Activation of locus coeruleus heme oxygenase-carbon monoxide pathway promoted an anxiolytic-like effect in rats

The heme oxygenase-carbon monoxide pathway has been shown to play an important role in many physiological processes and is capable of altering nociception modulation in the nervous system by stimulating soluble guanylate cyclase (sGC). In the central nervous system, the locus coeruleus (LC) is known to be a region that expresses the heme oxygenase enzyme (HO), which catalyzes the metabolism of heme to carbon monoxide (CO). Additionally, several lines of evidence have suggested that the LC can be involved in the modulation of emotional states such as fear and anxiety. The purpose of this investigation was to evaluate the activation of the heme oxygenase-carbon monoxide pathway in the LC in the modulation of anxiety by using the elevated plus maze test (EPM) and light-dark box test (LDB) in rats. Experiments were performed on adult male Wistar rats weighing 250-300 g (n=182). The results showed that the intra-LC microinjection of heme-lysinate (600 nmol), a substrate for the enzyme HO, increased the number of entries into the open arms and the percentage of time spent in open arms in the elevated plus maze test, indicating a decrease in anxiety. Additionally, in the LDB test, intra-LC administration of heme-lysinate promoted an increase on time spent in the light compartment of the box. The intracerebroventricular microinjection of guanylate cyclase, an sGC inhibitor followed by the intra-LC microinjection of the heme-lysinate blocked the anxiolytic-like reaction on the EPM test and LDB test. It can therefore be concluded that CO in the LC produced by the HO pathway and acting via cGMP plays an anxiolytic-like role in the LC of rats.

Importancia de la corrección de la KCO informada computarizada en pacientes con volumen alveolar disminuído / Importance to adjust computerized informed KCO in patients with low alveolar volume

La disminución del factor de transferencia de monóxido de carbono (TLCO) y del Volumen Alveolar (VA) no es uniforme. Los informes de los equipos computadorizados entregan un valor de KCO que no toma en cuenta este detalle.Objetivo: Realizar el cálculo de KCO a través de la corrección de Stam (J Apply Physiol 1994) y compararlas con las informadas por el software de un equipo de laboratorio pulmonar computadorizado reconocido (Collins).Material y Método: Fueron incluídos pacientes consecutivos derivados al Laboratorio Pulmonar de la Unidad para realizar una prueba de TLCO por enfermedad intersticial pulmonar entre Enero y Junio de 2008. Se realizaron las pruebas según recomendacionesATS/ERS por el método de respiración única y con el método de toma de muestra de Ogilvie. Se analizó la KCO según lo informa el software del equipo Collins Plus/SQL System (1995Warren Collins), y luego se lo recalculó corregida según el cálculo de Stam (J Apply Physiol 1994). Se incluyó en este análisis si tenían <80% del volumen alveolar predicho. Resultados: Fueron evaluados 15 pacientes (media edad: 57.5 ± 12.9 años, sexo femenino 66.7%) con enfermedad intersticial.La media de VA fue 3.5±0.8 L(64.3±11.6%). La media de KCO informada a través del software fue 4.2± 1.3ml/min/mmHg/L. La media de KCO corregida fue 3.7 ± 1.2ml/min/mmHg/L (Δ 11.8±3.8, rango: 6.8%-21.1%). Se observó una relación lineal y negativa entre el %VA y el delta de KCO corregida/informada (r2= -0.99). La elección de diferentes tablas de valores normales de VA altera hasta 12% el valor de la misma, pero la KCO corregida se altera en grado mínimo (3%). Conclusiones: Cuando el VA está disminuído, se debe realizar la corrección del informe computadorizado de la KCO, porque se observa una diferencia promedio del 12%, sobreestimando la real KCO del paciente. Otros factores, como la tabla de valores predictivos de VA, influencia muy poco la corrección de KCO.

The decrease of the Transfer Factor of the Lung for Carbon Monoxide (TLCO) and the Alveolar Volume (VA) is not uniform. Software of lung computed machine informs the carbon monoxide transfer coefficient TLCO/VA (KCO) by calculating the ratio without adjusting for that assumption. Objectives: To calculate KCO using a correction by the Stam´s equation (J Apply Physiol1994), to compare the corrected KCO with the result informed by the software of Collins lung laboratory equipment, and to evaluate the impact of using different predictive tables of VA in the estimates of KCO. Materials: Consecutive patients with intersticial lung disease who attended the LungLaboratory to perform the TLCO between January and June 2008 were included in the study. TLCO was performed according to ATS/ERS recommendations by the single-breathand Ogilvie methods. KCO was calculated by the software of Collins Plus/SQL System (1995 Warren Collins), and then recalculated by Stam´s equation. Only patients withless than 80% of VA predictive value were included. Results: 15 patients with interstitial lung disease were evaluated (age: 57.53 ± 12.93 years old, female: 66.66%). The mean VA was 3.55 ±0.83 L (64.33 ±11.56%) and the mean KCO informed by software was 4.17 ±1.31 ml/min/mmHg/L. The corrected KCO was 3.76 ±1.33 ml/min/mmHg/L(Δ 11.84 ±3.84, range: 6.82%-21.1%). It was observed a negative and lineal relation between %VA and Δ KCO corrected/informed (R2= -0.99). The election of different tables of VA normal values distorts up to12% the individualvalues, but the corrected KCO is little modified (3%). Conclusion: When the VA is reduced, the correction of the KCO must be performed, to avoid on average a 12% overestimate. Other factors such as the election of VA predictive tables have little influence on the KCO correction.

The role of endogenous carbon monoxide in the hypoxic vascular remodeling of rat model of hypoxic pulmonary hypertension / 华中科技大学学报（医学）（英德文版）

We investigated the expression of heme oxygenase-1 (HO-1) gene and production of endogenous carbon monoxide (CO) in the rat lung tissue at different time points of chronic hypoxic pulmonary hypertension and the effect of hemin on the expression of HO-1 gene and pulmonary hypertension. A rat model of hypoxic pulmonary hypertension was recreated by exposure to intermittent normobaric hypoxic environment (10% O2). Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to determine the level of HO-1 mRNA in the rat lung tissue and double wave length spectrophotometry was used to evaluate the quantity of COHb in arterial blood. Cardiac catheterization was employed to measure the right ventricular systolic pressure (RVSP) and HE staining was performed in dissected lung tissue to observe the pathological changes of the intra-acinar pulmonary arteries (IAPA). It was found that (1) There was a low level of HO-1 mRNA in normal rat lung tissue, but the level of HO-1 mRNA increased by 2-4 times in the lung tissue of hypoxic rats (P<0.01). The quantity of COHb was 2-3 times those of control group (P<0.01 or P<0.05). These were accompanied by the increased of RVSP and the thickened IAPA; (2) Hemin could keep the HO-1 mRNA and COHb in the hypoxic rat lung tissue at a high level, and partially suppressed the increase of rat RVSP, thereby ameliorating the pathological changes of IAPA. In conclusion, the upregulation of the expression of HO-1 gene and production of CO in the rat lung of hypoxic pulmonary hypertension plays a role of inhibition in the development of hypoxic pulmonary hypertension. Hemin has a therapeutic effect on hypoxic pulmonary hypertension.

Monóxido de carbono e as vias aéreas / Endogenous carbon monoxide and the airways

Objetivo: Apresentar o conhecimento atual sobre o papel do monóxido de carbono (CO) endógeno nas vias aéreas. Métodos: Foram analisados artigos catalogados na base de dados eletrônica Medline através da busca por: monóxido de carbono, asma, rinite e nariz. Resultados: O CO é um gás gerado pela ação das isoenzimas hemeoxigenases (constitutiva e indutível) ou pela peroxidação não enzimática dos lipídios da membrana celular. Este gás tem papel importante na homeostase por atuar como neurotransmissor e promover a regulação do tônus da musculatura lisa brônquioa, além de possuir ação antiinflamatória e proteger contra a apoptose. Nas vias aéreas superiores, é produzido por ação enzimática no epitélio nasal e nas glândulas da lâmina própria, com importante poder antiviral local. Nos brônquios, é encontrado no epitélio e em fibras neurais parassimpáticas e modula a broncodilatação.Clinicamente, o CO pode ser detectado no ar nasal e exalado pela técnica de cromatografia gasosa, método não invasivo e útil para monitorar a resposta ao tratamento medicamentoso na asma e outras doenças pulmonares. Nas asma, doença pulmonar obstrutiva crônica, discinesia ciliar primária e fibrose cística, sua concentração encontra-se elevada no ar exalado. Conclusões: O monóxido de carbono está envolvido na regulação da inflamação da via aérea. As pesquisas sobre o gás devem se intensificar, pois seu papel fisiológico no aparelho respiratório ainda não está completamente elucidado.