that this type of adverse events to 5-ASA compounds can be easily overlooked but it has significant morbidity if not promptly diagnosed.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Fiebre/diagnóstico , Mesalamina/uso terapéutico , Pericarditis/diagnóstico , Fenilhidrazinas/uso terapéutico , Adulto , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/uso terapéutico , Fiebre/inducido químicamente , Humanos , Masculino , Mesalamina/efectos adversos , Pericarditis/inducido químicamente , Fenilhidrazinas/efectos adversosRESUMEN
When the erythroid integrins α5ß1 and α4ß1 were each deleted previously at the stem cell level, they yielded distinct physiologic responses to stress by affecting erythoid expansion and terminal differentiation or only the latter, respectively. To test at what stage of differentiation the integrin effects were exerted, we created mice with α4- or α5-integrin deletions only in erythroid cells and characterized them at homeostasis and after phenylhydrazine-induced hemolytic stress. Unlike our prior data, the phenotype of mice with α5-erythroid deletions was similar to controls, especially after stress. These outcomes seem to reconcile divergent prior views on the role of α5-integrin in erythropoiesis. By contrast, α4 integrins whether deleted early or late have a dominant effect on bone marrow retention of erythroblasts and on terminal erythroid maturation at homeostasis and after stress.
Asunto(s)
Eritroblastos/metabolismo , Eritropoyesis/fisiología , Integrina alfa4/metabolismo , Integrina alfa5/metabolismo , Animales , Eritroblastos/citología , Eritropoyesis/efectos de los fármacos , Eliminación de Gen , Hemólisis/efectos de los fármacos , Integrina alfa4/genética , Integrina alfa5/genética , Ratones , Ratones Noqueados , Oxidantes/efectos adversos , Oxidantes/farmacología , Fenilhidrazinas/efectos adversos , Fenilhidrazinas/farmacologíaRESUMEN
Hepcidin, the key regulatory hormone of iron homeostasis, and iron carriers such as transferrin receptor1 (TFR1), divalent metal transporter1 (DMT1), and ferroportin (FPN) are expressed in kidney. Whether hepcidin plays an intrinsic role in the regulation of renal iron transport is unknown. Here, we analyzed the renal handling of iron in hemochromatosis Hepc(-/-) and Hjv(-/-) mouse models, as well as in phenylhydrazine (PHZ)-treated mice. We found a marked medullary iron deposition in the kidneys of Hepc(-/-) mice, and iron leak in the urine. The kidneys of Hepc(-/-) mice exhibited a concomitant decrease in TFR1 and increase in ferritin and FPN expression. Increased FPN abundance was restricted to the thick ascending limb (TAL). DMT1 protein remained unaffected despite a significant decrease of its mRNA level, suggesting that DMT1 protein is stabilized in the absence of hepcidin. Treatment of kidney sections from Hepc(-/-) mice with hepcidin decreased DMT1 protein, an effect confirmed in renal cell lines where hepcidin markedly decreased (55)Fe transport. In the kidneys of Hjv(-/-) mice exhibiting low hepcidin expression, the iron overload was similar to that in the kidneys of Hepc(-/-) mice. However, in PHZ mice, iron accumulation resulting from hemoglobin leak was detected in the proximal tubule. Thus, kidneys exhibit a tissue-specific handling of iron that depends on the extra iron source. Hepcidin may control the expression of iron transporters to prevent renal iron overload.
Asunto(s)
Hemocromatosis/metabolismo , Hepcidinas/metabolismo , Homeostasis/fisiología , Hierro/metabolismo , Túbulos Renales Distales/metabolismo , Animales , Proteínas de Transporte de Catión/metabolismo , Línea Celular , Células Cultivadas , Modelos Animales de Enfermedad , Proteínas Ligadas a GPI , Hemocromatosis/inducido químicamente , Hemocromatosis/genética , Proteína de la Hemocromatosis , Hepcidinas/deficiencia , Hepcidinas/genética , Técnicas In Vitro , Túbulos Renales Distales/patología , Asa de la Nefrona/metabolismo , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Zarigüeyas , Fenilhidrazinas/efectos adversos , Receptores de Transferrina/metabolismoAsunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Taponamiento Cardíaco/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Pericarditis/inducido químicamente , Antiinflamatorios no Esteroideos/uso terapéutico , Femenino , Humanos , Mesalamina/efectos adversos , Mesalamina/uso terapéutico , Fenilhidrazinas/efectos adversos , Fenilhidrazinas/uso terapéutico , Sulfasalazina/efectos adversos , Sulfasalazina/uso terapéutico , Adulto JovenRESUMEN
Phenylhydrazine injections (0.3 mg kg(-1) , followed by a second injection of 0.1 mg kg(-1) 7 days later) induced a reproducible and stable anaemia in Atlantic halibut Hippoglossus hippoglossus, reducing the haematocrit and haemoglobin by 70.0 and 75.5%, respectively, over 3 weeks. There were no changes in blood electrolyte or lactate concentrations, although anaemic fish showed a 37.5 and 33.0% increase in cardiac somatic index and ventricular somatic index, respectively, compared with dimethyl sulphur oxide (DMSO) and saline vehicle controls. Changes in cardiac somatic indices did not correlate with the ratio of ventricular length:height and length:width did correlate with haematocrit and haemoglobin indicating that changes in cardiac shape may occur as a function of anaemic hypoxemia.
Asunto(s)
Anemia/inducido químicamente , Lenguado/anatomía & histología , Corazón/fisiopatología , Fenilhidrazinas/efectos adversos , Remodelación Ventricular/efectos de los fármacos , Animales , Dimetilsulfóxido , Corazón/efectos de los fármacos , Hematócrito , Hemoglobinas/análisisRESUMEN
The BMP/SMAD signalling pathway plays an important role in iron homeostasis, regulating hepcidin expression in response to body iron levels. However, the role of this pathway in the reduction in hepcidin associated with increased erythropoiesis (and secondary iron loading) is unclear. To investigate this, we established a mouse model of chronic stimulated erythropoiesis with secondary iron loading using the haemolytic agent phenylhydrazine. We then examined the expression of components of the BMP6/SMAD signalling pathway in these animals. We also examined this pathway in the Hbb(th3/+) mouse, a model of the iron loading anaemia ß-thalassaemia intermedia. Increasing doses of phenylhydrazine led to a progressive increase in both liver iron levels and Bmp6 mRNA expression, but, in contrast, hepatic Hamp expression declined. The increase in Bmp6 expression was not associated with a corresponding change in the phosphorylation of hepatic SMAD1/5/8, indicating that stimulated erythropoiesis decreases the ability of BMP6 to alter SMAD phosphorylation. Increased erythropoiesis also reduces the capacity of phosphorylated SMAD (pSMAD) to induce hepcidin, as Hamp levels declined despite no changes in pSMAD1/5/8. Similar results were seen in Hbb(th3/+) mice. Thus the erythroid signal probably affects some components of BMP/SMAD signalling, but also may exert some independent effects.
Asunto(s)
Péptidos Catiónicos Antimicrobianos/metabolismo , Proteína Morfogenética Ósea 6/metabolismo , Eritropoyesis/efectos de los fármacos , Sobrecarga de Hierro/metabolismo , Anemia Hemolítica/inducido químicamente , Anemia Hemolítica/metabolismo , Animales , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Factor 15 de Diferenciación de Crecimiento/metabolismo , Hemólisis/efectos de los fármacos , Hepcidinas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fenilhidrazinas/efectos adversos , Fenilhidrazinas/farmacología , Fosforilación , Receptores de Transferrina/metabolismo , Transducción de Señal , Proteínas Smad/metabolismo , Bazo/metabolismo , Transferrina/metabolismo , Talasemia beta/metabolismoRESUMEN
Hemolytic anemia is one of the most common inherited disorders. To identify candidate proteins involved in hemolytic anemia pathophysiology, we utilized a label-free comparative proteomic approach to detect differences in RBCs from normal and beta-adducin (Add2) knock-out mice. We detected 7 proteins that were decreased and 48 proteins that were increased in the beta-adducin knock-out RBC ghost. Since hemolytic anemias are characterized by reticulocytosis, we compared reticulocyte-enriched samples from phenylhydrazine-treated mice with mature RBCs from untreated mice. Label-free analysis identified 47 proteins that were increased in the reticulocyte-enriched samples and 21 proteins that were decreased. Among the proteins increased in Add2 knockout RBCs, only 11 were also found increased in reticulocytes. Among the proteins decreased in Add2 knockout RBCs, beta- and alpha-adducin showed the greatest intensity difference, followed by NHE-1 (Slc9a1), the sodium-hydrogen exchanger. We verified these mass spectrometry results by immunoblot. This is the first example of a deficiency of NHE-1 in hemolytic anemia and suggests new insights into the mechanisms leading to fragile RBCs. Our use of label-free comparative proteomics to make this discovery demonstrates the usefulness of this approach as opposed to metabolic or chemical isotopic labeling of mice.
Asunto(s)
Anemia Hemolítica/genética , Proteínas de Unión a Calmodulina , Proteínas de Transporte de Catión/genética , Eritrocitos/metabolismo , Fragilidad Osmótica/genética , Fenilhidrazinas/efectos adversos , Isoformas de Proteínas/genética , Proteómica/métodos , Reticulocitos/metabolismo , Intercambiadores de Sodio-Hidrógeno/genética , Secuencia de Aminoácidos , Anemia Hemolítica/inducido químicamente , Anemia Hemolítica/metabolismo , Anemia Hemolítica/patología , Animales , Western Blotting , Proteínas de Unión a Calmodulina/deficiencia , Proteínas de Unión a Calmodulina/genética , Proteínas de Transporte de Catión/deficiencia , Modelos Animales de Enfermedad , Recuento de Eritrocitos , Membrana Eritrocítica/genética , Membrana Eritrocítica/metabolismo , Eritrocitos/citología , Perfilación de la Expresión Génica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Datos de Secuencia Molecular , Fenilhidrazinas/farmacología , Isoformas de Proteínas/metabolismo , Recuento de Reticulocitos , Reticulocitos/citología , Intercambiador 1 de Sodio-Hidrógeno , Espectrometría de Masas en TándemRESUMEN
Malaria is one of the most lethal parasitic infections in the world. The lethality of the parasite depends on the rate of multiplication of the parasite within host erythrocytes. Different strains of the malaria parasite often respond in a different way to the same strain of mice or vice versa. In the present study, we investigated the course of infection of the arteether-sensitive and arteether-resistant Plasmodium vinckei parasites in Swiss albino AKR (inbred) and AJ (outbred) mice. The higher parasite burden and mortality were observed in the sensitive parasite-infected mice, whereas the infection with the resistant parasite was non-lethal. Resistant parasite-infected mice developed a moderate level of parasitemia that decreased gradually throughout the infection. The microscopic examination suggests that the resistant parasite invades reticulocytes more efficiently than normocytes, regardless of the mouse strain examined. Since the reticulocytes are rare in blood circulation, it limits the increase in parasite proliferations, while arteether-sensitive parasites can invade both mature normocytes and reticulocytes, resulting in the mortality of the mice. However, treatment with phenylhydrazine in Swiss mice results in reticulocytosis, which transforms the non-lethal resistant parasites to produce lethal infections. Our findings demonstrate that the characteristic response during infections with the arteether-resistant strain is dependent on the availability of reticulocytes in peripheral blood circulation. We can use this model for identifying the interaction between host and artemisinin derivative-resistant parasites.
Asunto(s)
Eritrocitos/parasitología , Malaria/parasitología , Plasmodium/patogenicidad , Reticulocitos/parasitología , Enfermedades de los Roedores/parasitología , Animales , Artemisininas/farmacología , Colorantes Azulados , Resistencia a Medicamentos , Eritrocitos/citología , Especificidad del Huésped/efectos de los fármacos , Interacciones Huésped-Parásitos/efectos de los fármacos , Malaria/tratamiento farmacológico , Ratones , Microscopía , Parasitemia , Fenilhidrazinas/administración & dosificación , Fenilhidrazinas/efectos adversos , Plasmodium/efectos de los fármacos , Plasmodium/fisiología , Recuento de Reticulocitos , Reticulocitos/citología , Enfermedades de los Roedores/tratamiento farmacológico , Especificidad de la EspecieRESUMEN
Acclimation of crucian carp and goldfish to temperatures below 15°C causes covering of the gill lamellae by a mass of cells termed the interlamellar cell mass (ILCM). Here we explore the cues underlying gill remodeling (removal or growth of an ILCM) and specifically test the hypotheses that 1) depletion of internal O(2) stores in the absence of any change in external O(2) status can trigger the removal of the ILCM in goldfish acclimated to 7°C, 2) exposing fish acclimated to 25°C to an abundance of O(2) (hyperoxia) can reverse the gill remodeling (i.e., cause the covering of lamellae by an expansion of the ILCM), and 3) neuroepithelial cells (NECs) are involved in signaling the shedding of the ILCM. Hypoxemia induced by phenylhydrazine (anemia) or 5% CO caused a decrease in the ILCM from 80% to 23% and 35%, respectively. Hyperoxia exposure at 25°C caused an increase to 67% of total ILCM and a smaller decrease in the size of the ILCM when fish were transferred from 7 to 25°C. Daily sodium cyanide injections were used to stimulate NECs; this treatment led to a significant decrease in the ILCM. Thus, the three major conclusions of this study are 1) that gill remodeling can occur during periods of internal hypoxemia, 2) that O(2) supply and demand may be a significant driving force shaping gill remodeling in goldfish, and 3) the NECs may play a role in triggering the shedding of the ILCM during hypoxia.
Asunto(s)
Adaptación Fisiológica/fisiología , Branquias/anatomía & histología , Carpa Dorada/anatomía & histología , Carpa Dorada/fisiología , Hiperoxia/fisiopatología , Hipoxia/fisiopatología , Temperatura , Animales , Monóxido de Carbono/efectos adversos , Branquias/citología , Branquias/efectos de los fármacos , Hemoglobinas/metabolismo , Hipoxia/inducido químicamente , Inyecciones , Células Neuroepiteliales/citología , Células Neuroepiteliales/efectos de los fármacos , Células Neuroepiteliales/fisiología , Oxígeno/metabolismo , Oxígeno/farmacología , Fenilhidrazinas/efectos adversos , Transducción de Señal/fisiología , Cianuro de Sodio/administración & dosificación , Cianuro de Sodio/farmacologíaRESUMEN
OBJECTIVE: To investigate the effect of Coptis chinensis on oxidative hemolysis of erythrocytes in mice. METHOD: Acetylphenyhydrazine (APH)-induced oxidative hemolysis of erythrocytes in mice were used. The contents of free hemoglobin of blood plasma, indirect bilirubin of serum, reticulocytes of blood, and malondialdehyde (MDA) of erythrocytes were measured. The activity of superoxide dismutase (SOD), reduced glutathione hormone (GSH), and glucose-6-phosp hate dehydrogenase (G-6-PD) of erythrocytes were also determined and the total-antioxygen capability (T-AOC) of blood was analyzed. RESULT: The levels or amount of free hemoglobin of blood plasma, indirect bilirubin of serum, reticulocytes of blood and MDA of erythrocytes were higher in APH (0.03 g x kg(-1))-induced mice than normal mice. The activity or content of SOD, GSH and G-6-PD was lower in APH-induced mice than in normal mice. Primaquine (0.058 g x kg(-1)) could aggravated the degree of elevated hemolysis of erythrocytes in APH-induced mice. C. chinensis (0.6 g x kg(-1) could deprssed significantly the elevated levels of indirect bilirubin in serum. The levels of free hemoglobin of blood plasma, indirect bilirubin of serum, reticulocytes of blood, the production of SOD and GSH and T-AOC were also decressed by C. chinensis (0.6 g x kg(-1)). CONCLUSION: C. chinensis suppressed t he degree of hemolysis of erythrocytes in APH-induced mice due to the suppression of the production of lipid peroxidation and increasing of the activity of antioxidase of erythrocytes.
Asunto(s)
Coptis/química , Medicamentos Herbarios Chinos/administración & dosificación , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Hemólisis/efectos de los fármacos , Animales , Femenino , Masculino , Ratones , Oxidación-Reducción , Fenilhidrazinas/efectos adversos , Plasma/metabolismo , Distribución AleatoriaRESUMEN
We report a case of unilateral eosinophilic pneumonia secondary to balsalazide monotherapy for ulcerative colitis. After commencing balsalazide, the patient presented with a history of cough, progressive dyspnoea and lethargy. Blood counts revealed peripheral eosinophilia. Her chest radiograph showed left-sided infiltration, and high-resolution computerised tomography demonstrated widespread nodular shadowing and ground glass opacifiction in the left lung. The right lung was normal. Transbronchial lung biopsy confirmed eosinophilic pneumonia. There was rapid clinical and radiological improvement after with-drawing balsalazide. Drug-induced eosinophilic pneumonia has been described with mesalazine and sulfasalazine, but no case reports of balsalazide-induced eosinophilic pneumonitis have been found.