Kiwi fruit essence reduces radiation-induced lung injury by down-regulating TNF-α and PDGF-B in rats / 细胞与分子免疫学杂志

Objective To observe the role of tumor necrosis factor-α (TNF-α) and platelet-derived growth factor-B (PDGF-B) in kiwi fruit essence-mediated protection of radiation-induced lung injury (RILI) in rats. Methods 96 male healthy Sprague-Dawley rats were divided into normal control group, model group, and kiwi fruit essence treatment group(60 and 240 mg/kg) by the random number table method, with 24 animals in each group. The whole lungs underwent 6 MV X-ray irradiation (18 Gy) to induce RILI animal models in rats of the latter three groups. On the next day after irradiation, rats in the latter two groups were intragastrically administrated with 60 or 240 mg/kg kiwi fruit essence, once a day. The rats in the normal control and model groups were treated with 9 g/L sodium chloride solution. Eight rats in the latter three groups were randomly sacrificed on days 14, 28, and 56, while normal control rats were sacrificed on day 56 as the overall control. Blood samples were collected and separated. Serum concentrations of TNF-α and PDGF-B were detected using ELISA. The lung tissues were isolated for HE and Masson staining to evaluate alveolitis and pulmonary fibrosis (PF). The hydroxyproline (HYP) content in lung tissues was detected. The mRNA and protein expression of pulmonary TNF-α and PDGF-B were determined by quantitative real-time PCR and immunohistochemistry. Results Compared with the model group, treatment with 60 and 240 mg/kg kiwi fruit essence group significantly reduced alveolitis on days 14 and 28 as well as PF lesions on days 28 and 56. Compared with the normal control group, HYP content in the lung tissue of the model group increased on day 28 and day 56, while TNF-α and PDGF-B levels in the serum and lung tissues increased at each time point. Compared with the model group during the same period, 60 and 240 mg/kg kiwi fruit essence element treatment group reported the diminished levels of serum and pulmonary TNF-α on day 14 and day 28. Consistently, the lung tissue HYP content and serum and pulmonary PDGF-B levels on day 28 and day 56 were reduced. In addition, the above indicators in the 240 mg/kg kiwi fruit essence treatment group were lower than those for the 60 mg/kg kiwi fruit essence treatment group. Conclusion Kiwi fruit essence can alleviate RILI in rats, which is related to the down-regulation of TNF-α expression at the early stage and decreased PDGF-B level at the middle and late stages.

Research Progress on the Protective Effect of Intestinal Flora on Radiation-induced Lung Injury in Thoracic Tumors / 中国肺癌杂志

Radiation therapy is one of the main treatment methods for patients with thoracic malignant tumors, which can effectively improve the survival rate of the patients. However, radiation therapy can also cause damage to normal tissues while treating tumors, leading to radiation-induced lung injury such as radiation pneumonia and pulmonary fibrosis. Radiation-induced lung injury is a complex pathophysiological process involving many factors, and its prevention and treatment is one of the difficult problems in the field of radiation medicine. Therefore, the search for sensitive predictors of radiation-induced lung injury can guide clinical radiotherapy and reduce the incidence of radiation-induced lung injury. With the in-depth study of intestinal flora, it can drive immune cells or metabolites to reach lung tissue through the circulatory system to play a role, and participate in the occurrence, development and treatment of lung diseases. At present, there are few studies on intestinal flora and radiation-induced lung injury. Therefore, this paper will comprehensively elaborate the interaction between intestinal flora and radiation-induced lung injury, so as to provide a new direction and strategy for studying the protective effect of intestinal flora on radiation-induced lung injury.
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Injuria pulmonar autoinducida por el paciente / Patient self-inflicted lung injury

La Injuria Pulmonar Autoinducida por el Paciente (p-SILI) es una entidad recientemente reconocida. Clásicamente, el daño producido por la ventilación mecánica (VM) se asoció al uso de presión positiva, y para disminuirlo se crearon distintas estrategias conocidas como parámetros de protección pulmonar. Sin embargo, es importante reconocer los potenciales efectos deletéreos de la ventilación espontánea dependientes de la injuria pulmonar previa que sufra el paciente y del esfuerzo que realice. En este artículo se explican los distintos mecanismos que pueden producir p-SILI y las estrategias descritas en la literatura para prevenirla (AU)

Patient self-inflicted lung injury (p-SILI) is a recently recognized disorder. Classically, damage produced by mechanical ventilation (MV) was associated with the use of positive pressure, and different strategies known as lung protection parameters were created to reduce it. Nevertheless, it is important to recognize the potential deleterious effects of the effort made during spontaneous breathing due to previous lung injury suffered by the patient. This article explains the different mechanisms that may produce p-SILI and the prevention strategies described in the literature. (AU)

Tea grape reduces abdominal aortic occlusion-induced lung injury

Abstract Introduction: Ischemia-associated mortality caused by aortic cross-clamps, as in ruptured abdominal aorta aneurysm surgeries, and reperfusion following their removal represent some of the main emergency conditions in cardiovascular surgery. The purpose of our study was to examine the potential protective effect of tea grape against aortic occlusion-induced lung injury using biochemical, histopathological, immunohistochemical, and quantitative analyses. Methods: Thirty-two male Sprague-Dawley rats were randomly assigned into four groups: control (healthy), glycerol + ischemia/reperfusion (I/R) (sham), I/R, and I/R + tea grape. Results: Following aortic occlusion, we observed apoptotic pneumocytes, thickening in the alveolar wall, edematous areas in interstitial regions, and vascular congestion. We also observed an increase in pulmonary malondialdehyde (MDA) levels and decrease in pulmonary glutathione (GSH). However, tea grape reduced apoptotic pneumocytes, edema, vascular congestion, and MDA levels, while increased GSH levels in lung tissue. Conclusion: Our findings suggest that tea grape is effective against aortic occlusion-induced lung injury by reducing oxidative stress and apoptosis.

Pathogenic role leukotriene B4 in lung injury induced by lung-protective mechanical ventilation in rabbits / 南方医科大学学报

OBJECTIVE@#To elucidate the pathogenic role of leukotriene B4 (LTB4) in pulmonary hyper-permeability and inflammation induced by lung-protective mechanical ventilation (LPMV) in rabbits.@*METHODS@#Thirty-two healthy Japanese white rabbits were randomized into 4 groups for treatment with vehicle or bestatin (a leukotriene A4 hydrolase inhibitor that inhibits LTB4 production) administered intragastrically at the daily dose of 8 mg/kg for 5 days, followed by sham operation (group S and group BS, respectively, in which the rabbits were anesthetized only) or LPMV (group PM and group BPM, respectively, in which the rabbits received ventilation with 50% oxygen at a tidal volume of 8 mL/kg for 5 h). The concentrations of LTB4 and cyclic adenosine monophosphate (cAMP) in the lung tissues were analyzed by ELISA. cAMP content, protein kinase A (PKA) protein expression and the Rap1-GTP protein to total Rap1 protein ratio were determined to assess the activities of cAMP/PKA and Rap1 signaling pathways. The lung injury was evaluated by assessing lung permeability index, lung wet/dry weight ratio, polymorphonuclear leukocyte (PMN) count in bronchoalveolar lavage fluid (BALF), pulmonary myeloperoxidase (MPO) activity and lung histological scores.@*RESULTS@#None of the examined parameters differed significantly between group S and group BS. All the parameters with the exception of lung histological score increased significantly in group PM and group BPM as compared to those in group S (@*CONCLUSIONS@#LPMV can induce LTB4 overproduction to down-regulate cAMP/PKA and Rap1 signaling pathways in the lungs of rabbits, which results in lung hyper-permeability and inflammation. Bestatin can inhibit LTB4 production in the lungs to protect against LPMV-induced lung hyper-permeability and inflammation.

Investigation of the protective effect of enoxaparin and ticagrelor pretreatment against ischemia-reperfusion injury in rat lung tissue

SUMMARY OBJECTIVES This study was conducted to reveal the possible protective effects of ticagrelor and enoxaparin pretreatment against ischemia-reperfusion (IR)-induced injury on the lung tissue of a rat model. METHODS Wistar albino rats were randomly divided into 4 groups as follows: group-1 (control-sham), group-2 (control-saline+IR), group-3 (ticagrelor+IR), group-4 (enoxaparin+IR). Before the ischemic period, saline, ticagrelor, and enoxaparin were administered to the 2nd-4th groups, respectively. In these groups, IR injury was induced by clamping the aorta infrarenally for 2 h, followed by 4 h of reperfusion except group-1. After the rats were euthanized, the lungs were processed for histological examinations. Paraffin sections were stained with Haematoxylin&Eosin (H&E) for light microscopic observation. Apoptosis was evaluated by caspase-3 immunoreactivity. Data were statistically analyzed using the SPSS software. RESULTS In the lung sections stained with H&E, a normal histological structure was observed in group-1, whereas disorganized epithelial cells, hemorrhage, and inflammatory cell infiltration were seen in the alveolar wall in group-2. The histologic structure of the treatment groups was better than that of group-2. Caspase-3(+) apoptotic cells were noticeable in sections of group-2 and were lower in the treatment groups. In group-4, caspase-3 immunostaining was lower than in group-3. In group-2, apoptotic cells were significantly higher than in the other groups (p<0.001). CONCLUSION Based on the histological results, we suggested that both therapies ameliorated the detrimental effects of IR. Caspase-3 immunohistochemistry results also revealed that pre-treatment with enoxaparin gave better results in an IR-induced rat injury model. In further studies, other parameters such as ROS and inflammatory gene expressions should be evaluated for accurate results.

RESUMO OBJETIVOS Este estudo foi realizado para revelar os possíveis efeitos protetores do ticagrelor e do pré-tratamento da enoxaparina no tecido pulmonar contra o modelo de lesão induzida por isquemia-reperfusão (IR). MÉTODOS Ratos albinos Wistar foram randomizados e divididos em quatro grupos: grupo 1 (controle-sham), grupo 2 (controle-salina + IR), grupo 3 (ticagrelor + IR), grupo 4 (enoxaparina + IR). Antes do período isquêmico, salina, ticagrelor e enoxaparina foram administrados nos grupos 2-4, respectivamente. Nesses grupos, a lesão de IR foi induzida pelo clampeamento da aorta na região da infrarrenal por duas horas, seguida por quatro horas de reperfusão, exceto no grupo 1. Após a sacrificação, os pulmões foram processados para exames histológicos. Secções de parafina foram coradas com hematoxilina e eosina (H&E) para observação microscópica de luz. A apoptose foi avaliada pela imunorreatividade da caspase-3. Os dados foram analisados estatisticamente pelo programa SPSS. RESULTADOS Nas secções pulmonares coradas com H&E, estrutura histológica normal foi observada no grupo 1, enquanto células epiteliais desorganizadas, hemorragia e infiltração de células inflamatórias foram observadas na parede alveolar no grupo 2. A estrutura histológica dos grupos de tratamento foi melhor que o grupo 2. Células apoptóticas caspase-3 (+) foram notadas em secções do grupo 2, e essas células foram mais baixas nos grupos de tratamento. No grupo 4, a imunocoloração com caspase-3 foi menor que no grupo 3. No grupo 2, as células apoptóticas foram significativamente maiores que nos outros grupos (p<0,001). CONCLUSÃO Com base nos resultados histológicos, sugerimos que ambas as terapias atenuaram os efeitos prejudiciais da RI. Resultados de imuno-histoquímica com caspase-3 também revelaram que o pré-tratamento com enoxaparina proporcionou melhores resultados no modelo de lesão induzida por IR. Em estudos posteriores, outros parâmetros, como ROS e expressões gênicas inflamatórias, devem ser avaliados quanto a resultados precisos.

Dexmedetomidine preconditioning protects against lung injury in hemorrhagic shock rats / Pré-condicionamento com dexmedetomidina protege contra lesão pulmonar em ratos com choque hemorrágico

Abstract Background and objectives: Dexmedetomidine has demonstrated protective effects against lung injury in vitro. Here, we investigated whether dexmedetomidine preconditioning protected against lung injury in hemorrhagic shock rats. Methods: Male Sprague-Dawley rats were randomly divided into four groups (n = 8): control group, hemorrhagic shock group, 5 ug.kg-1 dexmedetomidine (DEX1) group, and 10 ug.kg-1 dexmedetomidine (DEX2) group. Saline or dexmedetomidine were administered over 20 min. 30 min after injection, hemorrhage was initiated in the hemorrhagic shock, DEX1 and DEX2 group. Four hours after resuscitation, protein and cellular content in bronchoalveolar lavage fluid, and the lung histopathology were measured. The malondialdehyde, superoxide dismutase, Bcl-2, Bax and caspase-3 were also tested in the lung tissue. Results: Compare with hemorrhagic shock group, 5 ug.kg-1 dexmedetomidine pretreatment reduced the apoptosis (2.25 ± 0.24 vs. 4.12 ± 0.42%, p < 0.05), histological score (1.06 ± 0.12 vs. 1.68 ± 0.15, p < 0.05) and protein (1.92 ± 0.38 vs. 3.95 ± 0.42 mg.mL-1, p < 0.05) and WBC (0.42 ± 0.11 vs. 0.92 ± 0.13 × 109/L, p < 0.05) in bronchoalveolar lavage fluid. Which is correlated with increased superoxide dismutase activity (8.35 ± 0.68 vs. 4.73 ± 0.44 U.mg-1 protein, p < 0.05) and decreased malondialdehyde (2.18 ± 0.19 vs. 3.28 ± 0.27 nmoL.mg-1 protein, p < 0.05). Dexmedetomidine preconditioning also increased the Bcl-2 level (0.55 ± 0.04 vs. 0.34 ± 0.05, p < 0.05) and decreased the level of Bax (0.46 ± 0.03 vs. 0.68 ± 0.04, p < 0.05), caspase-3 (0.49 ± 0.03 vs. 0.69 ± 0.04, p < 0.05). However, we did not observe any difference between the DEX1 and DEX2 groups for these (p > 0.05). Conclusion: Dexmedetomidine preconditioning has a protective effect against lung injury caused by hemorrhagic shock in rats. The potential mechanisms involved are the inhibition of cell death and improvement of antioxidation. But did not show a dose-dependent effect.

Resumo Justificativa e objetivos: Dexmedetomidina demonstrou efeitos protetores contra a lesão pulmonar in vitro. Neste estudo, investigamos se o pré-condicionamento com dexmedetomidina protege contra a lesão pulmonar em ratos com choque hemorrágico. Métodos: Ratos machos, Sprague-Dawley, foram aleatoriamente divididos em quatro grupos (n = 8): grupo controle, grupo com choque hemorrágico, grupo com 5 µg.kg-1 de dexmedetomidina (DEX1) e grupo com 10 µg.kg-1 de dexmedetomidina (DEX2). Solução salina ou dexmedetomidina foi administrada durante 20 minutos. Trinta minutos após a injeção, a hemorragia foi iniciada nos grupos choque hemorrágico, DEX1 e DEX2. Quatro horas após a ressuscitação, a proteína e o conteúdo celular no lavado broncoalveolar e a histopatologia pulmonar foram medidos. Malondialdeído, superóxido dismutase, Bcl-2, Bax e caspase-3 também foram testados no tecido pulmonar. Resultados: Na comparação com o grupo choque hemorrágico, o pré-tratamento com 5 ug.kg-1 de dexmedetomidina reduziu a apoptose (2,25 ± 0,24 vs. 4,12 ± 0,42%, p < 0,05), escore histológico (1,06 ± 0,12 vs. 1,68 ± 0,15, p < 0,05) e proteína (1,92 ± 0,38 vs. 3,95 ± 0,42 mg.mL-1, p < 0,05) e leucócitos (0,42 ± 0,11 vs. 0,92 ± 0,13 × 109/L, p < 0,05) no lavado broncoalveolar; o que está correlacionado com o aumento da atividade da superóxido dismutase (8,35 ± 0,68 vs. 4,73 ± 0,44 U.mg-1 de proteína, p < 0,05) e diminuição do malondialdeído (2,18 ± 0,19 vs. 3,28 ± 0,27 nmoL.mg-1 de proteína, p < 0,05). O pré-condicionamento com dexmedetomidina também aumentou o nível de Bcl-2 (0,55 ± 0,04 vs. 0,34 ± 0,05, p < 0,05) e diminuiu o nível de Bax (0,46 ± 0,03 vs. 0,68 ± 0,04, p < 0,05), caspase-3 (0,49 ± 0,03 vs. 0,69 ± 0,04, p < 0,05). No entanto, não houve diferença entre os grupos DEX1 e DEX2 para essas proteínas (p > 0,05). Conclusão: O pré-condicionamento com dexmedetomidina tem um efeito protetor contra a lesão pulmonar causada por choque hemorrágico em ratos. Os potenciais mecanismos envolvidos são a inibição da morte celular e a melhora da antioxidação. Porém, não mostrou um efeito dose-dependente.

The role of PI3K/Akt signal pathway in the protective effects of propofol on intestinal and lung injury induced by intestinal ischemia/reperfusion

Abstract Purpose: To investigate the role of PI3k/Akt signal pathway in the protective effects of propofol on intestinal and lung injury induced by intestinal ischemia/reperfusion(I/R). Methods: Male Sprague-Dawley rats were subjected to 45 min of ischemia by occluding the superior mesenteric artery and to 2h of reperfusion to establish the model of I/R. Twenty four rats were randomly divided into four groups: Sham, intestinal I/R (II/R), propofol (P), wortmannin (W). In groups P, W, propofol was injected intravenously and continuously at the onset of reperfusion via infusion pump. PI3K inhibitor (wortmannin) was administered intravenously in group W 25 min before ischemia. Intestinal tissues and lung tissues were obtained for determination of histologic injury, wet/dry weight ratio, malondialdehyde (MDA) levels, superoxide dismutase (SOD) and myeloperoxidase (MPO) activities. Meanwhile, the expressions of caspase-3 and phosphorylated Akt (p-Akt) in intestines and lungs were detected by western blot. Results: Propofol treatment alleviated intestinal and lung morphological changes which were observed in II/R group，Moreover, wet/dry weight ratio, the MDA level, MPO activity and expression of caspase-3 were significantly decreased whereas the SOD activity and p-Akt expression were significantly increased. Notably, the protections were significantly reversed by pretreatment of wortmannin. Conclusion: PI3K/Akt pathway activation play a critical role in the protective effects of propofol on intestinal and lung injury induced by ischemia/reperfusion.

Protective effect of omega 3 and vitamin D in preventing lung-tissue damage of newborn rats exposed to cigarette smoke during intrauterine period / Efecto protector de omega 3 y vitamina D en la prevención del daño en el tejido pulmonar de ratas recién nacidas expuestas al humo del cigarrillo durante el período intrauterino

SUMMARY: This study aimed to investigate the toxic effects of cigarette smoke exposure on lung and the protective role of Omega 3 and Vitamin D against these toxic effects biochemically and histologically. 28 pregnant Wistar Albino rats were divided into four groups. The first group was control group; the second group was exposed to smoke of 10 cigarette by puff device 2 hours/day after pregnancy; the third group was exposed to cigarette smoke together with Omega 3 (0.5 mg/kg/day) and the fourth group was exposed to cigarette smoke together with vitamin D (42 microgram/kg/day). Finally, lung tissue sections of the newborn rats were stained with Hemotoxilen eosine and Masson tricromite. Malondialdehyde (MDA) and Fluorescent Oxidation Products (FOU) levels were measured. Fetal weights and the number of fetuses were significantly lower in the group received only cigarette smoke (both p<0.001). Histopathologically, pulmonary volume, number of developed alveols and parenchyma elasticity decreased significantly, meanwhile interstitial tissue increased, elastin and collagen did not develop adequately. Histopathologic changes significantly decreased in the group given Omega 3 and Vitamin D. Statistically, MDA and FOU levels were found to be higher in the group exposed to cigarette smoke compared to the control group, and MDA and FOU levels were lower in the group given Omega 3 along with cigarette smoke (p<0.001). Cigarette smoke caused histologically significant damage to fetal lung tissue, oxidative stress and increased MDA and FOU levels. This damage was significantly reduced with Omega 3 and Vitamine D supplementation. Omega 3 is an important antioxidant; vitamin D has no significant antioxidant effect.

RESUMEN: Este estudio tuvo como objetivo investigar los efectos tóxicos de la exposición al humo de cigarrillo en el pulmón, y el papel protector de Omega 3 y la Vitamina D contra esos efectos. 28 ratas Wistar albino preñadas fueron separadas en cuatro grupos. El primer grupo grupo control; el segundo grupo estuvo expuesto al humo de 10 cigarrillos por dispositivo de inhalación 2 horas / día después de la preñez; el tercer grupo se expuso al humo del cigarrillo junto con Omega 3 (0,5 mg / kg / día) y el cuarto grupo se expuso al humo del cigarrillo junto con vitamina D (42 microgramos / kg / día). Secciones de tejido pulmonar de las ratas recién nacidas se tiñeron con Hematoxilina Eosina y tricrómico de Masson. Se midieron los niveles de malondialdehído (MDA) y productos de oxidación fluorescente (POF). Los pesos fetales y el número de fetos fueron significativamente más bajos en el grupo que recibió solamente humo de cigarrillo (ambos p <0,001). Histopatológicamente, el volumen pulmonar, el número de alveolos desarrollados y la elasticidad del parénquima disminuyeron significativamente; mientras que el tejido intersticial aumentó y la elastina y el colágeno no se desarrollaron adecuadamente. Los cambios histopatológicos disminuyeron significativamente en el grupo que recibió Omega 3 y Vitamina D. Estadísticamente, se encontró que los niveles de MDA y POF eran más altos en el grupo expuesto al humo de cigarrillo en comparación con el grupo control, además los niveles de MDA y POF fueron más bajos en el grupo que recibió Omega 3 junto con el humo del cigarrillo (p <0,001). El humo del cigarrillo causó daños histológicamente significativos en el tejido pulmonar fetal, el estrés oxidativo y el aumento de los niveles de MDA y FOU. Este daño se redujo significativamente con los suplementos de Omega 3 y Vitamina D. El omega 3 es un importante antioxidante; la vitamina D no tiene ningún efecto antioxidante significativo.

Effects of Hippo signaling pathway on lung injury repair by mesenchymal stem cells in acute respiratory distress syndrome / 中华危重病急救医学

OBJECTIVE@#To investigate the effects of Hippo signaling pathway on lung injury repair of mesenchymal stem cells (MSC) in acute respiratory distress syndrome (ARDS) and its mechanism.@*METHODS@#Mouse bone marrow-derived MSC (mMSCs) cell lines with low expression of large tumor suppressor 2 (LATS2) were constructed by lentiviral vector transfection. Male C57BL/6 mice aging 6-8 weeks old were divided into four groups according to random number table (n = 36). The ARDS animal model (ARDS group) was reproduced by intratracheally injection of 2 g/L lipopolysaccharide (LPS) 50 μL, the normal saline (NS) control group was injected with an equal volume of NS. After 4 hours of model reproduction, 5×104 mMSCs transfected with blank lentivirus vector (MSC-shcontrol group) or shLATS2 lentivirus vector (MSC-shLATS2 group) were transplanted intratracheally, while NS control group and ARDS group were injected with equal volume of phosphate buffered saline (PBS). Mice were sacrificed at 3, 7, and 14 days after modeling, and lung tissue and bronchoalveolar lavage fluid (BALF) were harvested. Near-infrared fluorescence imaging, immunofluorescence staining and Western Blot were used to track mMSCs in lung tissue. Retension and proportion of mMSC differentiation into type II alveolar epithelial cells (AEC II) were evaluated. Lung tissue wet weight/body weight ratio (LWW/BW) and total protein (TP) and albumin (ALB) in BALF were determined to reflect pulmonary edema. The expression of Occludin protein in lung epithelium was tested by Western Blot to reflect permeability of epithelium. The levels of interleukins (IL-1β, IL-6, IL-10) in BALF were assessed by enzyme-linked immunosorbent assay (ELISA) to reflect lung inflammation. Hematoxylin-eosin (HE) staining and modified Masson staining were carried out, and the scores were assessed to reflect lung injury and evaluate pulmonary fibrosis.@*RESULTS@#The signal intensity of isolated lung fluorescence images at 3 days in the MSC-shLATS2 group was significantly higher than that in the MSC-shcontrol group (fluorescence intensity: 0.039±0.005 vs. 0.017±0.002, P < 0.05), the number of green fluorescent protein (GFP)-positive cells in lung tissue was also significantly higher than that in the MSC-shcontrol group (cells/HP: 29.65±6.98 vs. 17.50±4.58, P < 0.05), but they all decreased with time; and the proportion of mMSCs differentiated into AEC II was significantly increased [(64.12±15.29)% vs. (19.64±3.71)%, P < 0.05]. Compared with the NS control group, the levels of surface active protein C (SPC) and Occludin protein in the ARDS group were significantly decreased, LWW/BW ratio and TP, ALB and inflammatory factors levels in BALF were significantly increased; extensive alveolar and interstitial edema, hemorrhage and diffuse inflammatory cell infiltration were found in lung tissue, and the lung injury score was significantly increased; collagen fibers were deposited in alveolar septum and alveolar cavity, and pulmonary fibrosis score was also increased significantly. Compared with the ARDS group, the expression levels of SPC and Occludin at 14 days in the MSC-shcontrol group and the MSC-shLATS2 group were significantly increased (SPC/β-actin: 0.51±0.12, 0.68±0.10 vs. 0.27±0.08, Occludin/β-actin: 0.49±0.19, 0.79±0.11 vs. 0.25±0.08, all P < 0.05), TP, ALB, IL-1β, IL-6 levels in BALF at 3 days were significantly decreased [TP (g/L): 8.08±1.72, 5.12±0.87 vs. 12.55±2.09; ALB (g/L): 0.71±0.21, 0.44±0.18 vs. 1.18±0.29, IL-1β (ng/L): 99.26±14.32, 60.11±8.58 vs. 161.86±25.17, IL-6 (ng/L): 145.54±13.29, 101.74±11.55 vs. 258.79±27.88, all P < 0.05], and IL-10 was significantly increased (ng/L: 190.83±22.61, 316.65±37.88, both P < 0.05). Furthermore, all the above parameters in the MSC-shLATS2 group were significantly improved as compared with those in the MSC-shcontrol group (all P < 0.05). LWW/BW ratio in the MSC-shLATS2 group was significantly lower than that in the ARDS group and the MSC-shcontrol group (mg/g: 9.85±1.51 vs. 16.78±1.92, 14.88±1.74, both P < 0.05).@*CONCLUSIONS@#Inhibiting Hippo signaling pathway by low expression of LATS2 could promote the retention of mMSCs in lung tissue and differentiation into AEC II cells of ARDS mice, improve pulmonary edema and alveolar epithelial permeability, regulate pulmonary inflammatory response, and alleviate pathological damage and fibrosis of lung tissue.

The influence of allopurinol and post-conditioning on lung injuries induced by lower-limb ischemia and reperfusion in Wistar rats

Abstract Purpose: To analyze the effects of allopurinol and of post-conditioning on lung injuries induced by lower-limb ischemia and reperfusion. Methods: Thirty rats were used. They were divided in 5 groups: (1) group A: abdominal aortic dissection only, (2) group B: ischemia and reperfusion, (3) group C: administered allopurinol (100mg/Kg) a few hours before procedure, (4) group D: post-conditioned and (5) group E: administered allopurinol and post-conditioned. With the exception of group A, all groups were submitted to infrarenal aortic ischemia for 2 hours, and reperfusion for 72 hours. After euthanasia, lungs were removed for histological analysis. They were graded under two scores: pulmonary injury (neutrophil infiltration, interstitial edema, vascular congestion, and destruction of lung architecture) and lymphocytic score (neutrophil infiltration, lymphoid aggregate and secondary follicle). Results: On the pulmonary injury score, the degree of injury was smaller than in groups D and E, when compared to group B, p<0.05. Group C did not obtain the same result (p>0,05). On the lymphocytic score, there was no statistic difference among groups, p>0.05. Conclusion: Both post-conditioning and the combination of allopurinol and post-conditioning were effective in remote lung protection induced by lower-limbs I/R. When used in isolation, allopurinol showed no protective effect.

Ventilação mecânica variável / Variable mechanical ventilation

RESUMO Objetivo: Revisar a literatura em relação à utilização da ventilação variável e aos principais desfechos relacionados à sua utilização. Métodos: Busca, seleção e análise de todos os artigos originais sobre ventilação variável, sem restrição quanto ao período de publicação e ao idioma, nas bases de dados eletrônicas LILACS, MEDLINE® e PubMed, encontrados por meio de busca pelos termos "variable ventilation" OR "noisy ventilation" OR "biologically variable ventilation". Resultados: Foram selecionados 36 artigos na busca. Após a análise, 24 artigos eram originais; destes 21 experimentais e 3 clínicos. Conclusão: Diversos estudos experimentais evidenciaram os efeitos benéficos de variadas estratégias ventilatórias variáveis sobre a função pulmonar em diferentes modelos de lesão pulmonar e em pulmões saudáveis. A ventilação variável parece ser uma estratégia viável para o aprimoramento da troca gasosa e mecânica respiratória, assim como para prevenção de lesão pulmonar associada à ventilação mecânica. Entretanto, estudos clínicos são necessários para investigar o potencial destas estratégias ventilatórias variáveis na melhora clínica dos pacientes submetidos à ventilação mecânica.

ABSTRACT Objective: To review the literature on the use of variable mechanical ventilation and the main outcomes of this technique. Methods: Search, selection, and analysis of all original articles on variable ventilation, without restriction on the period of publication and language, available in the electronic databases LILACS, MEDLINE®, and PubMed, by searching the terms "variable ventilation" OR "noisy ventilation" OR "biologically variable ventilation". Results: A total of 36 studies were selected. Of these, 24 were original studies, including 21 experimental studies and three clinical studies. Conclusion: Several experimental studies reported the beneficial effects of distinct variable ventilation strategies on lung function using different models of lung injury and healthy lungs. Variable ventilation seems to be a viable strategy for improving gas exchange and respiratory mechanics and preventing lung injury associated with mechanical ventilation. However, further clinical studies are necessary to assess the potential of variable ventilation strategies for the clinical improvement of patients undergoing mechanical ventilation.

Effects of N-acetylcysteine and pentoxifylline on remote lung injury in a rat model of hind-limb ischemia/reperfusion injury / Efeitos da N-acetilcisteína e pentoxifilina na lesão pulmonar remota em um modelo de lesão de isquemia/reperfusão de membro posterior em ratos

Objective : To investigate the effects of N-acetylcysteine (NAC) and pentoxifylline in a model of remote organ injury after hind-limb ischemia/reperfusion (I/R) in rats, the lungs being the remote organ system. Methods : Thirty-five male Wistar rats were assigned to one of five conditions (n = 7/group), as follows: sham operation (control group); hind-limb ischemia, induced by clamping the left femoral artery, for 2 h, followed by 24 h of reperfusion (I/R group); and hind-limb ischemia, as above, followed by intraperitoneal injection (prior to reperfusion) of 150 mg/kg of NAC (I/R+NAC group), 40 mg/kg of pentoxifylline (I/R+PTX group), or both (I/R+NAC+PTX group). At the end of the trial, lung tissues were removed for histological analysis and assessment of oxidative stress. Results : In comparison with the rats in the other groups, those in the I/R group showed lower superoxide dismutase activity and glutathione levels, together with higher malondialdehyde levels and lung injury scores (p < 0.05 for all). Interstitial inflammatory cell infiltration of the lungs was also markedly greater in the I/R group than in the other groups. In addition, I/R group rats showed various signs of interstitial edema and hemorrhage. In the I/R+NAC, I/R+PTX, and I/R+NAC+PTX groups, superoxide dismutase activity, glutathione levels, malondialdehyde levels, and lung injury scores were preserved (p < 0.05 for all). The differences between the administration of NAC or pentoxifylline alone and the administration of the two together were not significant for any of those parameters (p > 0.05 for all). Conclusions : Our results suggest that NAC and pentoxifylline both protect lung tissue from the effects of skeletal muscle I/R. However, their combined use does not appear to increase the level of that protection.

Objetivo : Investigar os efeitos da N-acetilcisteína (NAC) e pentoxifilina em um modelo de lesão pulmonar remota após isquemia/reperfusão (I/R) de membro posterior em ratos. Métodos : Trinta e cinco ratos Wistar machos foram divididos em cinco grupos (n = 7/grupo), cada qual submetido ao seguinte: operação simulada (grupo controle); isquemia de membro posterior, induzida por pinçamento da artéria femoral esquerda por 2 h, seguida por de 24 h de reperfusão (grupo I/R); e isquemia de membro posterior, como descrito acima, seguida de injeção intraperitoneal (antes da reperfusão) de 150 mg/kg de NAC (grupo I/R+NAC), 40 mg/kg de pentoxifilina (grupo I/R+PTX) ou ambas (grupo I/R+NAC+PTX). Ao final do experimento, tecidos pulmonares foram removidos para análise histológica e avaliação do estresse oxidativo. Resultados : Comparados aos ratos dos outros grupos, os do grupo I/R apresentaram menor atividade de superóxido dismutase e menores níveis de glutationa, além de maiores níveis de malondialdeído e maiores escores de lesão pulmonar (p < 0,05 para todos). Infiltração celular inflamatória intersticial dos pulmões também foi bem maior no grupo I/R do que nos outros grupos. Além disso, os ratos do grupo I/R apresentaram vários sinais de edema intersticial e hemorragia. Nos grupos I/R+NAC, I/R+PTX e I/R+NAC+PTX, a atividade de superóxido dismutase, níveis de glutationa, níveis de malondialdeído e escores de lesão pulmonar foram preservados (p < 0,05 para todos). As diferenças entre a administração de NAC ou pentoxifilina isoladamente e a das duas combinadas não foi significativa para nenhum desses parâmetros (p > 0,05 para todos). Conclusões : Nossos resultados sugerem que tanto NAC quanto pentoxifilina protegem o tecido pulmonar dos efeitos de I/R de músculo esquelético. Entretanto, seu uso combinado não parece aumentar o nível dessa proteção.

Effect of ozone oxidative preconditioning in preventing early radiation-induced lung injury in rats

Ionizing radiation causes its biological effects mainly through oxidative damage induced by reactive oxygen species. Previous studies showed that ozone oxidative preconditioning attenuated pathophysiological events mediated by reactive oxygen species. As inhalation of ozone induces lung injury, the aim of this study was to examine whether ozone oxidative preconditioning potentiates or attenuates the effects of irradiation on the lung. Rats were subjected to total body irradiation, with or without treatment with ozone oxidative preconditioning (0.72 mg/kg). Serum proinflammatory cytokine levels, oxidative damage markers, and histopathological analysis were compared at 6 and 72 h after total body irradiation. Irradiation significantly increased lung malondialdehyde levels as an end-product of lipoperoxidation. Irradiation also significantly decreased lung superoxide dismutase activity, which is an indicator of the generation of oxidative stress and an early protective response to oxidative damage. Ozone oxidative preconditioning plus irradiation significantly decreased malondialdehyde levels and increased the activity of superoxide dismutase, which might indicate protection of the lung from radiation-induced lung injury. Serum tumor necrosis factor alpha and interleukin-1 beta levels, which increased significantly following total body irradiation, were decreased with ozone oxidative preconditioning. Moreover, ozone oxidative preconditioning was able to ameliorate radiation-induced lung injury assessed by histopathological evaluation. In conclusion, ozone oxidative preconditioning, repeated low-dose intraperitoneal administration of ozone, did not exacerbate radiation-induced lung injury, and, on the contrary, it provided protection against radiation-induced lung damage.

Effect of tramadol on lung injury induced by skeletal muscle ischemia-reperfusion: an experimental study / Efeito do tramadol na lesao pulmonar induzida por isquemia-reperfusao de musculo esqueletico: um estudo experimental

OBJECTIVE: To determine whether tramadol has a protective effect against lung injury induced by skeletal muscle ischemia-reperfusion. METHODS: Twenty Wistar male rats were allocated to one of two groups: ischemia-reperfusion (IR) and ischemia-reperfusion + tramadol (IR+T). The animals were anesthetized with intramuscular injections of ketamine and xylazine (50 mg/kg and 10 mg/kg, respectively). All of the animals underwent 2-h ischemia by occlusion of the femoral artery and 24-h reperfusion. Prior to the occlusion of the femoral artery, 250 IU heparin were administered via the jugular vein in order to prevent clotting. The rats in the IR+T group were treated with tramadol (20 mg/kg i.v.) immediately before reperfusion. After the reperfusion period, the animals were euthanized with pentobarbital (300 mg/kg i.p.), the lungs were carefully removed, and specimens were properly prepared for histopathological and biochemical studies. RESULTS: Myeloperoxidase activity and nitric oxide levels were significantly higher in the IR group than in the IR+T group (p = 0.001 for both). Histological abnormalities, such as intra-alveolar edema, intra-alveolar hemorrhage, and neutrophil infiltration, were significantly more common in the IR group than in the IR+T group. CONCLUSIONS: On the basis of our histological and biochemical findings, we conclude that tramadol prevents lung tissue injury after skeletal muscle ischemia-reperfusion. .

OBJETIVO: Investigar se o tramadol tem um efeito protetor contra a lesão pulmonar induzida por isquemia-reperfusão de músculo esquelético. MÉTODOS: Vinte ratos Wistar machos foram divididos em dois grupos: grupo isquemia-reperfusão (IR) e grupo isquemia-reperfusão + tramadol (IR+T). Os animais foram anestesiados com cetamina e xilazina (i.m., 50 mg/kg e 10 mg/kg, respectivamente). Todos os animais foram submetidos a 2 h de isquemia por oclusão da artéria femoral e 24 h de reperfusão. Antes da oclusão da artéria femoral, foram administrados 250 UI de heparina pela veia jugular para impedir a coagulação. Os ratos do grupo IR+T foram tratados com tramadol (20 mg/kg i.v.) imediatamente antes da reperfusão. Após o período de reperfusão, os animais foram sacrificados com pentobarbital (300 mg/kg i.p.), os pulmões foram removidos cuidadosamente, e os espécimes foram preparados adequadamente para estudos histopatológicos e bioquímicos. RESULTADOS: A atividade de mieloperoxidase e os níveis de óxido nítrico foram significativamente maiores no grupo IR que no grupo IR+T (p = 0,001 para ambos). Anormalidades histológicas, como edema intra-alveolar, hemorragia intra-alveolar e infiltração neutrofílica, foram significativamente mais frequentes no grupo IR que no grupo IR+T. CONCLUSÕES: Com base nos resultados histológicos e bioquímicos ...

Efeitos da metilprednisolona na atividade inflamatória e estresse oxidativo nos pulmões de ratos com morte cerebral / Effects of methylprednisolone on inflammatory activity and oxidative stress in the lungs of brain-dead rats

OBJETIVO: Avaliar os efeitos da administração sistêmica precoce e tardia de metilprednisolona nos pulmões em um modelo de morte encefálica em ratos. MÉTODOS: Vinte e quatro ratos Wistar machos foram anestesiados e randomizados em quatro grupos (n = 6 por grupo): sham, somente morte encefálica (ME), metilprednisolona i.v. (30 mg/kg) administrada 5 min após a morte encefálica (MP5) e 60 min após a morte encefálica (MP60). Os grupos ME, MP5 e MP60 foram submetidos à morte encefálica por insuflação de um balão no espaço extradural. Todos os animais foram observados e ventilados durante 120 min. Foram determinadas variáveis hemodinâmicas e gasométricas, relação peso úmido/seco, escore histológico, thiobarbituric acid reactive substances (TBARS, substâncias reativas ao ácido tiobarbitúrico), atividade de superóxido dismutase (SOD) e de catalase, assim como contagem diferencial de células brancas, proteína total e nível de desidrogenase lática no LBA. A atividade da mieloperoxidase, peroxidação lipídica e níveis de TNF-α foram avaliados no tecido pulmonar. RESULTADOS: Não foram observadas diferenças significativas nas variáveis hemodinâmicas e gasométricas, relação peso úmido/seco, análises do LBA, escore histológico, SOD, mieloperoxidase e catalase entre os grupos. Os níveis de TBARS foram significativamente maiores nos grupos MP5 e MP60 do que nos grupos sham e ME (p < 0,001). Os níveis de TNF-α foram significativamente menores nos grupos MP5 e MP60 do que no grupo ME (p < 0,001). CONCLUSÕES: Neste modelo de morte cerebral, a administração precoce e tardia de metilprednisolona apresentou efeitos semelhantes sobre a inflamação e a peroxidação lipídica no tecido pulmonar.

OBJECTIVE: To evaluate the effects that early and late systemic administration of methylprednisolone have on lungs in a rat model of brain death. METHODS: Twenty-four male Wistar rats were anesthetized and randomly divided into four groups (n = 6 per group): sham-operated (sham); brain death only (BD); brain death plus methylprednisolone (30 mg/kg i.v.) after 5 min (MP5); and brain death plus methylprednisolone (30 mg/kg i.v.) after 60 min (MP60). In the BD, MP5, and MP60 group rats, we induced brain death by inflating a balloon catheter in the extradural space. All of the animals were observed and ventilated for 120 min. We determined hemodynamic and arterial blood gas variables; wet/dry weight ratio; histological score; levels of thiobarbituric acid reactive substances (TBARS); superoxide dismutase (SOD) activity; and catalase activity. In BAL fluid, we determined differential white cell counts, total protein, and lactate dehydrogenase levels. Myeloperoxidase activity, lipid peroxidation, and TNF-α levels were assessed in lung tissue. RESULTS: No significant differences were found among the groups in terms of hemodynamics, arterial blood gases, wet/dry weight ratio, BAL fluid analysis, or histological score-nor in terms of SOD, myeloperoxidase, and catalase activity. The levels of TBARS were significantly higher in the MP5 and MP60 groups than in the sham and BD groups (p < 0.001). The levels of TNF-α were significantly lower in the MP5 and MP60 groups than in the BD group (p < 0.001). CONCLUSIONS: In this model of brain death, the early and late administration of methylprednisolone had similar effects on inflammatory activity and lipid peroxidation in lung tissue.

Protective role of recombinant human erythropoietin in kidney and lung injury following renal bilateral ischemia-reperfusion in rat model

Acute kidney injury [AKI] has been recognized as one of the most complex clinical complications in modern medicine, and ischemia/reperfusion [I/R] injury is well-known as a main reason of AKI. In addition, AKI leads to important systemic consequences such as acute lung injury. This study was designed to investigate the role of erythropoietin [EPO] on kidney function makers and tissue damage; and lung endothelial permeability and lung water content [LWC] in bilateral renal I/R injury model in rats. Male Wistar rats were randomly divided into three groups of sham, I/R, and I/R treated with EPO [I/R + EPO] groups. The I/R and I/R + EPO groups were subjected to bilateral renal I/R injury; however, only the I/R + EPO group received EPO [500 IU/kg, i.p.] 2 h before ischemia surgery, and the same dose was continued once a day for 3 days after ischemia. The sham group underwent a surgical procedure without ischemia process. The blood urea nitrogen [BUN] and serum creatinine [Cr] levels, kidney tissue damage score [KTDS], and kidney weight [KW] per 100 g body weight significantly increased in I/R group [P < 0.05]. EPO administration decreased levels of BUN and Cr significantly [P < 0.05], and KTDS and KW insignificantly [P = 0.1]. No significant differences in kidney and serum levels of malondialdehyde, and lung vascular permeability and LWC were observed between the groups. The serum and kidney levels of nitrite were not significantly different between I/R and sham groups; however, administration of EPO increased the renal level of nitrite [P < 0.05]. EPO protected the kidney against I/R injury; however, it may not protect the lung tissue from the damage induced by renal I/R injury in rats

N-acetylcysteine prevents kidney and lung disturbances in renal ischemia/ reperfusion injury in rat

One of the most common causes of acute kidney injury [AKI] is kidney ischemia/reperfusion injury [IRI]. The distant organ injury such as acute lung injury is one of the side effects of AKI or kidney IRI. In this study, we performed bilateral renal IRI in rats and the protective role of N acetylcysteine [NAC] in kidney and lung was investigated. Rats [n = 30] were randomly assigned to four experiment groups. The group 1 was assigned as sham operated group. Before kidney IRI performance, the others groups were treated with saline [group 2], 150 mg/kg [group 3] or 500 mg/kg [group 4] of NAC, and the treatment were continued daily after IRI for next 3 days. At day 3, the all groups' animals were subjected for the measurements. The serum level of blood urea nitrogen [BUN] and creatinine [Cr] in the control group increased significantly [P < 0.05], and administration of NAC [150 mg/kg] decreased the serum levels of Cr and BUN. However, only the serum level of Cr decreased significantly [P < 0.05]. NAC did not improve kidney weight and damage; however, its low dose [150 mg/kg] attenuated the lung injury score [P < 0.05] when compared with the control group. No significant differences were observed in lung water content and endothelial permeability, serum levels of malondialdehyde and nitrite between the groups. Low dose of NAC as a protectant agent may protect the kidney function and lung tissue damage after kidney IRI

Effect of N-acetylcysteine on pulmonary cell death in a controlled hemorrhagic shock model in rats / Efeito da N-acetilcisteína na morte celular pulmonar em um modelo de choque hemorrágico controlado em ratos

PURPOSE: To evaluate the effect of N-acetylcysteine (NAC) combined with fluid resuscitation on pulmonary cell death in rats induced with controlled hemorrhagic shock (HS). METHODS: Two arteries (MAP calculation and exsanguination) and one vein (treatments) were catheterized in 22 anesthetized rats. Two groups of male albino rats were induced with controlled HS at 35mmHg MAP for 60 min. After this period, the RL group was resuscitated with Ringer's lactate and the RL+NAC group was resuscitated with Ringer's lactate combined with 150mg/Kg NAC. The control group animals were cannulated only. The animals were euthanized after 120 min of fluid resuscitation. Lung tissue samples were collected to evaluate the following: histopathology, TUNEL and imunohistochemical expression of caspase 3. RESULTS: RL showed a greater number of cells stained by TUNEL than RL + NAC, but there was no change in caspase 3 expression in any group. CONCLUSION: N-acetylcysteine associate to fluid resuscitation, after hemorrhagic shock, decreased cell death attenuating lung injury.

OBJETIVO: Avaliar o efeito da N-acetilcisteína (NAC) combinada ao fluido de reposição volêmica na morte celular pulmonar de ratos submetidos ao choque hemorrágico (CH) controlado. MÉTODOS: Duas artérias (cálculo da PAM e exsanguinação) e uma veia (tratamentos) foram cateterizadas em 22 ratos anestesiados. Dois grupos de ratos machos albinos foram induzidos ao CH controlado com PAM de 35mmHg por 60 min. Após este período, o grupo RL foi ressuscitado com Ringer lactato e o grupo RL+NAC foi ressuscitado com Ringer lactato associado com 150mg/Kg de NAC. O grupo controle sofreu somente o procedimento cirúrgico de cateterização. Os animais sofreram eutanásia após 120 min. da ressuscitação. Amostras de tecido pulmonar foram coletadas para histopatologia, TUNEL e a imuno-expressão da caspase 3. RESULTADOS: RL apresentou maior número de células marcadas pelo TUNEL do que RL+NAC, porém sem alteração na expressão da caspase 3 em nenhum dos grupos estudados. CONCLUSÃO: A N-acetilcisteína teve um papel protetor na morte celular em modelo de choque hemorrágico controlado.