[Ion transporters in the lungs. Use as therapeutic targets]. / Transportadores de iones en pulmón. Uso como dianas terapéuticas.

The chloride channels, sodium and bicarbonate channels, and aquaporin water channels are coordinated to maintain the airway surface liquid that is necessary for mucociliary clearance. The general mechanism for the transport of electrolytes and fluids depends mainly on the differential expression and distribution of ion transporters and pumps. Ions and water move through the paracellular or transcellular pathways. The transcellular route of electrolyte transport requires an active transport (dependent on ATP) or passive (following electrochemical gradients) of ions. The paracellular pathway is a passive process that is ultimately controlled by the predominant transepithelial electrochemical gradients. Cystic fibrosis is a hereditary disease that is produced by mutations in the gene that encode cystic fibrosis transmembrane conductance regulatory protein (CFTR) that acts as a chloride channel and performs functions of hydration of periciliary fluid and maintenance of luminal pH. The dysfunction of the chlorine channel in the respiratory epithelium determines an alteration in the bronchial secretions, with an increase in its viscosity and alteration of the mucociliary clearance and that associated with infectious processes can lead to irreversible lung damage. CFTR dysfunction has also been implicated in the pathogenesis of acute pancreatitis, chronic obstructive pulmonary disease, and bronchial hyperreactivity in asthma. There are drugs that exploit physiological mechanisms in the transport of ions with a therapeutic objective.

Los canales de cloruros, de sodio, de bicarbonato y los de agua (aquaporinas) se coordinan para mantener la cubierta líquido superficial de las vías respiratorias, que es necesaria para el aclaramiento mucociliar. El mecanismo general para el transporte de electrolitos y agua depende principalmente de la expresión diferencial y distribución de los transportadores y bombas de iones. Los iones y el agua se mueven a través de las vía paracelular o transcelular. La ruta transcelular del transporte de electrolitos requiere un transporte activo (dependiente de ATP) o pasivo (siguiendo gradientes electroquímicos) de iones. La ruta paracelular es un proceso pasivo que está controlado, en última instancia, por los gradientes electroquímicos transepiteliales predominantes. La fibrosis quística es una enfermedad hereditaria que se produce por mutaciones en el gen que codifica la proteína reguladora de la conductibilidad transmembrana de la fibrosis quística (CFTR) que actúa como un canal de cloro y cumple funciones de hidratación del líquido periciliar y mantenimiento del pH luminal. La disfunción del canal de cloro en el epitelio respiratorio determina una alteración en las secreciones bronquiales, con aumento de su viscosidad y alteración de la depuración mucociliar y que asociado a procesos infecciosos puede conducir a daño pulmonar irreversible. La disfunción del CFTR, también se ha visto implicado en la patogénesis de la pancreatitis aguda, en la enfermedad pulmonar obstructiva crónica y la hiperreactividad en el asma. Existen fármacos que aprovechan los mecanismos fisiológicos en el transporte de iones, con un objetivo terapéutico.

Transportadores de iones en pulmón: Uso como dianas terapéuticas / Ion transporters in the lungs. Use as therapeutic targets

Los canales de cloruros, de sodio, de bicarbonato y los de agua (aquaporinas) se coordinan para mantener la cubierta líquido superficial de las vías respiratorias, que es necesaria para el aclaramiento mucociliar. El mecanismo general para el transporte de electrolitos y agua depende principalmente de la expresión diferencial y distribución de los transportadores y bombas de iones. Los iones y el agua se mueven a través de las vía paracelular o transcelular. La ruta transcelular del transporte de electrolitos requiere un transporte activo (dependiente de ATP) o pasivo (siguiendo gradientes electroquímicos) de iones. La ruta paracelular es un proceso pasivo que está controlado, en última instancia, por los gradientes electroquímicos transepiteliales predominantes. La fibrosis quística es una enfermedad hereditaria que se produce por mutaciones en el gen que codifica la proteína reguladora de la conductibilidad transmembrana de la fibrosis quística (CFTR) que actúa como un canal de cloro y cumple funciones de hidratación del líquido periciliar y mantenimiento del pH luminal. La disfunción del canal de cloro en el epitelio respiratorio determina una alteración en las secreciones bronquiales, con aumento de su viscosidad y alteración de la depuración mucociliar y que asociado a procesos infecciosos puede conducir a daño pulmonar irreversible. La disfunción del CFTR, también se ha visto implicado en la patogénesis de la pancreatitis aguda, en la enfermedad pulmonar obstructiva crónica y la hiperreactividad en el asma. Existen fármacos que aprovechan los mecanismos fisiológicos en el transporte de iones, con un objetivo terapéutico.

The chloride channels, sodium and bicarbonate channels, and aquaporin water channels are coordinated to maintain the airway surface liquid that is necessary for mucociliary clearance. The general mechanism for the transport of electrolytes and fluids depends mainly on the differential expression and distribution of ion transporters and pumps. Ions and water move through the paracellular or transcellular pathways. The transcellular route of electrolyte transport requires an active transport (dependent on ATP) or passive (following electrochemical gradients) of ions. The paracellular pathway is a passive process that is ultimately controlled by the predominant transepithelial electrochemical gradients. Cystic fibrosis is a hereditary disease that is produced by mutations in the gene that encode cystic fibrosis transmembrane conductance regulatory protein (CFTR) that acts as a chloride channel and performs functions of hydration of periciliary fluid and maintenance of luminal pH. The dysfunction of the chlorine channel in the respiratory epithelium determines an alteration in the bronchial secretions, with an increase in its viscosity and alteration of the mucociliary clearance and that associated with infectious processes can lead to irreversible lung damage. CFTR dysfunction has also been implicated in the pathogenesis of acute pancreatitis, chronic obstructive pulmonary disease, and bronchial hyperreactivity in asthma. There are drugs that exploit physiological mechanisms in the transport of ions with a therapeutic objective.

Lipid metabolism in liver of rat exposed to cadmium.

We investigated the effect of exposition to cadmium (Cd, 15ppm for 8 weeks) through drinking water on liver lipid metabolism in adult male Wistar rats. As compared to metal non-exposed (control) rats, the serum triglycerides, cholesterol and LDL+VLDL cholesterol concentrations increased. This was associated to a decrease of lipoprotein lipase activity in post heparinic plasma. The VLDL secretion from liver was not modified. Cd treatment increased triglycerides and decreased esterified cholesterol contents in liver. The high triglyceride mass was related to the increased glycerol-3-phosphate acyltransferase mRNA expression. In addition, the liver fatty acids synthesis increased, as determined by an increment of fatty acid synthetase and isocitrate dehydrogenase activities, and [(14)C]-acetate incorporation into saponifiable lipid fraction. The relative percentage of palmitic acid (16:0) and total saturated fatty acids were increased compared with control. Hepatic glucose-6-phosphate dehydrogenase, malic dehydrogenase and cholesteryl ester hydrolase activities were unchanged. In liver, the Cd treatment decreased triglyceride and cholesterol in mitochondria, also increased triglyceride in cytosol, and cholesterol and phospholipid contents in nuclei, compared with control. In addition, an increase of nuclei phosphatidylcholine synthesis was observed. Cd exposure alters directly or indirectly the serum lipid content and liver lipid metabolism.

Reduction of mammary and liver lipogenesis and alteration of milk composition during lactation in rats by hypothyroidism.

OBJECTIVE: The profound impairment in litter growth produced by untreated maternal hypothyroidism (HypoT) may be a consequence of maternal metabolic dysfunctions affecting lactation. In this work we studied the effects of HypoT on mammary and liver lipid metabolism and its consequences on milk quality. DESIGN: We studied the effects of prolonged 6-propyl-2-thiouracil (PTU)-induced HypoT (0.01% PTU in drinking water starting 8 days before mating until sacrifice) on milk macronutrient composition, liver and mammary lipid metabolism and content and serum lipid, and glucose and insulin concentrations in rats on days 7, 15 (L15), and 20 (L20) of lactation. Mammary and hepatic mRNA abundances of lipogenic enzymes were measured using semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) on L15 and L20. MAIN OUTCOME: Milk lactose and triglycerides (TG) were reduced by HypoT, as well as mammary acetyl CoA carboxylase (ACC) activity on L15 and L20, and ACC and lipoprotein lipase (LPL) mRNA on L20. HypoT also decreased hepatic ACC activity on both days, ACC mRNA on L15 and liver [(3)H]H(2)O incorporation to TGs and TG content on L20. HypoT diminished insulinemia, increased serum total lipids, and decreased serum TGs on some or all the days of lactation studied. CONCLUSION: HypoT produces a drastic decrease in milk TGs; the main cause for this seems to be the decreases in liver TG synthesis and in circulating TGs, which, along with reduced mammary uptake of fatty acids caused by decreased LPL expression and possibly diminished mammary lipogenesis, result in an impaired mammary output of TGs to the milk. Thus, the impaired growth of the litters of HypoT mothers can be largely attributed to the low milk quality along with the impaired milk ejection.

Effects of hypothyroidism on mammary and liver lipid metabolism in virgin and late-pregnant rats.

Untreated maternal hypothyroidism (hypoT) has serious consequences in offspring development that may result from the effect on lactation of maternal metabolism dysfunction. We studied the effects of prolonged propylthiouracil (PTU)-induced hypoT (0.1% PTU in drinking water starting 8 days before mating until day 21 of pregnancy or for 30 days in virgin rats) on liver and mammary lipid metabolism and serum lipid concentrations. In virgins, hypoT reduced hepatic mRNAs associated with triglyceride (TG) and cholesterol synthesis (including fatty acid synthase and 3-hydroxy-3-methylglutaryl coenzyme A reductase), and induced lobuloalveolar mammary development. Pregnancy increased hepatic mRNAs associated with TG and cholesterol synthesis and uptake (including LDL receptor) and with lipid oxidation, such as acyl CoA oxidase. HypoT decreased mRNAs and the activity of proteins associated with TG synthesis, and mRNAs associated with cholesterol uptake and lipid oxidation. Pregnancy increased mammary mRNAs related to lipid oxidation and decreased cholesterol synthesis, whereas hypoT decreased mRNAs and activities of proteins associated with TG synthesis and decreased epithelial mammary tissue. Virgin and pregnant hypoT rats had increased circulating VLDL + LDL cholesterol. HypoT decreased circulating TGs in pregnant rats. The observed effects of hypoT may result in decreased mammary lipid availability. This, along with the decreased epithelial mammary tissue during lactogenesis, may contribute to the future lactational deficit of hypoT mothers.

The expression of estrogen, prolactin, and progesterone receptors in mammary gland and liver of female rats during pregnancy and early postpartum: regulation by thyroid hormones.

The aim of this study was to examine, using semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) the changes in mRNA expression of the two estrogen receptor (ER) subtypes, ERalpha and ERbeta, prolactin receptor long and short form, and progesterone (Pg) receptor (PgR), in liver and mammary gland during gestation, early lactation, and weaning in both hyperthyroid (HT) and normal rats. Pregnancy increased long prolactin receptors (PRL-R(L)) and ERalpha mRNAs in liver and PRL-R(I) in mammary gland. Lactation decreased PRL-R(L) in liver and ERbeta and PgR in mammary gland. HT decreased PRL-R(L), at the end of pregnancy (G21), ERalpha (in G21 and L1) in liver and PRL-R(L) in L1 as well as short prolactin receptors (PRL-R(S)) (G7, L1) and ERbeta (G7, G14, L4) in mammary gland. In conclusion, our data indicated that (1) PRL-R1 and ERalpha expression levels are differentially regulated in the liver, and PgR and ERbeta in mammary gland during pregnancy and lactation (2) ERbeta is variably expressed depending on the state of thyroid hormones, however the ERalpha gene expression remained constant in mammary gland. (3) PRL-R1 mRNA expression is highly induced in the mammary gland during late pregnancy and abruptly declines on the first day of lactation for the HT rats.

Incidencia de la ß-talasemia en San Luis, Argentina: índices hematimétricos en la diferenciación entre ß-talasemia y anemia ferropénica / The frecuency of ß-thalassemia in San Luis, Argentina: hematimetric indexs in the differentiation between ß-thelassemia and ferropenic anemia

A fin de determinar la incidencia de la ß-talasemia en la provincia de San Luis, se analizaron 4400 muestras de pacientes que asistieron a hospitales públicos de toda la provincia. Se detectaron 390 anemias microcíticas (8.86 por ciento) de las cuales 7 resultaron ß-talasemia (0.16 por ciento del total) las que presentaron Hb A2 mayor de 3.5 por ciento. Para determinar las diferencias entre pacientes ferropénicos y ß-talasémicos se analizaron los datos de índices hematimétricos, hierro sérico, ferritina, transferrina, protoporfirina libre eritrocitaria, reticulocitos y HbA2. En pacientes talasémicos se observó que no hubo diferencias significativas en el valor de los índices hematimétricos respecto de los controles y ferropénicos, excepto que incrementó significativamente el contenido de reticulocitos y de HbA2. En pacientes ferropénicos se observó un incremento significativo de los valores de RDW y de protoporfirinas libres eritrocitarias respecto de los talasémicos y los controles. La incidencia de la ß-talasemia en la provincia de San Luis es de 1,6 por cada 1000 habitantes, la cual resulta inferior a la observada en otras provincias, probablemente por las corrientes migratorias que habitaron la región (AU)

Incidencia de la ß-talasemia en San Luis, Argentina: índices hematimétricos en la diferenciación entre ß-talasemia y anemia ferropénica / The frecuency of ß-thalassemia in San Luis, Argentina: hematimetric indexs in the differentiation between ß-thelassemia and ferropenic anemia

A fin de determinar la incidencia de la ß-talasemia en la provincia de San Luis, se analizaron 4400 muestras de pacientes que asistieron a hospitales públicos de toda la provincia. Se detectaron 390 anemias microcíticas (8.86 por ciento) de las cuales 7 resultaron ß-talasemia (0.16 por ciento del total) las que presentaron Hb A2 mayor de 3.5 por ciento. Para determinar las diferencias entre pacientes ferropénicos y ß-talasémicos se analizaron los datos de índices hematimétricos, hierro sérico, ferritina, transferrina, protoporfirina libre eritrocitaria, reticulocitos y HbA2. En pacientes talasémicos se observó que no hubo diferencias significativas en el valor de los índices hematimétricos respecto de los controles y ferropénicos, excepto que incrementó significativamente el contenido de reticulocitos y de HbA2. En pacientes ferropénicos se observó un incremento significativo de los valores de RDW y de protoporfirinas libres eritrocitarias respecto de los talasémicos y los controles. La incidencia de la ß-talasemia en la provincia de San Luis es de 1,6 por cada 1000 habitantes, la cual resulta inferior a la observada en otras provincias, probablemente por las corrientes migratorias que habitaron la región