Fisiología respiratoria: circulación pulmonar / Respiratory physiology: pulmonary circulation

El pulmón recibe sangre desde la circulación bronquial y pulmonar. La circulación pulmonar presenta importantes diferencias con la sistémica, sus vasos sanguíneos poseen características únicas que le permiten cumplir sus diferentes funciones, siendo la más importante el intercambio gaseoso. Existen múltiples factores, activos y pasivos, que están involucrados en la regulación de la resistencia vascular y flujo sanguíneo pulmonar.

The lung receives blood from the bronchial and the pulmonary circulation. The pulmonary circulation presents important differences with the systemic circulation, its blood vessels have unique characteristics that allow them to fulfill their different functions, the most important being gas exchange. There are multiple factors, active and passive, that are involved in the regulation of vascular resistance and pulmonary blood flow.

The architecture of alveolar capillaries in the lungs of bactrian camels (Camelus bactrianus) / Arquitectura de los capilares alveolares de pulmones de camellos bactrianos (Camelus bactrianus)

SUMMARY: The Bactrian camel, which is native to China and Mongolia, is large in size and is an even-toed ungulate species. The double humps on the Bactrian camel back differentiate it from the dromedary camel, which has a single hump. This species has adapted to unsuitable conditions (lack of food and water) in the Gobi Desert and is advanced in unique anatomical and physiological characteristics during a prolonged evolution period. Several studies have been conducted on the anatomical features of the Bactrian camel, but none have given attention to the alveolar capillaries of the Bactrian camel lung. Therefore, the current study aims to explore the architecture of the alveolar capillary in the Bactrian camel lung and further explain the mechanism of blood flow in its lung. The current study extracted and examined the architecture of the alveolar capillary in the lung of the Bactrian camel (Camelus bactrianus) and further explained the mechanism of blood flow by performing lung casting and replica scanning electron microscopy methods. The reports showed that the resources of the alveolar-capillary originated from the capillaries of the subpleural space or interlobular septulum, sometimes originating from the precapillary arterioles or directly from the terminal arterioles. The alveolar capillaries anastomosed and formed a single layer of dense, basket-like network surrounding the alveolus. The mash diameter of the alveolar-capillary network was larger than that of the capillary, and the appearance of the mash was oval and elliptical. Many of the collapsed alveolar-capillary networks were found in the alveolar microvascular architecture in the lung of the Bactrian camel. The study found that, due to many collapsed alveoli in the Bactrian camel lung, the disproportional pressure between the pulmonary alveoli induced less imbalance of blood flow in the alveolar capillary, which affected the gas exchange efficiency. Therefore, the function of the anastomosing capillary branch was likely to regulate the blood flow between the alveolar-capillary network.

RESUMEN: El camello bactriano, es originario de China y Mongolia, es de gran tamaño y es una especie de ungulado de dedos pares. Las dobles jorobas del lomo del camello bactriano lo diferencian del dromedario, que tiene una sola joroba. Esta especie se ha adaptado a condiciones inadecuadas (falta de alimento y agua) en el desierto de Gobi y ha avanzado en características anatómicas y fisiológicas únicas durante un período de evolución prolongado. Se han realizado varios estudios sobre las características anatómicas del camello bactriano, pero ninguno ha prestado atención a los capilares alveolares del pulmón de este animal. Por lo tanto, el presente estudio tuvo como objetivo principal explorar la arquitectura del capilar alveolar en el pulmón del camello bactriano y explicar el mecanismo del flujo sanguíneo. A partir de nuestro trabajo se examinó la arquitectura del capilar alveolar en el pulmón del camello bactriano (Camelus bactrianus) mediante la realización de métodos de microscopía electrónica de barrido y escaneo pulmonar. Los informes mostraron que los recursos del alvéolo-capilar se originaban en los capilares del espacio subpleural o del tabique interlobulillar y a veces se originaban en las arteriolas precapilares o directamente en las arteriolas terminales. Los capilares alveolares se anastomosaban y formaban una densa red de capa única en forma de cesta que rodeaba el alvéolo. El diámetro del macerado de la red alveolar-capilar era mayor que el del capilar y el aspecto del macerado era ovalado y elíptico. Muchas de las redes alvéolo-capilares colapsadas se encontraron en la arquitectura microvascular alveolar en el pulmón del camello bactriano. El estudio encontró que, muchos alvéolos colapsados en el pulmón del camello bactriano, la presión desproporcionada entre los alvéolos pulmonares inducía un menor desequilibrio del flujo sanguíneo en el capilar alveolar, lo que afectaba la eficiencia del intercambio de gases. Por lo tanto, la función de la rama capilar anastomosante probablemente regularía el flujo sanguíneo entre la red alveolar-capilar.

Lung cavities in chronic thromboembolic pulmonary hypertension

OBJECTIVES: Chronic thromboembolic pulmonary hypertension (CTEPH) is a unique form of pulmonary hypertension (PH) that arises from obstruction of the pulmonary vessels by recanalized thromboembolic material. CTEPH has a wide range of radiologic presentations. Commonly, it presents as main pulmonary artery enlargement, peripheral vascular obstructions, bronchial artery dilations, and mosaic attenuation patterns. Nevertheless, other uncommon presentations have been described, such as lung cavities. These lesions may be solely related to chronic lung parenchyma ischemia but may also be a consequence of concomitant chronic infectious conditions. The objective of this study was to evaluate the different etiologies that cause lung cavities in CTEPH patients. METHODS: A retrospective data analysis of the medical records of CTEPH patients in a single reference PH center that contained or mentioned lung cavities was conducted between 2013 and 2016. RESULTS: Seven CTEPH patients with lung cavities were identified. The cavities had different sizes, locations, and wall thicknesses. In two patients, the cavities were attributed to pulmonary infarction; in 5 patients, an infectious etiology was identified. CONCLUSION: Despite the possibility of being solely associated with chronic lung parenchyma ischemia, most cases of lung cavities in CTEPH patients were associated with chronic granulomatous diseases, reinforcing the need for active investigation of infectious agents in this setting.

Efeitos da morte cerebral na microvasculatura pulmonar em um modelo experimental de doador de pulmão / Brain death effects on lung microvasculature in an experimental model of lung donor

RESUMO Objetivo A morte cerebral (MC) desencadeia alterações hemodinâmicas e inflamatórias importantes, comprometendo a viabilidade dos órgãos empregados em transplantes. Para compreender melhor as alterações microcirculatórias nos pulmões de doadores com MC, o presente estudo investigou a microcirculação pulmonar em um modelo de roedor com MC via microscopia intravital. Métodos Ratos Wistar machos foram anestesiados e ventilados mecanicamente. Eles foram submetidos a trepanação e a MC induzida por meio do aumento da pressão intracraniana. Os ratos do grupo Sham (SH), utilizado como controle, foram submetidos apenas à trepanação. Em ambos os grupos, foram monitorados o O2 expiratório e o CO2, e, após 3 horas, foi realizada a toracotomia e criada uma janela para observar a superfície pulmonar usando o sistema de microscopia intravital. As expressões pulmonares das moléculas de adesão intercelular (ICAM)-1 e da óxido nítrico-sintase endotelial (eNOS) foram avaliadas por imuno-histoquímica, e as citocinas foram medidas em amostras pulmonares. Resultados Três horas após os procedimentos cirúrgicos, a perfusão pulmonar foi de 73% no grupo SH. Por outro lado, os animais com MC apresentaram uma importante diminuição na perfusão do órgão para 28% (p = 0,036). O comprometimento microcirculatório pulmonar após a indução de MC foi associado a um aumento do número de leucócitos recrutados para o tecido pulmonar, além de uma redução na expressão de eNOS e um aumento na expressão de ICAM-1 nas células endoteliais do pulmão. Os ratos com MC apresentaram valores mais elevados de O2 expiratório e valores mais baixos de CO2 em comparação com os animais SH após 3 horas de monitorização. Conclusões Os dados apresentados demonstraram que a MC desencadeia uma importante hipoperfusão e inflamação nos pulmões, comprometendo a microcirculação pulmonar do doador.

ABSTRACT Objective Brain death (BD) triggers important hemodynamic and inflammatory alterations, compromising the viability of organs suitable for transplantation. To better understand the microcirculatory alterations in donor lungs caused by BD. The present study investigated the pulmonary microcirculation in a rodent model of BD via intravital microscopy. Methods Male Wistar rats were anaesthetized and mechanically ventilated. They were trepanned and BD was induced through the increase in intracranial pressure. As control group, sham-operated (SH) rats were trepanned only. In both groups, expiratory O2 and CO2 were monitored and after three hours, a thoracotomy was performed, and a window was created to observe the lung surface using an epi-fluorescence intravital microscopy. Lung expression of intercellular adhesion molecule (ICAM)-1 and endothelial nitric oxide synthase (eNOS) was evaluated by immunohistochemistry, and cytokines were measured in lung samples. Results Three hours after the surgical procedures, pulmonary perfusion was 73% in the SH group. On the other hand, BD animals showed an important decrease in organ perfusion to 28% (p = 0.036). Lung microcirculatory compromise after BD induction was associated with an augmentation of the number of leukocytes recruited to lung tissue, and with a reduction in eNOS expression and an increase in ICAM-1 expression on lung endothelial cells. BD rats showed higher values of expiratory O2 and lower values of CO2 in comparison with SH animals after three hours of monitoring. Conclusion Data presented showed that BD triggers an important hypoperfusion and inflammation in the lungs, compromising the donor pulmonary microcirculation.

Valoración de ecuaciones derivadas del flujo pulmonar y regurgitación tricuspídea: utilidad en el test de vasoreactividad pulmonar / Valuation of equations derived from Pulmonary Flow and Tricuspid Regurgitation: usefulness in Pulmonary Vasoreactivity Testing

RESUMEN: Antecedentes: La presión media arterial pulmonar (PMAP) es una variable hemodinámica indispensable para el diagnóstico, clasificación y pronóstico de la Hipertensión Pulmonar (HP). Su cuantificación se realiza en forma invasiva por cateterismo cardíaco derecho (CCD) y no invasivamente por ecocardiografía Doppler. Masuyama propuso su medición mediante el gradiente transvalvular pulmonar diastólico derivado de la velocidad máxima inicial de la regurgitación pulmonar (∆RPi2) correspondiendo cercanamente a la medición invasiva. Objetivos: Revalidar 3 métodos ecocardiográficos que estiman la PMAP y valorar la utilidad del método de Chemla en el Test de Reactividad Vascular Pulmonar (TRVP). Métodos: Estudio prospectivo, observacional, doble ciego divido en dos etapas. A) o I) 30 pacientes se realizó ecocardiografía Doppler diagnóstica en nuestro centro. Se midieron regurgitación tricuspídea (RT) y tiempo de aceleración pulmonar (TAP) para derivar las siguientes ecuaciones: 1) 0.61xPSAP+1.95 (Chemla) 2) Gradiente presión media RT (∆PmRT) +PAD (presión-aurícula derecha) (Aduen) y 3) 79-0.45xTAP o 90-0.60xTAP, según sea el valor del TAP. B) o II) 10 pacientes enrolados para realizar el TRVP comparando la medición ecocardiográfica (Chemla) con CCD. Resultados: En la primera parte del estudio se encontró alta correlación entre las 3 ecuaciones: ChemlaAduen, R2=0.91; Chemla-Kitabatake, R2=0.87; Aduen-Kitabatake, R2=0,91. En la segunda parte comparando la PMAP-Chemla y Cateterismo derecho (CD) obtuvimos alta correlación: en tiempo 0, 30 min y recuperación:(R2=0.87, 0.99, 0.98, respectivamente). Ambas partes del estudio mostraron límites de concordancia satisfactoria con valor medio de la diferencia entre los métodos cercano a 1 en el t30 y tR del TRVP. Conclusión: los métodos dependientes de la medición de la RT son efectivos y confiables para estimar la PMAP. El método de Chemla es útil en el TRVP.

ABSTRACTS: Background: Mean Pulmonary arterial pressure (PMAP)is an indispensable hemodynamic variable for the diagnosis, classification and prognosis of Pulmonary Hypertension (PH). Its quantification is performed invasively by cardiac catheterization and non-invasively by Doppler echocardiography. Masuyama proposed its measurement by the transvalvular diastolic pulmonary gradient derived from the initial maximum velocity of pulmonary regurgitation(ΔPRi2) corresponding closely to the invasive measurement. Objectives: to compare 3 known echocardiographic methods to estimate MPAP and demonstrate the usefulness of the Chemla method in the Pulmonary Vascular Reactivity Test (PVRT). Methods: prospective, observational, double-blind study divided into two stages. A) 30 patients underwent diagnostic Doppler echocardiography. Tricuspid regurgitation (TR) and pulmonary acceleration time (PAT) were measured to derive the equations: 1) 0.61xSPAP + 1.95 (Chemla) 2) Gradient mean pressure TR (ΔPmTR) + RAP (right atrium pressure) (Aduen).3) 79-0.45xPAT o 90-0.60xPAT depending on the value of PAT. B) 10 patients enrolled to PVRT comparing the echocardiographic measurement (Chemla) with right catheterization. Results: in the first part of the study a high correlation between the 3 equations was found : ChemlaAduen, R2 = 0.91; Chemla-Kitabatake, R2=0.87; Aduen-Kitabatake, R2=0.91. In the second part comparing the MPAP-Chemla and RHC we obtained a high correlation in time 0, 30 min and recovery: (R2=0.87,0,99,0.98, respectively). Both parts of the study showed satisfactory limits concordance with mean value of the difference between the methods close to 1 in the t30 and tR of the TRVP. Conclusion: the methods dependent on the measurement of the TR are effective and reliable for estimating MPAP. The Chemla method is useful in the PVRT.

El biomodelo porcino en la investigación médica traslacional: del biomodelo al humano en trasplante pulmonar / The porcine biomodel in translational medical research: From biomodel to human lung transplantation

Resumen Introducción. La anatomía humana y porcina son comparables. En consecuencia, el biomodelo porcino tiene el potencial de ser implementado para entrenar al profesional quirúrgico en áreas como el trasplante de órganos sólidos. Objetivo. Describir los procedimientos y hallazgos obtenidos mediante experimentos de medicina respiratoria traslacional con biomodelos porcinos realizados en un laboratorio de experimentación animal, y hacer una revisión comparativa entre el pulmón humano y el porcino. Materiales y métodos. El experimento se llevó a cabo en nueve cerdos de raza híbrida en un laboratorio de cirugía experimental. Se estudiaron la anatomía y la histología de las vías respiratorias mediante fibrobroncoscopia, biopsia bronquial y lavado broncoalveolar. El lavado broncoalveolar se estudió con citología en base líquida y se evaluó con las coloraciones de Papanicolau y hematoxilina y eosina. Se utilizaron técnicas de patología molecular, como inmunohistoquímica, citometría de flujo y microscopía electrónica. Los cerdos se sometieron a neumonectomía izquierda con posterior implante del injerto en otro cerdo experimental. Resultados. Los estudios histopatológicos y moleculares evidenciaron un predominio de macrófagos alveolares (98 %) y linfocitos T (2 %) en el lavado broncoalveolar porcino. En los estudios del parénquima pulmonar porcino se encontró tejido linfoide hiperplásico asociado a las paredes bronquiales. La microscopía electrónica evidenció linfocitos T dentro del epitelio y el diámetro de las cilias porcinas fue similar al de las humanas. Conclusiones. El biomodelo porcino es viable en la investigación traslacional para el entendimiento de la anatomía del sistema respiratorio y el entrenamiento en trasplante pulmonar. La implementación de este modelo experimental podría fortalecer los grupos que planean implementar un programa institucional de trasplante pulmonar en humanos.

Abstract Introduction: Human and porcine anatomy are comparable. In consequence, the porcine biomodel has the potential to be implemented in the training of surgical professionals in areas such as solid organ transplantation. Objectives: We described the procedures and findings obtained in the experiments of translational respiratory medicine with the porcine biomodel, within an experimentation animal laboratory, and we present a comparative review between human and porcine lung. Materials and methods: The experiment was done in nine pigs of hybrid race within a laboratory of experimental surgery. The anatomy and histology of the respiratory tract were studied with fibrobronchoscopy, bronchial biopsy and bronchoalveolar lavage. The bronchoalveolar lavage was studied with liquid-based cytology and assessed with Papanicolau and hematoxylin-eosin staining. Molecular pathology techniques such as immunohistochemistry, flow cytometry, and electronic microscopy were implemented. The pigs were subjected to left pneumonectomy with posterior implantation of the graft into another experimental pig. Results: Histopathologic and molecular studies evidenced predominance of alveolar macrophages (98%) and T-lymphocytes (2%) in the porcine bronchoalveolar lavage. Studies on the porcine lung parenchyma revealed hyperplasic lymphoid tissue associated with the bronchial walls. Electronic microscopy evidenced the presence of T-lymphocytes within the epithelium and the cilia diameter was similar to the human. Conclusions: The porcine biomodel is a viable tool in translational research applied to the understanding of the respiratory system anatomy and the training in lung transplantation. The implementation of this experimental model has the potential to strength the groups who plan to implement an institutional program of lung transplantation in humans.

Effect of sevoflurane pretreatment in relieving liver ischemia/reperfusion-induced pulmonary and hepatic injury

Abstract Purpose To investigate the effect of sevoflurane preconditioning on ischemia/reperfusion (I/R)-induced pulmonary/hepatic injury Methods Fifty-one Wistar rats were randomly grouped into sham, I/R, and sevoflurane groups. After reperfusion, the structural change of the lung was measured by Smith score, the wet and dry weights (W/D) were determined, malondialdehyde (MDA) myeloperoxidase (MPO) content was determined colorimetrically and by fluorescence, respectively, and matrix metalloprotein-9 (MMP-9) mRNA was quantified by RT-PCR. Biopsy and morphological analyses were performed on liver tissue, activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined, and tumor necrosis factor-alpha (TNF-α) level was determined. Results The sham group showed no changes in tissue structure. Structural lesions in the sevoflurane and I/R groups were mild and severe, respectively. Smith score, W/D, MDA, MPO, and MMP mRNA showed the same trend, and were increased in the I/R group and recovered in the sevoflurane group, compared with the sham group (both P<0.05). AST and ALT were significantly increased compared to the sham group (AST: 655±52.06 vs . 29±9.30 U/L; ALT: 693±75.56 vs . 37±6.71 U/L; P<0.05). In the sevoflurane group, AST and ALT levels were significantly decreased (464±47.71 and 516±78.84 U/L; P<0.001). TNF-α presented similar results. Conclusion The protection of lung and liver by sevoflurane may be mediated by inhibited leukocyte recruitment and MMP-9 secretion.

Evaluation and reconditioning of donor organs for transplantation through ex vivo lung perfusion / Avaliação e recondicionamento de pulmões doados para transplante por meio da perfusão pulmonar ex vivo

ABSTRACT Objective: To assess the feasibility and impact of ex vivo lung perfusion with hyperoncotic solution (Steen Solution™) in the utilization of these organs in Brazil. Methods: In this prospective study, we subjected five lungs considered to be high risk for transplantation to 4 hours of ex vivo lung perfusion, with evaluation of oxygenation capacity. High-risk donor lungs were defined by specific criteria, including inflammatory infiltrates, pulmonary edema and partial pressure of arterial oxygen less than 300mmHg (inspired oxygen fraction of 100%). Results: During reperfusion, the mean partial pressure of arterial oxygen (inspired oxygen fraction of 100%) of the lungs did not change significantly (p=0.315). In the first hour, the mean partial pressure of arterial oxygen was 302.7mmHg (±127.66mmHg); in the second hour, 214.2mmHg (±94.12mmHg); in the third hour, 214.4mmHg (±99.70mmHg); and in the fourth hour, 217.7mmHg (±73.93mmHg). Plasma levels of lactate and glucose remained stable during perfusion, with no statistical difference between the moments studied (p=0.216). Conclusion: Ex vivo lung perfusion was reproduced in our center and ensured the preservation of lungs during the study period, which was 4 hours. The technique did not provide enough improvement for indicating organs for transplantation; therefore, it did not impact on use of these organs.

RESUMO Objetivo: Avaliar a exequibilidade e o impacto da perfusão pulmonar ex vivo com solução hiperoncótica (Steen Solution™) na taxa de utilização desses órgãos no Brasil. Métodos: Neste estudo prospectivo, submetemos cinco pulmões considerados de alto risco para o transplante a 4 horas de perfusão pulmonar ex vivo, com avaliação da capacidade de oxigenação pulmonar. Os pulmões de doadores de alto risco foram definidos por critérios específicos, incluindo infiltrado inflamatório, edema pulmonar e pressão parcial de oxigênio arterial inferior a 300mmHg (fração inspirada de oxigênio de 100%). Resultados: Durante a reperfusão, a pressão parcial de oxigênio arterial (fração inspirada de oxigênio de 100%) média dos pulmões não sofreu alteração significativa (p=0,315). Na primeira hora, a pressão parcial de oxigênio arterial média foi de 302,7mmHg (±127,66mmHg); na segunda, 214,2mmHg (±94,12mmHg); na terceira, 214,4mmHg (±99,70mmHg); e na quarta, 217,7mmHg (±73,93mmHg). Os níveis plasmáticos de lactato e glicose se mantiveram estáveis ao longo da perfusão, sem diferença estatística na comparação entre os momentos estudados (p=0,216). Conclusão: A perfusão pulmonar ex vivo foi reproduzida em nosso centro e garantiu a preservação de pulmões durante o período de estudo, que foi de 4 horas. A técnica não promoveu melhora suficiente para indicação do órgão para o transplante e, portanto, não impactou na taxa de utilização desses órgãos.

Vascular and ventilatory mechanical responses in three different stages of pulmonary development in the rabbit model of congenital diaphragmatic hernia

Abstract Purpose: To evaluate the vascular ventilatory response in different stages of lung development and to compare them to the neonates with congenital diaphragmatic hernia (CDH) in a rabbit model. Methods: New Zealand rabbits were divided into 8 groups (n=5): E25, E27, E30, and CDH. All groups were ventilated on a FlexiVent (Scireq, Montreal, QC, Canada), compounding the other 4 groups. The CDH surgery was performed at E25 and the harvest at E30. Dynamic compliance (CRS), dynamic elastance (ERS) and dynamic resistance (RRS) were measured every 4 min/24 min. Median wall thickness (MWT) and airspace were measured. ANOVA Bonferroni tests were used to perform statistical analysis. Significance was considered when p<0.05. Results: CRS was higher in E30 compared to all other groups (p<0.05). CRS and RRS of CDH and E27 were similar and were higher in E25 (p<0.05). MWT was decreased according to the gestational age, was increased in E27V and E30V (p<0.05) and decreased in CDHV (p<0.05), airspace was decreased in E25 and increased in all ventilated groups (p<0.05). Conclusions: The ventilation response of congenital diaphragmatic hernia is like the pseudoglandular stage of the lung development. These findings add information about the physiology of pulmonary ventilation in CDH.

Expressions of TOLL-like receptor 4 (TLR-4) and matrix metalloproteinase 9 (MMP-9)/Tissue inhibitor of metalloproteinase 1 (TIMP-1) in pulmonary blood vessels with chronic obstructive pulmonary diseases and their relationships with pulmonary vascular remodelling

SUMMARY OBJECTIVE: This study aims at investigating the expressions of TOLL-like receptor 4 (TLR-4) and matrix metalloproteinase 9 (MMP-9)/ tissue inhibitor of metalloproteinase 1 (TIMP-1) in pulmonary blood vessels with chronic obstructive pulmonary disease (COPD) and their relationships with pulmonary vascular remodelling (PVR). METHODS: 60 para-tumour tissues were divided into the COPD group and the control group (n=30); the inflammations, pulmonary artery wall area/total artery area (WA%), and wall thickness/vascular outer diameter (WT%) were compared. The expressions of TLR-4, MMP-9/TIMP-1, and PCNA in pulmonary vascular smooth muscle cells were detected, and their relationships with PVR were then analysed. RESULTS: The inflammations (1.6±0.8), WA% (44.0±6.4), and WT% (27.3±3.3) in the COPD group were higher than in the control group (0.3±0.5, 26.1±2.8, 15.6±1.8), and the expressions of TLR-4 (31.4±147) and MMP-9/TIMP-1 (2.2±2.6) were increased compared to the control group (4.7±4.5, 1.9±12). Correlation analysis: TLR-4 and MMP-9/TIMP-1 were positively correlated with the inflammations (r=0.18, P<0.01), WA% (r=0.68, P<0.01), and WT% (r=0.73, P<0.01), as well as positively correlated with the expression of PCNA (r=0.44, P<0.01); the upregulation of TLR-4 was positively correlated with the expressions of MMP-9 and TIMP-1. CONCLUSIONS: The upregulation of TLR-4 in the pulmonary arterial smooth muscle cells of COPD patients could promote the inflammations and the MMP-9 expression, thus causing abnormal degradation of extracellular matrix, so it played an important role in the process of PVR.

RESUMO OBJETIVO: Este estudo tem como objetivo investigar as expressões de TOLL-like receptor 4 (TLR-4) e metaloproteinase 9 da matriz (MMP-9)/inibidor de tecido da metaloproteinase 1 (TIMP-1) em vasos sanguíneos pulmonares com doença pulmonar obstrutiva crônica (DPOC) e suas relações com o remodelamento vascular pulmonar (PVR). MÉTODOS: Sessenta tecidos paratumorais foram divididos em grupo COPD e o grupo controle (n = 30). Foram comparadas as inflamações, área da parede da artéria pulmonar/área da artéria total (WA%) e espessura da parede/diâmetro externo vascular (WT%). As expressões de TLR-4, MMP-9/TIMP-1 e PCNA em células de músculo liso vascular pulmonar foram detectadas, e suas relações com PVR foram então analisadas. RESULTADOS: As inflamações (1,6 ± 0,8), WA% (44,0 ± 6,4) e WT% (27,3 ± 3,3) no grupo COPD foram maiores que no grupo controle (0,3 ± 0,5; 26,1 ± 2,8; 15,6 ± 1,8). E as expressões de TLR-4 (31,4 ± 14,7) e MMP-9/TIMP-1 (2,2 ± 2,6) foram aumentadas em relação ao grupo controle (4,7 ± 4,5, 1,9 ± 1,2). Na análise de correlação, TLR-4 e MMP-9/TIMP-1 foram positivamente correlacionadas com as inflamações (r = 0,18; P <0,01), WA% (r = 0,68; P <0,01) e WT% (r = 0,73; P <0,01), bem como correlacionadas positivamente com a expressão de PCNA (r = 0,44; P <0,01). A elevação da TLR-4 foi correlacionada positivamente com as expressões de MMP-9 e TIMP-1. CONCLUSÕES: A regulação positiva do TLR-4 nas células do músculo liso arterial pulmonar de pacientes com DPOC poderia promover as inflamações e a expressão de MMP-9, causando assim uma degradação anormal da matriz extracelular, por isso desempenhou um papel importante no processo de PVR.

Effect of ischemic postconditioning and atorvastatin in the prevention of remote lung reperfusion injury

Abstract Objective: The aim of the present study was to evaluate the ability of ischemic postconditioning, atorvastatin and both associated to prevent or minimize reperfusion injury in the lung of rats subjected to ischemia and reperfusion by abdominal aortic clamping. Methods: We used 41 Wistar norvegic rats, which were distributed into 5 groups: ischemia and reperfusion (I/R), ischemic postcondictioning (IPC), postconditioning + atorvastatin (IPC+A), atorvastatin (A) and SHAM. It was performed a medium laparotomy, dissection and isolation of the infra-renal abdominal aorta; except for the SHAM group, all the others were submitted to the aortic clamping for 70 minutes (ischemia) and posterior clamp removal (reperfusion, 70 minutes). In the IPC and IPC+A groups, postconditioning was performed between the ischemia and reperfusion phases by four cycles of reperfusion and ischemia lasting 30 seconds each. In the IPC+A and A groups, preceding the surgical procedure, administration of 3.4 mg/day of atorvastatin was performed for seven days by gavage. After the surgical procedure, the right caudal lobe was removed from the lung for histological study, using tissue injury score ranging from grade 1 (normal tissue) to grade 4 (intense lesion). Results: The mean lung injury was 3.6 in the I/R group, 1.6 in the IPC group, 1.2 in the IPC+A group, 1.2 in the A group, and 1 in the SHAM group (P<0.01). Conclusion: Ischemic postconditioning and atorvastatin were able to minimize lung reperfusion injury, alone or in combination.

The protective effect of dexmedetomidine in a rat ex vivo lung model of ischemia-reperfusion injury

Abstract Purpose: To investigate the effect of dexmedetomidine (Dex) in a rat ex vivo lung model of ischemia-reperfusion injury. Methods: An IL-2 ex vivo lung perfusion system was used to establish a rat ex vivo lung model of ischemia-reperfusion injury. Drugs were added to the perfusion solution for reperfusion. Lung injury was assessed by histopathological changes, airway pressure (Res), lung compliance (Compl), perfusion flow (Flow), pulmonary venous oxygen partial pressure (PaO2), and lung wet/dry (W/D) weight ratio. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), 78 kDa glucose-regulated protein (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) were measured, respectively. Results: The introduction of Dex attenuated the post-ischemia-reperfusion lung damage and MDA level, improved lung histology, W/D ratio, lung injury scores and SOD activity. Decreased mRNA and protein levels of GRP78 and CHOP compared with the IR group were observed after Dex treatment. The effect of Dex was dosage-dependence and a high dose of Dex (10 nM) was shown to confer the strongest protective effect against lung damage (P<0.05). Yohimbine, an α2 receptor antagonist, significantly reversed the protective effect of Dex in lung tissues (P<0.05). Conclusion: Dex reduced ischemia-reperfusion injury in rat ex vivo lungs.

Ventilation-induced changes correlate to pulmonary vascular response and VEGF, VEGFR-1/2, and eNOS expression in the rat model of postnatal hypoxia

Neonatal asphyxia occurs due to reduction in oxygen supply to vital organs in the newborn. Rapid restoration of oxygen to the lungs after a long period of asphyxia can cause lung injury and decline of respiratory function, which result from the activity of molecules that induce vascular changes in the lung such as nitric oxide (NO) and vascular endothelial growth factors (VEGF). In this study, we evaluated the pulmonary and vascular morphometry of rats submitted to the model of neonatal asphyxia and mechanical ventilation, their expression of pulmonary VEGF, VEGF receptors (VEGFR-1/VEGFR-2), and endothelial NO synthase (eNOS). Neonate Sprague-Dawley rats (CEUA #043/2011) were divided into four groups (n=8 each): control (C), control submitted to ventilation (CV), hypoxia (H), and hypoxia submitted to ventilation (HV). The fetuses were harvested at 21.5 days of gestation. The morphometric variables measured were body weight (BW), total lung weight (TLW), left lung weight (LLW), and TLW/BW ratio. Pulmonary vascular measurements, VEGFR-1, VEGFR-2, VEGF, and eNOS immunohistochemistry were performed. The morphometric analysis showed decreased TLW and TLW/BW ratio in HV compared to C and H (P<0.005). Immunohistochemistry showed increased VEGFR-2/VEGF and decreased VEGFR-1 expression in H (P<0.05) and lower eNOS expression in H and HV. Median wall thickness was increased in H, and the expression of VEGFR-1, VEGFR-2, VEGF, and eNOS was altered, especially in neonates undergoing H and HV. These data suggested the occurrence of arteriolar wall changes mediated by NO and VEGF signaling in neonatal hypoxia.

Mecanismos regulatorios del tono vascular pulmonar neonatal: una perspectiva molecular / Regulatory mechanisms of neonatal pulmonary vascular tone: a molecular perspective

La adaptación al medio extrauterino incluye un aumento considerable de la PaO2, que induce especialmente cambios estructurales y vasoactivos en la circulación pulmonar, que llevarán a una circulación previamente pobremente irrigada, a recibir ∼100% del gasto cardíaco del recién nacido, permitiendo el normal intercambio gaseoso. La regulación local de la circulación arterial pulmonar neonatal basal, es mantenida por un delicado equilibrio entre agentes vasoconstrictores y vasodilatadores. Este equilibrio, permite mantener la circulación pulmonar como un territorio de gran flujo sanguíneo y baja resistencia. La acción de los vasoconstrictores permite la formación de las interacciones entre actina y la cadena liviana de la miosina, esta es inducida en la célula muscular lisa principalmente por dos vías: a) dependiente de calcio, que consiste en aumentar el calcio intracelular, facilitando finalmente la unión de actina y miosina, y b) independiente de calcio, la cual a través de consecutivas fosforilaciones logra sensibilizar a las proteínas involucradas promoviendo la unión de actina y miosina. Estas acciones son mediadas por agonistas generados principalmente en el endotelio pulmonar, como endotelina-1 y tromboxano, o por agonistas provenientes de otros tipos celulares como la serotonina. Los agentes vasodilatadores regulan la respuesta vasoconstrictora, principalmente inhibiendo la señalización que induce la vasocontricción independiente de calcio, a través de la activación de proteínas quinasas que inhibirán la función de la ROCK quinasa, uno de los últimos efectores de la vasocontricción antes de la formación de la unión de actina y miosina. Esta revisión describe estos mecanismos de primordial importancia en las primeras horas de nuestra vida como individuos independientes.

The extrauterine-milieu adaptation includes a considerable increase in PaO2, that specifically induces structural and vasoactive changes at pulmonary circulation. Such changes transform a poor irrigated circulation into a circulation that receive ∼100% of neonatal cardiac output, supporting the normal alveolar-capillary gas exchange. Local regulation of basal neonatal pulmonary circulation is maintaining by a delicate equilibrium between vasoconstrictor and vasodilator agents. This equilibrium, allows to maintain the pulmonary circulation as an hemodynamic system with a high blood flow and a low vascular resistance. Vasocontrictors action allows actin and light-chain myosin interaction. Two main pathways induced this effect in smooth muscle cell: a) a calcium dependent pathway, that increases intracellular calcium, facilitating actin - myosin binding, and b) the independent calcium pathway, which achieves through consecutive phosphorylation reactions sensitize the proteins involved, promoting the binding of actin and light-chain myosin. These actions are mediated by agonists produced mainly in the pulmonary endothelium, such as endothelin-1 and thromboxane, or by agonists from other cell types such as serotonin. Vasodilator agents regulate the vasoconstrictor response, mainly by inhibiting signals that induce calcium-independent vasoconstriction, through activation of protein kinases, which in turn will inhibit the function of ROCK kinase, one of the last effectors of vasoconstriction before formation of the actin and light-chain myosin binding. This review will focus on describing these mechanisms of primal importance in the first hours of our lives as independent individuals.

The role of bradykinin in lung ischemia-reperfusion injury in a rat lung transplantation model

ABSTRACT PURPOSE: To investigate the role of bradykinin in a rat lung transplantation (LTx) model and preliminarily discuss the relationship between bradykinin and CD26/DPP-4. METHODS: Rats were randomly divided into four groups: Control (CON), Sham, low potassium dextranglucose (LPD), and AB192 (n=15/group). Orthotopic single LTx was performed in the LPD and AB192 groups. The donor lungs were flush-perfused and preserved with low potassium dextranglucose (LPD) or LPD+CD26/DPP-4 catalytic inhibitor (AB192). LTx was performed after 18 h cold ischemia time and harvested two days post-LTx. Blood gas analysis (PO2), wet/dry weight ratio (W/D), myeloperoxidase activity (MPO), and lipid peroxidation (MDA) were analyzed at 48 hr after transplantation. Immunohistochemical (IHC) analysis was performed in the same sample and validated by Western-Blot. RESULTS: Compared to the LPD group, the AB192 group showed higher PO2, lower W/D ratio, and decreased MPO and MDA. IHC studies showed strong bradykinin β2 receptor (B2R) staining in the LPD group, especially in inflammatory cells, alveolar macrophages, and respiratory epithelial cells. Expression of B2R by Western-Blot was significantly different between the AB192 and LPD groups. CONCLUSION: Bradykinin may be a competitive substrate of DPP-4, and decreased bradykinin levels may enhance protective effects against ischemia/reperfusion injury during LTx.

Evaluation of pulmonary sequestration with multidetector computed tomography angiography in a select cohort of patients: A retrospective study

OBJECTIVES: This study aimed to evaluate the role of multidetector computed tomography angiography in diagnosing patients with pulmonary sequestration. METHODS: We retrospectively analyzed the computed tomography studies and clinical materials of 43 patients who had undergone preoperative multidetector computed tomography angiography in our hospital and had pathologically proven pulmonary sequestration. Each examination of pulmonary sequestration was reviewed for type, location, parenchymal changes, arterial supply and venous drainage on two-dimensional and three-dimensional computed tomography images. RESULTS: Multidetector computed tomography successfully detected all pulmonary sequestrations in the 43 patients (100%). This included 40 patients (93.0%) with intralobar sequestration and 3 patients (7.0%) with extralobar sequestration. The locations of pulmonary sequestration were left lower lobe (28 cases, 70% of intralobar sequestrations), right lower lobe (12 cases, 30% of intralobar sequestrations) and costodiaphragmatic sulcus (3 cases). Cases of sequestered lung presented as mass lesions (37.2%), cystic lesions (32.6%), pneumonic lesions (16.3%), cavitary lesions (9.3%) and bronchiectasis (4.6%). The angioarchitecture of pulmonary sequestration, including feeding arteries from the thoracic aorta (86.1%), celiac truck (9.3%), abdominal aorta (2.3%) and left gastric artery (2.3%) and venous drainage into inferior pulmonary veins (86.0%) and the azygos vein system (14.0%), was visualized on multidetector computed tomography. Finally, the multidetector computed tomography angiography results of the sequestered lungs and angioarchitectures were surgically confirmed in all the patients. CONCLUSIONS: As a noninvasive modality, multidetector computed tomography angiography is helpful for making diagnostic decisions regarding pulmonary sequestration with high confidence and for visualizing the related parenchymal characteristics, arterial supply, and venous drainage features to help plan surgical strategies.

Direct intraperitoneal resuscitation with lidocaine, methylene blue and pentoxiphylline combination does not decreases inflammation after intestinal ischemia-reperfusion injury in rats

ABSTRACT PURPOSE: To evaluate the effects of an intraperitoneal solution of methylene blue (MB), lidocaine and pentoxyphylline (PTX) on intestinal ischemic and reperfusion injury METHODS: Superior mesenteric artery was isolated and clamped in 36 adult male Sprague Dawley rats. After 60 minutes, clamp was removed and a group received intraperitoneally UNITO solution (PTX 25mg/kg + lidocaine 5mg/kg + MB 2mg/kg), while the other group was treated with warm 0.9% NaCl solution. Rats were euthanized 45 min after drug administration. Lung and bowel were collected for histological evaluation (using Park's score) and determination of myeloperoxidase (MPO) and malondialdehyde (MDA) levels. RESULTS: Control samples showed lymphoplasmocytic infiltrate and crypt necrosis of villi. MPO and MDA measurements shown no differences between treated and control groups. CONCLUSION: The combination of lidocaine, methylene blue and pentoxyphylline administered intraperitoneally at the studied dose, did not decreased histological lesion scores and biochemical markers levels in intestinal ischemia/reperfusion injury.