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Objective To investigate the effect of dexmedetom idine(DEX)on lung tissue and Ras homolog gene family member A(RhoA)/Rho kinase 1(ROCK1)signaling pathway in lung tissue of rats with ventilator-induced lung injury(VILI).Methods A VILI rat model was established and separated into control group,model group(VILI group),dexmedetomidine low and high dose groups(DEX-L,DEX-H group),and high dose dexmedetomi-dine+lysophosphatidic acid(LPA)group(DEX-H+LPA group).Determination of wet/dry mass ratio of rat lung tissue(W/D);HE staining microscopy was applied to observe morphology of lung tissue;ELISA kit was applied to detect the level of tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β)and interleukin-6(IL-6)in bronchoalveolar lavage fluid(BALF);TUNEL staining method was applied to detect lung epithelial cell death;Immunoblotting was applied to detect the expression levels of apoptosis-related proteins,and RhoA,ROCK1 pro-teins.Results DEX could reduce lung injury,lung injury score,W/D,apoptosis rate,levels of TNF-α,IL-1β,IL-6,and expression of Bax,cleaved caspase-3,RhoA,ROCK,α-SMA in VILI rats(P<0.05),while increased the expression of Bcl-2(P<0.05);LPA could aggravate lung injury and increase lung injury score,W/D,apopto-sis rate,level of TNF-α,IL-1β,IL-6 and expressions of Bax,cleaved caspase-3,RhoA,ROCK and α-SMA(P<0.05);Bcl-2 expression level was decreased(P<0.05).Conclusions Dexmedetomidine may protect rats with ventilator-induced lung injury by the inhibition of RhoA/ROCK1 signaling pathway.
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ABSTRACT Objective: To compare and analyze pulmonary function and respiratory mechanics parameters between healthy children and children with cystic fibrosis. Methods: This cross-sectional analytical study included healthy children (HSG) and children with cystic fibrosis (CFG), aged 6-13 years, from teaching institutions and a reference center for cystic fibrosis in Florianópolis/SC, Brazil. The patients were paired by age and sex. Initially, an anthropometric evaluation was undertaken to pair the sample characteristics in both groups; the medical records of CFG were consulted for bacterial colonization, genotype, and disease severity (Schwachman-Doershuk Score — SDS) data. Spirometry and impulse oscillometry were used to assess pulmonary function. Results: In total, 110 children were included, 55 in each group. In the CFG group, 58.2% were classified as excellent by SDS, 49.1% showed the ΔF508 heterozygotic genotype, and 67.3% were colonized by some pathogens. Statistical analysis revealed significant differences between both groups (p<0.05) in most pulmonary function parameters and respiratory mechanics. Conclusions: Children with cystic fibrosis showed obstructive ventilatory disorders and compromised peripheral airways compared with healthy children. These findings reinforce the early changes in pulmonary function and mechanics associated with this disease.
RESUMO Objetivo: Comparar e analisar parâmetros de função pulmonar e de mecânica respiratória entre escolares saudáveis e com fibrose cística (FC). Métodos: Estudo transversal que incluiu escolares saudáveis (GES) e com FC (GFC), com idades entre seis e 13 anos, provenientes de instituições de ensino e de um centro de referência da FC em Florianópolis/SC, Brasil, pareados por idade e sexo, respectivamente. Inicialmente, conduziu-se avaliação antropométrica para pareamento e caracterização de ambos os grupos e, no GFC, consultou-se prontuário médico para registro dos dados de colonização bacteriana, genótipo e gravidade da doença (Escore de Schwachman-Doershuk — ESD). Para a avaliação da função pulmonar, realizou-se espirometria e a avaliação da mecânica respiratória foi conduzida por meio do sistema de oscilometria de impulso. Resultados: Participaram 110 escolares, 55 em cada grupo. No GFC, 58,2% foram classificados pelo ESD como excelentes, 49,1% apresentaram genótipo ∆F508 heterozigoto e 67,3% eram colonizados por alguma patógeno. Houve diferença significativa (p<0,05) na maioria dos parâmetros de função pulmonar e de mecânica respiratória entre os grupos. Conclusões: Escolares com FC apresentaram distúrbio ventilatório obstrutivo e com comprometimento de vias aéreas periféricas, em comparação aos escolares hígidos. Esse evento reforça o início precoce da alteração de função pulmonar e de mecânica respiratória nessa enfermidade, evidenciados pelos achados desta investigação.
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ABSTRACT Background: Driving pressure has been suggested to be the main driver of ventilator-induced lung injury and mortality in observational studies of acute respiratory distress syndrome. Whether a driving pressure-limiting strategy can improve clinical outcomes is unclear. Objective: To describe the protocol and statistical analysis plan that will be used to test whether a driving pressure-limiting strategy including positive end-expiratory pressure titration according to the best respiratory compliance and reduction in tidal volume is superior to a standard strategy involving the use of the ARDSNet low-positive end-expiratory pressure table in terms of increasing the number of ventilator-free days in patients with acute respiratory distress syndrome due to community-acquired pneumonia. Methods: The ventilator STrAtegy for coMmunIty acquired pNeumoniA (STAMINA) study is a randomized, multicenter, open-label trial that compares a driving pressure-limiting strategy to the ARDSnet low-positive end-expiratory pressure table in patients with moderate-to-severe acute respiratory distress syndrome due to community-acquired pneumonia admitted to intensive care units. We expect to recruit 500 patients from 20 Brazilian and 2 Colombian intensive care units. They will be randomized to a driving pressure-limiting strategy group or to a standard strategy using the ARDSNet low-positive end-expiratory pressure table. In the driving pressure-limiting strategy group, positive end-expiratory pressure will be titrated according to the best respiratory system compliance. Outcomes: The primary outcome is the number of ventilator-free days within 28 days. The secondary outcomes are in-hospital and intensive care unit mortality and the need for rescue therapies such as extracorporeal life support, recruitment maneuvers and inhaled nitric oxide. Conclusion: STAMINA is designed to provide evidence on whether a driving pressure-limiting strategy is superior to the ARDSNet low-positive end-expiratory pressure table strategy for increasing the number of ventilator-free days within 28 days in patients with moderate-to-severe acute respiratory distress syndrome. Here, we describe the rationale, design and status of the trial.
RESUMO Contexto: Em estudos observacionais sobre a síndrome do desconforto respiratório agudo, sugeriu-se que a driving pressure é o principal fator de lesão pulmonar induzida por ventilador e de mortalidade. Não está claro se uma estratégia de limitação da driving pressure pode melhorar os desfechos clínicos. Objetivo: Descrever o protocolo e o plano de análise estatística que serão usados para testar se uma estratégia de limitação da driving pressure envolvendo a titulação da pressão positiva expiratória final de acordo com a melhor complacência respiratória e a redução do volume corrente é superior a uma estratégia padrão envolvendo o uso da tabela de pressão positiva expiratória final baixa do protocolo ARDSNet, em termos de aumento do número de dias sem ventilador em pacientes com síndrome do desconforto respiratório agudo devido à pneumonia adquirida na comunidade. Métodos: O estudo STAMINA (ventilator STrAtegy for coMmunIty acquired pNeumoniA) é randomizado, multicêntrico e aberto e compara uma estratégia de limitação da driving pressure com a tabela de pressão positiva expiratória final baixa do protocolo ARDSnet em pacientes com síndrome do desconforto respiratório agudo moderada a grave devido à pneumonia adquirida na comunidade internados em unidades de terapia intensiva. Esperamos recrutar 500 pacientes de 20 unidades de terapia intensiva brasileiras e duas colombianas. Eles serão randomizados para um grupo da estratégia de limitação da driving pressure ou para um grupo de estratégia padrão usando a tabela de pressão positiva expiratória final baixa do protocolo ARDSnet. No grupo da estratégia de limitação da driving pressure, a pressão positiva expiratória final será titulada de acordo com a melhor complacência do sistema respiratório. Desfechos: O desfecho primário é o número de dias sem ventilador em 28 dias. Os desfechos secundários são a mortalidade hospitalar e na unidade de terapia intensiva e a necessidade de terapias de resgate, como suporte de vida extracorpóreo, manobras de recrutamento e óxido nítrico inalado. Conclusão: O STAMINA foi projetado para fornecer evidências sobre se uma estratégia de limitação da driving pressure é superior à estratégia da tabela de pressão positiva expiratória final baixa do protocolo ARDSnet para aumentar o número de dias sem ventilador em 28 dias em pacientes com síndrome do desconforto respiratório agudo moderada a grave. Aqui, descrevemos a justificativa, o desenho e o status do estudo.
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ABSTRACT Objective: To assess the effect of atelectasis during mechanical ventilation on the periatelectatic and normal lung regions in a model of atelectasis in rats with acute lung injury induced by lipopolysaccharide. Methods: Twenty-four rats were randomized into the following four groups, each with 6 animals: the Saline-Control Group, Lipopolysaccharide Control Group, Saline-Atelectasis Group, and Lipopolysaccharide Atelectasis Group. Acute lung injury was induced by intraperitoneal injection of lipopolysaccharide. After 24 hours, atelectasis was induced by bronchial blocking. The animals underwent mechanical ventilation for two hours with protective parameters, and respiratory mechanics were monitored during this period. Thereafter, histologic analyses of two regions of interest, periatelectatic areas and the normally-aerated lung contralateral to the atelectatic areas, were performed. Results: The lung injury score was significantly higher in the Lipopolysaccharide Control Group (0.41 ± 0.13) than in the Saline Control Group (0.15 ± 0.51), p < 0.05. Periatelectatic regions showed higher lung injury scores than normally-aerated regions in both the Saline-Atelectasis (0.44 ± 0.06 x 0.27 ± 0.74 p < 0.05) and Lipopolysaccharide Atelectasis (0.56 ± 0.09 x 0.35 ± 0.04 p < 0.05) Groups. The lung injury score in the periatelectatic regions was higher in the Lipopolysaccharide Atelectasis Group (0.56 ± 0.09) than in the periatelectatic region of the Saline-Atelectasis Group (0.44 ± 0.06), p < 0.05. Conclusion: Atelectasis may cause injury to the surrounding tissue after a period of mechanical ventilation with protective parameters. Its effect was more significant in previously injured lungs.
RESUMO Objetivo: Avaliar o efeito da atelectasia durante a ventilação mecânica nas regiões periatelectáticas e pulmonares normais em um modelo de atelectasia em ratos com lesão pulmonar aguda induzida por lipopolissacarídeo. Métodos: Foram distribuídos aleatoriamente 24 ratos em quatro grupos, cada um com 6 animais: Grupo Salina-Controle, Grupo Lipopolissacarídeo-Controle, Grupo Salina-Atelectasia e Grupo Lipopolissacarídeo-Atelectasia. A lesão pulmonar aguda foi induzida por injeção intraperitoneal de lipopolissacarídeo. Após 24 horas, a atelectasia foi induzida por bloqueio brônquico. Os animais foram submetidos à ventilação mecânica por 2 horas com parâmetros ventilatórios protetores, e a mecânica respiratória foi monitorada durante esse período. Em seguida, foram realizadas análises histológicas de duas regiões de interesse: as áreas periatelectásicas e o pulmão normalmente aerado contralateral às áreas atelectásicas. Resultados: O escore de lesão pulmonar foi significativamente maior no Grupo Controle-Lipopolissacarídeo (0,41 ± 0,13) do que no Grupo Controle-Solução Salina (0,15 ± 0,51), com p < 0,05. As regiões periatelectásicas apresentaram escores maiores de lesão pulmonar do que as regiões normalmente aeradas nos Grupos Atelectasia-Solução Salina (0,44 ± 0,06 versus 0,27 ± 0,74, p < 0,05) e Atelectasia-Lipopolissacarídeo (0,56 ± 0,09 versus 0,35 ± 0,04, p < 0,05). O escore de lesão pulmonar nas regiões periatelectásicas foi maior no Grupo Atelectasia-Lipopolissacarídeo (0,56 ± 0,09) do que na região periatelectásica do Grupo Atelectasia-Solução Salina (0,44 ± 0,06), p < 0,05. Conclusão: A atelectasia pode causar lesão no tecido circundante após um período de ventilação mecânica com parâmetros ventilatórios protetores. Seu efeito foi mais significativo em pulmões previamente lesionados.
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Objective To investigate the effect of galectin-1 preconditioning on pyroptosis of venti-lator-induced lung injury(VILI)in mice.Methods Thirty clean grade healthy male C57BL/6 mice,aged 6-8 weeks,weighing 22-30 g,were divided into three groups by random number table method:control group(group C),VILI group(group V),and galectin-1+VILI group(group G),10 mice in each group.After endotracheal intubation,group C kept spontaneous breathing for 4 hours,groups V and G kept me-chanical ventilation for 4 hours.One hour before endotracheal intubation,groups C and V were intraperito-neally injected with normal saline 0.75 ml,and group G was intraperitoneally injected with galectin-1 3 μg.Arterial blood was collected before endotracheal intubation and after spontaneous respiration or ventilation to detect PaO2.Then mice were sacrificed and bronchoalveolar lavage fluid(BALF)was collected.Concentra-tions of IL-1β and IL-18 in BALF were detected by ELISA.Lung tissue was collected for determination of the wet weight/dry weight ratio(W/D).The expression of GSDMD,caspase-1,and caspase-11 mRNA and protein in lung tissues were detected by qRT-PCR and Western blot.Pathological changes of the lungs were observed and scored by HE staining.Results Compared with group C,PaO2 were significantly decreased,W/D,concentrations of IL-1β and IL-18 in BALF,mRNA and protein expressions of GSDMD,caspase-1 and caspase-11,and lung injury score were significantly increased in groups V and G(P<0.05).Com-pared with group V,PaO2 was significantly increased,W/D,concentrations of IL-1β and IL-18 in BALF,mRNA and protein expressions of GSDMD,caspase-1,and caspase-11,and lung injury score were signifi-cantly decreased in group G(P<0.05).Conclusion Galectin-1 can increase PaO2 in mice and reduce IL-1β and IL-18 concentration,mRNA expression and protein content of classical non-classical pyroptosis pathway related genes,and reduce VILI in mice.
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Objective To explore the impact of Jiawei Taoren Chengqi Decoction on autophagy in rats with mechanical ventilation-induced lung injury(VILI)through adenylate-activated protein kinase(AMPK)/mammalian target of rapamycin(mTOR)signaling pathway.Methods Sixty SPF male rats were randomly grouped into the sham operation group,the model group,the low-dose Jiawei Taoren Chengqi Decoction group(TCM-L group,2.85 g/kg),the high-dose Jiawei Taoren Chengqi Decoction group(TCM-H group,8.55 g/kg)and the high-dose Jiawei Taoren Chengqi Decoction + AMPK inhibitor Compound C group(TCM-H+CC group,Jiawei Taoren Chengqi Decoction 8.55 g/kg+ Compound C 250μg/kg),12 in each group.Oxygenation index(OI)was measured immediately after intubation and at 1 h,2 h and 4 h after mechanical ventilation.Bronchoalveolar lavage fluid(BALF)was collected after mechanical ventilation,levels of tumor necrosis factor(TNF)-α,interleukin(IL)-1β and IL-18 in BALF were detected by enzyme-linked immunosorbent assay(ELISA).Rats were sacrificed,and lung tissue was taken to measure the wet/dry weight(W/D)ratio.HE staining was used to observe pathological changes of lung tissue in each group of rats.Lung injury scores were carried out.Morphology of alveolar epithelial cells was observed by transmission electron microscopy.RT-qPCR was applied to detect mRNA expression levels of AMPK and mTORC1 in rat lung tissue.Western blot assay was applied to detect expression levels of AMPK,p-AMPK,mTORC1,p-mTORC1 and autophagy-related proteins in rat lung tissue.Results Compared with the sham group,the pathological damage of lung tissue was serious,lung W/D,levels of TNF-α,IL-1β and IL-18 in BALF,lung injury score,mTORC1 mRNA expression level,and p-mTORC1 protein expression were increased in the model group(P<0.05).OI values at 2 h and 4 h of mechanical ventilation,AMPK mRNA expression level,p-AMPK,LC3-II/LC3-I and Beclin-1 protein expression in lung tissue were decreased(P<0.05).Compared with the model group,the pathological damage of lung tissue was alleviated in the Chinese medicine-H group,and the trend of changes in related indexes was opposite to the above(P<0.05).Autophagosomes in alveolar epithelial cells were increased.Compound C attenuated the protective effect of Jiawei Taoren Chengqi Decoction on VILI rats(P<0.05).Conclusion Jiawei Taoren Chengqi Decoction may promote autophagy and reduce VILI in rats by activating AMPK/mTOR signaling pathway.
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Objective:To evaluate the effect of panaxydol on ventilator-induced lung injury(VILI) in mice, and the relationship with Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor E2-related factor 2 (Nrf2) signaling pathway.Methods:Fifty healthy clean-grade male C57BL/6 mice, aged 6-8 weeks, weighing 20-25 g, were divided into 5 groups ( n=10 each) using a random number table method: control group (group C), VILI group, low-dose panaxydol group (L-PX group, 5 mg/kg), medium-dose panaxydol group (M-PX group, 10 mg/kg) and high-dose panaxydol group (H-PX group, 20 mg/kg). The corresponding doses of panaxydol were intraperitoneally injected for 7 consecutive days once a day in L-PX group, M-PX group and H-PX group. The equal volume of normal saline was given instead in C group and VILI group. Only tracheotomy was performed and animals kept spontaneous breathing for 4 h in group C, and the animals were mechanically ventilated (tidal volume 30 ml/kg, respiratory rate 70 breaths/min, inspiratory/expiratory ratio 1∶2, fraction of inspired oxygen 21%) for 4 h in VILI, L-PX, M-PX and H-PX groups. Blood samples from the femoral artery were collected for arterial blood gas analysis at 4 h of ventilation, and PaO 2 was recorded. The mice were then sacrificed under deep anesthesia, and bronchoalveolar lavage fluid (BALF), lung tissues and serum samples were collected. The concentrations of TNF-α and IL-1β in BALF and serum were measured by enzyme-linked immunosorbent assay. The wet/dry lung weight (W/D) ratio was measured, the protein concentrations in BALF were measured by bicinchoninic acid assay, the pathological changes of lung tissues were examined by HE staining, lung injury was scored, and the level of ROS in lung tissues was detected by DCFH-DA fluorescence probe.The expression of Keap1 and Nrf2 in lung tissues was detected by Western blot. Results:Compared with group C, the PaO 2 was significantly decreased, the lung injury score, W/D ratio, protein concentrations in BALF and concentrations of TNF-α and IL-1β in BALF and serum were increased, the expression of Keap1 and Nrf2 was up-regulated, and the fluorescence of ROS was enhanced in the other four groups ( P<0.05). Compared with group VILI, PaO 2 was significantly increased, the lung injury score was decreased, lung W/D ratio, protein concentrations in BALF, and concentrations of TNF-α and IL-1 β in BALF and serum were decreased, and the fluorescence of ROS was weakened in L-PX, M-PX, and H-PX groups, and the expression of Keap1 was down-regulated, the fluorescence of ROS was weakened, and the expression of Nrf2 was up-regulated in M-PX and H-PX groups ( P<0.05). Compared with group L-PX, PaO 2 was significantly increased, the lung injury score, W/D ratio, protein concentrations in BALF and concentrations of TNF-α and IL-1β in BALF were decreased, the expression of Keap1 was down-regulated, and the expression of Nrf2 was up-regulated and the fluorescence of ROS was weakened in M-PX and H-PX groups ( P<0.05). Compared with group M-PX, PaO 2 was significantly increased, the lung injury score, W/D ratio, protein concentrations in BALF and concentrations of TNF-α and IL-1β in BALF were decreased, the expression of Keap1 was down-regulated, the expression of Nrf2 was up-regulated, and the fluorescence of ROS was weakened in H-PX group( P<0.05). Conclusions:Panaxydol can reduce VILI in mice, and the mechanism may be related to activation of the Keap1/Nrf2 signaling pathway and inhibition of oxidative stress.
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ICU acute respiratory distress syndrome has a high morbidity and mortality rate, and these patients usually need mechanical ventilation to maintain their respiratory function during treatment. However, improper setting of mechanical ventilation parameters may lead to ventilator-induced lung injury (VILI). In order to effectively prevent the occurrence of VILI, ARDSnet recommends the use of a protective ventilation strategy with low tidal volume and limited airway plateau pressure. However, from the perspective of ventilator energy transfer, VILI is actually the result of a combination of respiratory parameters such as tidal volume, airway pressure, and respiratory rate. The mechanical power well reflects the combined effect of the above parameters and is increasingly becoming a hot topic in clinical research. In this review paper, the definitions of mechanical energy and mechanical power were introduced, and the calculation methods of mechanical power under different respiratory modes are summarized. Moreover, the clinical studies related to mechanical power and VILI and further exploration of the safety threshold of mechanical power are reviewed. It is expected to provide new ideas for the future clinical development of personalized mechanical ventilation strategies and the effective prevention of VILI.
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Objective:To evaluate the role of heat shock transcription factor 1 (HSF1) in the endogenous protective mechanism underlying mechanical ventilator-induced lung injury (VILI) in mice and the relationship with high mobility group box 1 (HMGB1).Methods:Forty SPF healthy male C57BL/6 mice, aged 6-8 weeks, weighing 20-25 g, were divided into 4 groups ( n=10 each) by the random number table method: control group (group C), VILI group (group VILI), negative control siRNA + VILI group (group NV) and HSF1 siRNA + VILI group (group siRNA). At 48 h before mechanical ventilation, negative control siRNA 5 nmol and HSF1 siRNA 5 nmol were intratracheally injected in NV and siRNA groups respectively, and the solution was diluted to 50 μl with the sterile phosphate buffer in both groups. Group C kept spontaneous breathing for 4 h, and the rest animals were mechanically ventilated (tidal volume 35 ml/kg, respiratory rate 75 breaths/min, inspiratory/expiratory ratio 1∶2, fraction of inspired oxygen 21%) for 4 h. Blood samples from the femoral artery were collected for arterial blood gas analysis immediately after endotracheal intubation and at 4 h of ventilation, and PaO 2 was recorded. Then the mice were sacrificed under deep anesthesia to collect lung tissues and bronchoalveolar lavage fluid (BALF). The concentrations of interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and HMGB1 in BALF were determined by enzyme-linked immunosorbent assay. The pathological results were observed by hematoxylin-eosin staining, and lung injury was assessed and scored. The wet/dry (W/D) weight ratio of lung tissues was calculated. The expression of HMGB1 and HSF1 mRNA in lung tissues (by quantitative real-time polymerase chain reaction) and expression of HMGB1 and HSF1 protein in lung tissues (by Western blot) were determined. Results:Compared with group C, PaO 2 was significantly decreased at 4 h of ventilation, the concentrations of TNF-α, IL-1β and HMGB1 in BALF, W/D ratio and lung injury score were increased, and the expression of HMGB1 protein and mRNA in lung tissues was up-regulated in group VILI, group NV and group siRNA ( P<0.05 or 0.01). Compared with group VILI and group NV, PaO 2 was significantly decreased at 4 h of ventilation, the concentrations of TNF-α, IL-1β and HMGB1 in BALF, W/D ratio and lung injury score were increased, and the expression of HMGB1 protein and mRNA in lung tissues was up-regulated, and the expression of HSF1 protein and mRNA was down-regulated in group siRNA ( P<0.05 or 0.01). There was no significant difference in the parameters mentioned above between group VILI and group NV ( P>0.05). Conclusions:HSF1 is involved in the endogenous protective mechanism underlying VILI in mice, which may be related to the down-regulation of HMGB1 expression and attenuation of inflammatory responses in lung tissues.
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Objective:To evaluate the effects of GSK484 on ventilator-induced lung injury (VILI) and neutrophil extracelluar traps (NETs) in mice.Methods:Forty-eight SPF healthy male C57BL/6 mice, aged 5-6 weeks, weighing 15-20 g, were divided into 4 groups ( n=12 each) by a random number table method: spontaneous breathing group (group S), spontaneous breathing+ GSK484 intervention group (group SG), VILI group (group V), and VILI + GSK484 intervention group (group VG). The animals kept spontaneous breathing for 4 h after tracheal intubation in S and SG groups. The animals were mechanically ventilated for 4 h (tidal volume 30 ml/kg, respiratory rate 75 breaths/min, inspiratory/expiratory ratio 1∶2, positive end-expiratory pressure 0 mmHg, fraction of inspired oxygen 21%) in V and VG groups. At 3 days before developing the VILI model, GSK484 4 mg/kg was intraperitoneally injected once a day in SG and VG groups, while the equal volume of normal saline was given instead in S and V groups. Blood samples were collected from the abdominal aorta for blood gas analysis at 4 h of spontaneous breathing or mechanical ventilation, and PaO 2 was recorded. The mice were then sacrificed and bronchoalveolar lavage fluid (BALF) was collected and lung tissues were obtained for microscopic examination of the pathological changes (with a light microscope after HE staining) which were scored and for determination of wet to dry weight ratio (W/D ratio), concentrations of interleukin-1beta (IL-1β), IL-6, tumor necrosis factor-alpha (TNF-α) and myeloperoxidase (MPO) in BALF (by enzyme-linked immunosorbent assay), expression of peptidylarginine deiminase 4 (PAD4), neutrophil elastase (NE), high mobility group box 1 (HMGB1) and citrullinated-histone 3 (Cit-H3) in lung tissues (by Western blot). Results:Compared with S and SG groups, the lung injury score and W/D ratio were significantly increased, PaO 2 was decreased, concentrations of IL-1β, IL-6, TNF-α and MPO in BALF were increased, and the expression of PAD4, NE, HMGB1 and Cit-H3 in lung tissues was up-regulated in V and VG groups ( P<0.05). Compared with group V, the lung injury score and W/D ratio were significantly decreased, PaO 2 was increased, the concentrations of IL-1β, IL-6, TNF-α and MPO in BALF were decreased, and the expression of PAD4, NE, HMGB1 and Cit-H3 was down-regulated in group VG ( P<0.05). Conclusions:GSK484 can alleviate VILI in mice, and the mechanism is associated with inhibition of PAD4, reduction of the production of NETs and attenuation of inflammatory responses in lung tissues.
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RESUMEN Paciente varón de 20 años, con diagnóstico de asma conocida, llegó al departamento de emergencias de un hospital de su localidad con historia de disnea 1 d antes de la admisión. Posteriormente, se torna taquicárdico, taquipneico y cianótico, por lo que fue intubado de emergencia. En la UCI del hospital general de tercer nivel, presentó bron coespasmo grave, presiones de vía aérea elevadas durante la ventilación mecánica e hipoperfusión grave. Recibió cristaloides y norepinefrina como resucitación. Al tercer día, presentó enfisema subcutáneo, neumotórax e hipercapnia con acidosis mixta. Se decidió utilizar ventilación mecánica ultraprotectora asociada con Novalung®. Con esta estrategia, logramos reducir las presiones de la vía aérea, la PEEPi, la potencia mecánica (PM) resistiva y mejorar la hipercapnia y la acidosis. El paciente permaneció 10 d en Novalung® y mostró buena evolución posterior. Finalmente, es extubado, dado de alta de la UCI y salió del hospital en buenas condiciones.
ABSTRACT A 20-year-old male with known asthma arrived at the emergency department in the first hospital with story of shortness of breath 1 day before admission. He suddenly became tachycardic, tachypneic and cyanotic, for which he was intubated. In the tertiary care general hospital ICU, he showed severe bronchospasm, high airway pressures during mechanical ventilation (MV) and severe hypoperfusion. He received crystalloids and norepinephrine. On the third day, he developed subcutaneous emphysema, pneumo thorax and hypercapnia with mixed acidosis. We decided to use ultra-protective me chanical ventilation concomitant with Novalung®. With this strategy, we could reduce airway pressures, PEEPi, resistive mechanical power and improve hypercapnia and acidosis. The patient stayed for 10 days in Novalung® and showed good evolution. He was later extubated and discharged of ICU, leaving the hospital in good conditions.
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Resumen: Introducción: Las fuerzas mecánicas generadas durante la ventilación mecánica por la interacción entre el ventilador y el sistema respiratorio pueden dañar al pulmón en un proceso que se ha denominado lesión inducida por el ventilador. El grado de lesión se ha relacionado con la cantidad de energía transferida desde el ventilador mecánico al sistema respiratorio dentro de un periodo de tiempo determinado, denominado poder mecánico; datos experimentales basados en tomografías sugieren que el poder mecánico mayor de 12 J/min podría generar lesión. Se proyecta como otra de las variables a controlar dentro de las estrategias de protección pulmonar, determinado en estudios experimentales como un umbral de energía a partir del cual inician los cambios mecánicos en el pulmón que pueden conducir a lesión inducida por el ventilador. Material y métodos: Se realizó un estudio retrospectivo, analítico, comparativo, se incluyeron todos los pacientes con diagnóstico de neumonía por SARS-CoV-2 que requieren ventilación mecánica invasiva; en un periodo de tiempo comprendido de marzo-agosto de 2021 que ingresaron a la Unidad de Cuidados Intensivos y utilizaron el poder mecánico como variable para predecir la mortalidad. Resultados: La población estudiada se compuso de 67 pacientes; se evaluó la asociación entre el poder mecánico alto a las 48 horas y la mortalidad, se documentó que 49.25% (n = 33) de los casos que mantuvieron el poder mecánico alto en 48 horas murieron, 28.35% (n = 19) con poder mecánico alto no se asoció con mortalidad, 8.95% (n = 6) que no mantuvieron cálculo de poder mecánico alto murieron y 13.43% (n = 9) de los pacientes con poder mecánico menor a 12 J/min no murieron. Se realizó una prueba de asociación con χ2 de Pearson en la que se obtiene un valor de p = 0.105, por lo que no existe diferencia estadísticamente significativa y no se corrobora la asociación entre la mortalidad de los pacientes con poder mecánico alto (> 12 J/min) a las 48 horas. Conclusión: El poder mecánico puede considerarse como otra variable a controlar como estrategia de protección pulmonar del paciente con infección por SARS-CoV-2, basado en que la energía transmitida al pulmón tiene mayor impacto en los pacientes que reciben ventilación mecánica por un intervalo de tiempo mayor de siete días, con un promedio de estancia en la Unidad de Cuidados Intensivos 12.3 + 6.2 días y el promedio de días de ventilación mecánica invasiva 9.2 + 5.6.
Abstract: Introduction: The mechanical forces generated during mechanical ventilation by the interaction between the ventilator and the respiratory system can damage the lung in a process that has been called ventilator induced injury. The degree of injury has been related to the amount of energy transferred from the mechanical ventilator to the respiratory system within a given period of time, called mechanical power, experimental data based on tomographies suggest that mechanical power greater than 12 J/min could generate injury. It is projected as another variables to control within lung protection strategies, determining in experimental studies as an energy threshold from which mechanical changes in the lung begin that can lead to ventilator induced injury. Material and methods: A retrospective, analytical, comparative study was carried out. All patients with a diagnosis of SARS-CoV-2 pneumonia who required invasive mechanical ventilation were admitted; In a period of time between March-August 2021, they were admitted to the intensive care unit and used mechanical power as a variable to predict mortality. Results: The studied population consisted of 67 patients; the association between high mechanical power at 48 hours and mortality was evaluated, it was documented that 49.25% (n = 33) of the patients who maintained high mechanical power in 48 hours died, 28.35% (n = 19) with power high mechanical was not associated with mortality, 8.95% (n = 6) who did not have high mechanical power calculation died and 13.43% (n = 9) of patients with mechanical power less than 12 J/min survived. An association test was performed with Pearson's χ2 in which a p value of 0.105 was obtained, so there is no statistically significant difference and the association between the mortality of the patients is not corroborated. with high mechanical power (> 12 J/min) at 48 hours. Conclusion: Mechanical power can be considered as another variable to control as a lung protection strategy for patients with SARS-CoV-2 infection, based on the fact that the energy transmitted to the lung has a greater impact on patients who receive mechanical ventilation for an interval time greater than seven days, with an average stay in the intensive care unit 12.3 + 6.2 days and the average days of invasive mechanical ventilation 9.2 + 5.6.
Resumo: Introdução: As forças mecânicas geradas durante a ventilação mecânica pela interação entre o ventilador e o sistema respiratório podem lesar o pulmão em um processo que tem sido chamado de lesão induzida pelo ventilador. O grau de lesão tem sido relacionado à quantidade de energia transferida do ventilador mecânico para o sistema respiratório em um determinado período de tempo, denominado potência mecânica. Dados experimentais baseados em tomografia sugerem que potência mecânica superior a 12 J/min pode gerar lesão. Ele é projetado como mais uma das variáveis a serem controladas dentro das estratégias de proteção pulmonar, determinando em estudos experimentais como um limiar de energia a partir do qual se iniciam as alterações mecânicas no pulmão que podem levar à lesão induzida pelo ventilador. Material e métodos: Realizou-se um estudo retrospectivo, analítico e comparativo, foram admitidos todos os pacientes com diagnóstico de pneumonia por SARS-CoV-2 que necessitaram de ventilação mecânica invasiva; em um período de março a agosto de 2021 que foram internados na unidade de terapia intensiva e utilizaram a potência mecânica como variável para predizer mortalidade. Resultados: A população do estudo foi composta por 67 pacientes; Foi avaliada a associação entre alta potência mecânica em 48 horas e mortalidade, foi documentado que 49.25% (n = 33) dos pacientes que mantiveram potência mecânica alta em 48 horas morreram, 28.35% (n = 19) com potência mecânica alta não foi associado à mortalidade, 8.95% (n = 6) que ñao mantiveran o calculo de alta potencia mecanoca morreram e 13.4% (n = 9) dos pacientes com potencia mecanica menor que 12 J/min nao morreram. Realizou-se um teste de associação com o χ2 de Pearson, no qual se obtém um valor de p de 0.105, portanto não há diferença estatisticamente significante e a associação entre mortalidade do paciente não é corroborada com alta potência mecânica (> 12 Joul/min) em 48 horas. Conclusão: A potência mecânica pode ser considerada mais uma variável a ser controlada como estratégia de proteção pulmonar para pacientes com infecção por SARS-CoV-2, tendo em vista que a energia transmitida ao pulmão tem maior impacto em pacientes que recebem ventilação mecânica por um intervalo de tempo superior a 7 dias, com média de permanência na unidade de terapia intensiva 12.3 + 6.2 dias e média de dias de ventilação mecânica invasiva 9.2 + 5.6.
Résumé
Resumen Introducción: La pandemia por SARS-CoV-2 ha inspirado intriga sobre la respuesta inmune a dicho virus, especialmente en pacientes graves con síndrome de dificultad respiratoria aguda (SDRA). Este estudio describe el comportamiento de la respuesta inmune, la inmunosupresión y sus desenlaces en los pacientes con ventilación mecánica (VM). Material y métodos: Cohorte prospectiva. Del 23 de marzo al 31 de diciembre de 2020 se recolectó información basal, parámetros ventilatorios, gasométricos y estudios de laboratorio de todos los pacientes mayores de 18 años que recibieron VM por COVID-19 con registros hasta el día 15 de VM. Se dividieron los grupos en pacientes vivos a los 90 días y defunciones. Resultados: Registramos 218 pacientes, con mortalidad de 23%. En el día 1 de VM, los pacientes no presentaron diferencias en conteos celulares o reactantes de fase aguda, excepto dímero D de 1,020 (705-1,711) vs 1,328 (940-2,340) ng/dL p = 0.035. En el análisis de regresión lineal de efectos mixtos se observaron diferencias cronológicas estadísticamente significativas en leucocitos y proteína C reactiva (PCR) concordante con la elevación de la presión de distensión alveolar (PDalv). No se encontró asociación con mortalidad en el uso de tocilizumab 2.20 (0.279-17.358) y corticosteroides 0.54 (0.229-1.273) en riesgos proporcionales de Cox al día 1 de VM. Durante los 15 días de VM los pacientes que fallecieron recibieron dosis más altas de corticosteroides, dosis mayores de 150 mg/día equivalente a prednisona se asocian a mortalidad. Conclusiones: Existe evolución cronológica similar en elevación de PCR, leucocitos y elevación de la PDalv, las cuales se explican por la disminución de la distensibilidad pulmonar estática (Cstat) y la presión positiva al final de la espiración total (PEEP total). El uso de tocilizumab no tuvo asociación con la mortalidad y dosis equivalentes a prednisona entre 100-150 mg/día se asocian a mejores resultados.
Abstract Introduction: The SARS-CoV-2 pandemic has inspired interest in the immune response to the virus, especially in severe patients with acute respiratory distress syndrome (ARDS). The study describes the behaviour of the immune response, immune suppression, and their results in patients under mechanical ventilation (MV). Material and methods: Prospective cohort. From March 23rd to December 31st, 2020, we recollected basal information, MV parameters, blood gas analysis and laboratory studies of all the patients over 18 years who received MV secondary to COVID-19. We registered 15 continuous days of MV. We divided the groups in patients alive at day 60 and deaths. Results: We included 218 patients with a mortality of 23%. In day 1 of MV, the patients didn't have any differences in cell counts or acute phase reactants, except for D Dimer (705-1,711) vs 1,328 (940-2,340) ng/dL p = 0.035. In mixed effects linear regressions, we found statistically significant chronological differences in C reactive protein (CPR) and leucocyte count, concordant with the elevation of the driving pressure (DP). In the Cox regression we found no association with tocilizumab and corticosteroids with mortality on day 1 of MV. Patients who died received higher doses of corticosteroids throughout the 15 days of MV, with doses equivalent to prednisone over 150 mg/day are associated with mortality. Conclusions: There is a similar chronological behaviour in the elevation of acute phase reactants and the elevation con DP with no elevation of Vt, which can be explained by the drop of total PEEP and Cstat. There was no association with the use of tocilizumab and mortality, and a dose of 100-150 mg/día of equivalent of prednisone was associated with better results.
Resumo Introdução: A pandemia de SARS-CoV-2 inspirou intrigas sobre a resposta imune ao referido vírus, especialmente em pacientes gravemente doentes com síndrome do desconforto respiratório do adulto (SDRA). Este estudo descreve o comportamento da resposta imune, imunossupressão e seus desfechos em pacientes em ventilação mecânica (VM). Material e métodos: Coorte prospectiva. De 23 de março a 31 de dezembro de 2020, foram coletadas informações basais, parâmetros ventilatórios e gasométricos e estudos laboratoriais de todos os pacientes maiores de 18 anos que receberam VM para COVID-19 com registros até o dia 15 de VM. Os grupos foram divididos em pacientes vivos em 90 dias e óbitos. Resultados: Registramos 218 pacientes, com mortalidade de 23%. No dia 1 de VM, os pacientes não apresentaram diferenças na contagem de células ou reagentes de fase aguda, exceto dimero D 1020 (705-1711) vs 1328 (940-2340) ng/dL p = 0.035. Na análise de regressão linear dos efeitos mistos, observam-se diferenças cronológicas estatisticamente significativas nos leucócitos e na proteína C reativa (PCR), consistentes com o aumento da pressão de distensão alveolar (PDalv). Não foi encontrada associação com mortalidade no uso de tocilizumab 2.20 (0.279-17.358) e corticoide 0.54 (0.229-1.273) nos riscos proporcionais de COX no 1o dia de VM. Durante os 15 dias de VM, os pacientes que foram a óbito receberam doses maiores de corticosteróides, doses a partir de 150 mg/dia equivalentes a prednisona estão associadas à mortalidade. Conclusões: Há evolução cronológica semelhante em PCR e leucócitos elevados e PDalv elevados, explicados pela diminuição da complacência pulmonar estática (Cstat) e da pressão positiva ao final da expiração total (PEEPtotal). O uso de tocilizumab não foi associado à mortalidade e doses equivalentes à prednisona entre 100-150 mg/dia estão associadas a melhores resultados.
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Objective:To investigate differential expression gene (DEG) in mice with ventilator-induced lung injury (VILI) by bioinformatics analysis, and to verify the key genes by reproducing the VILI mouse model.Methods:① Experiment 1 (bioinformatics analysis): the microarray dataset of GSE9368 and GSE11662 regarding VILI mice and those in the spontaneous breathing control group were downloaded from the gene expression omnibus (GEO) database. DEG obtained by R and Venn map was further used to obtain common DEG. DAVID online database was used to obtain gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Finally, the protein-protein interaction (PPI) analysis of common DEG was carried out by using Search Tool for the Retrieval of Interacting Genes Database (STRING) and the key genes were screened out by using CytoScape software, molecular complex detection (MCODE) analysis plug-in and CytoHubba plug-in with maximum cluster centrality (MCC), maximum neighbor connectivity (MNC) and degree. ② Experiment 2 (related protein verification): VILI mouse model was reproduced by high tidal volume (20 mL/kg) ventilator. Spontaneous breathing control group was set up. Hematoxylin-eosin (HE) staining was performed to assess lung injury and the key genes screened in experiment 1 were verified by immunohistochemical staining.Results:① Experiment 1 results: a total of 114 DEG were screened from GSE9368 dataset, including 99 up-regulated genes and 15 down-regulated genes. A total of 258 DEG were screened from GSE11662 dataset, including 188 up-regulated genes and 70 down-regulated genes. Furthermore, 66 common DEG were obtained, including 61 up-regulated genes and 5 down-regulated genes. GO analysis showed that the common DEG were mainly involved in inflammatory response, immune response, leukocyte and neutrophil chemotaxis. KEGG analysis showed that the common DEG were involved cell adhesion, cytokine receptor interaction and tumor necrosis factor (TNF) signaling pathway. STRING and CytoScape analysis were used to construct gene PPI network diagram and important sub modules. And the CytoHubba plug-in with MCC, MNC and degree algorithms was used to perform topology analysis and then taken an intersection to obtain eight genes including suppressor of cytokine signaling 3 (SOCS3), interleukin-1β (IL-1β), matrix metalloproteinase-9 (MMP-9), integrin Itgam, CXC chemokine ligand 2 (CXCL2), CXC chemokine receptor 2 (CXCR2), Sell and CC chemokine receptor 1 (CCR1). ② Experiment 2 results: a mouse model of high tidal volume VILI was reproduced. Compared with the spontaneous breathing control group, the lung tissue was injured slightly at 0 hour after the end of ventilation, and the lung tissue structure was significantly damaged at 6 hours after the end of ventilation, showing bleeding in alveolar cavity, significant increase and collapse of alveolar wall thickness, and infiltration of inflammatory cells. The top three genes from intersection and topological analysis including IL-1β, SOCS3 and MMP-9 were verified by immunohistochemical staining. The results showed that the expressions of IL-1β, SOCS3 and MMP-9 were gradually increased with time of ventilation, the differences were found at 6 hours as compared with those in the spontaneous breathing control group [IL-1β (integral A value): 8.40±2.67 vs. 5.10±0.94, SOCS3 (integral A value): 9.74±1.80 vs. 5.95±1.31, MMP-9 (integral A value): 11.45±6.20 vs. 5.36±1.28, all P < 0.05]. Conclusion:Bioinformatics analysis based on GSE9368 and GSE11662 data sets found that VILI is mainly related to inflammatory injury, cytokines and immune cell infiltration; IL-1β, SOCS3 and MMP-9 might be biomarkers of VILI.
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Objective:To evaluate the effect of irisin on the alveolar macrophage polarization in a rat model of ventilator-induced lung injury (VILI).Methods:Thirty SPF healthy adult male Sprague-Dawley rats, aged 6-8 weeks, weighing 200-250 g, were divided into 3 groups ( n=10 each) using a random number table method: control group (group C), VILI group (group V) and irisin group (group I). The rats were mechanically ventilation (tidal volume 20 ml/kg, respiratory rate 80 times/min, inhaled oxygen concentration 21%, inspiratory/expiratory ratio 1∶2, positive end-expiratory pressure 0) for 4 h to develop VILI model.Group C kept spontaneous breathing for 4 h. Irisin 1 μg/kg was injected via the tail vein at 30 min before tracheal intubation in group I, while the equal volume of normal saline was given instead in the other groups.The rats were sacrificed at 4 h of mechanical ventilation, the lung tissues were removed for examination of pathological changes which were scored and for determination of wet to dry weight ratio (W/D ratio), and bronchoalveolar lavage fluid (BALF) was collected for determination of concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and IL-10 (by enzyme-linked immunosorbent assay), expression of inducible nitric oxide synthase (iNOS), argininase 1 (Arg-1), and phosphorylated nuclear factor kappa B (p-NF-κB) p65 and p-NF-κB p50 in alveolar macrophages (by Western blot), and percentage of M1 and M2 alveolar macrophages and M1/M2 ratio (by flow cytometry). Results:Compared with group C, the W/D ratio, lung injury score, and concentrations of IL-6, TNF-α and IL-10 in BALF were significantly increased, the expression of iNOS, Arg-1, p-NF-κB p65 and p-NF-κB p50 was up-regulated, and the percentage of M1 and M2 alveolar macrophages and M1/M2 ratio were increased in group V and group I ( P<0.05). Compared with group V, the W/D ratio, lung injury score, and concentrations of IL-6 and TNF-α in BALF were significantly decreased, the expression of iNOS and p-NF-κB p65 was down-regulated, the percentage of M1 alveolar macrophages and M1/M2 ratio were decreased ( P<0.05), and no significant change was found in levels of IL-10 and Arg-1 in BALF, percentage of M2 alveolar macrophages and expression of p-NF-κB p50 in group I ( P>0.05). Conclusions:The mechanism by which irisin reduces VILI may be related to inhibition of NF-κB signaling pathway activation and reduction of alveolar macrophage polarization to M1 phenotype in rats.
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Maintenance of spontaneous effort during mechanical ventilation has long been recognized to improve oxygenation. Such effort has been considered beneficial because oxygenation is a key management aim. However, accumulating evidence indicates that spontaneous effort during mechanical ventilation may cause or worsen acute lung injury. Recently, effort-dependent lung injury has been termed as patient-self inflicted lung injury (P-SILI). This paper describes pathophysiological changes of ventilation-induced lung injury (VILI) induced by mechanical ventilation and spontaneous breathing, and the role of spontaneous breathing during mechanical ventilation in acute respiratory distress syndrome (ARDS). Studies have shown that spontaneous breathing is a double-edged sword, depending on the intensity of spontaneous breathing activity and the severity of lung injury. Future studies are needed to determine ventilator strategies minimizing injury.
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Objective:To evaluate the role of cathepsin B (CTSB) in mechanical ventilator-induced lung injury (VILI) in rats and the relationship with NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome.Methods:Thirty-six SPF-grade healthy male Sprague-Dawley rats, aged 6-8 weeks, weighing 220-300 g, were divided into 3 groups ( n=12 each) by the random number table method: control group (group C), VILI group (group V) and VILI + CA074-me group (group Me). CA074-me 5 mg/kg was intraperitoneally injected in group Me, while the equal volume of normal saline was given instead in group C and group V. Group C kept spontaneous breathing for 4 h, and the animals were mechanically ventilated (tidal volume 20 ml/kg, respiratory rate 80 breaths/min, fraction of inspired oxygen 21%, PEEP 0 cmH 2O). Blood samples from femoral artery were collected for arterial blood gas analysis before tracheal intubation and after spontaneous breathing or ventilation, and PaO 2 was recorded.Rats were sacrificed, and bronchoalveolar lavage fluid (BALF) was collected and lung tissues were collected for determination of the wet/dry lung weight ratio (W/D ratio), serum interleukin-1beta (IL-1β) and IL-18 concentrations in BALF (by enzyme-linked immunosorbent assay), expression of CTSB, NLRP3, apoptosis-associated speck-like protein containing a caspase-1 recruitment domain (ASC) and caspase-1 mRNA in lung tissues (quantitative real-time polymerase chain reaction), and expression of CTSB, NLRP3, ASC and caspase-1 in lung tissues (by Western blot) and for microscopic examination of the pathological changes (using HE staining). Lung injury was assessed and scored. Results:Compared with group C, PaO 2 was significantly decreased after the end of ventilation, the lung injury score, W/D ratio and concentrations of IL-1β and IL-18 in serum and BALF were increased, and the expression of CTSB, NLRP3, ASC and caspase-1 protein and mRNA in lung tissues was up-regulated in group V and group Me ( P<0.01). Compared with group V, PaO 2 was significantly increased after the end of ventilation, the lung injury score, W/D ratio and concentrations of IL-1β and IL-18 in serum and BALF were decreased, and the expression of CTSB, NLRP3, ASC and caspase-1 protein and mRNA in lung tissues was down-regulated in group Me ( P<0.01). Conclusions:CTSB is involved in VILI in the rats, and the mechanism may be related to activation of NLRP3 inflammasomes.
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Objective:To evaluate the effects of dexmedetomidine on alveolar epithelial barrier function in rats with ventilator-induced lung injury (VILI), and the role of protein kinase C (PKC).Methods:One hundred clean-grade male Sprague-Dawley rats, weighing 270-320 g, aged 4-5 months, were divided into 5 groups ( n=20 each) using a random number table method: control group (group C), VILI group (group V), PKC inhibitor group (group B), dexmedetomidine group (group D), and dexmedetomidine plus PKC agonist group (DP group). The VILI model was developed by mechanical ventilation with a tidal volume of 40 ml/kg for 4 h in anesthetized animals.Group C breathed air autonomously for 4 h without mechanical ventilation.Group V was mechanically ventilated for 4 h. In group B, bisindolvlmaleimide I 0.12 mg/kg was injected intramuscularly 1 h before mechanical ventilation.In D and DP groups, dxmedetomidine 5.0 μg/kg was injected intravenously at 20 min before mechanical ventilation, and dexmedetomidine was intravenously infused at the rate of 5.0 μg·kg -1·h -1 during mechanical ventilation.In group DP, PKC agonist phorbol-12-myristic acid-13-acetate 15 μg/kg was intraperitoneally injected at 30 min before mechanical ventilation.At 4 h of mechanical ventilation, oxygenation index (OI), lung permeability index (LPI) and wet/dry lung weight (W/D) ratio were measured, the pathological changes of lung tissues were observed, and lung injury was assessed and scored.The expression of PKC, occludin and ZO-1 protein was detected by Western blot, and the expression of PKC mRNA, occludin mRNA and ZO-1 mRNA was determined by real-time polymerase chain reaction. Results:Compared with group C, OI was significantly decreased, LPI, W/D ratio and lung injury score were increased, the expression of PKC protein and mRNA was up-regulated, and the expression of occludin and ZO-1 protein and mRNA was down-regulated in V and DP groups ( P<0.05), and no significant change was found in the parameters mentioned above in B and D groups ( P>0.05). Compared with group V, OI was significantly increased, LPI, W/D ratio and lung injury score were decreased, the expression of PKC protein and mRNA was down-regulated, and the expression of occludin and ZO-1 protein and mRNA was up-regulated in B, D and DP groups ( P<0.05). Compared with group D, OI was significantly decreased, LPI, W/D ratio and lung injury score were increased, the expression of PKC protein and mRNA was up-regulated, and the expression of occludin and ZO-1 protein and mRNA was down-regulated in group DP ( P<0.05). Conclusions:Dexmedetomidine can reduce the damage to alveolar epithelial barrier function in rats with VILI, and the mechanism is related to inhibition of PKC activation and up-regulation of the expression of occludin and ZO-1.
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Objective:To evaluate the role of transient receptor potential vanilloid receptor 1 (TRPV1)/nuclear factor-κB (NF-κB) signaling pathway in dexmedetomidine-induced alleviation of ventilator-induced lung injury (VILI) in rats.Methods:One hundred clean-grade healthy male Sprague-Dawley rats, weighing 270-320 g, aged 4-5 months, were divided into 5 groups ( n=20 each) using a random number table method: control group (group C), VILI group (group V), AMG9810 group (group A), dexmedetomidine group (group D), and dexmedetomidine + RTX group (group DR). VILI model was prepared by mechanical ventilation with a tidal volume of 40 ml/kg for 4 h. In group A, TRPV1 inhibitor AMG9810 30 mg/kg was intraperitoneally injected at 1 h before mechanical ventilation.Dexmedetomidine 5.0 μg/kg was intravenously infused at 20 min before mechanical ventilation, and dexmedetomidine was intravenously infused at the rate of 5.0 μ g·kg -1·h -1 during ventilation in group D and group DR.In group DR, RTX 70 μ g/kg was intraperitoneally injected for 3 consecutive days before mechanical ventilation.At 4 h of mechanical ventilation, the concentrations of interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and IL-6 in bronchoalveolar lavage fluid (BALF) were detected, oxygenation index (OI) and wet/dry lung weight (W/D) ratio were measured, the histopathological changes of lung tissues were observed, and lung injury was assessed and scored.The expression of TRPV1 and NF-κB in lung tissues was detected by Western blot, and real-time polymerase chain reaction was used to detect the expression of TRPV1 and NF-κB mRNA. Results:Compared with group C, the concentrations of IL-1β, TNF-α and IL-6 in BALF were significantly increased, OI was decreased, the W/D ratio and lung injury scores were increased, and the expression of TRPV1 and NF-κB protein and mRNA was up-regulated in group V ( P<0.05). Compared with group V, the concentrations of IL-1β, TNF-α and IL-6 in BALF were significantly decreased, OI was increased, the W/D ratio and lung injury scores were decreased, and the expression of TRPV1 and NF-κB protein and mRNA was down-regulated in A, D and DR groups ( P<0.05). Compared with group D, the concentrations of IL-1β, TNF-α and IL-6 in BALF were significantly increased, OI was decreased, the W/D ratio and lung injury scores were increased, and the expression of TRPV1 and NF-κB protein and mRNA was up-regulated in group DR ( P<0.05). Conclusions:The mechanism by which dexmedetomidine alleviates VILI is partially related to inhibition of the activation of TRPV1/NF-κB signaling pathway and inhibition of the inflammatory responses in lung tissues of rats.
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Resumen La neumonía intersticial aguda, también conocida como síndrome de Hamman-Rich, se caracteriza por la presencia de insuficiencia respiratoria aguda, hallazgo imagenológico de infiltrados difusos bilaterales del parénquima pulmonar y daño alveolar difuso en histopatología pulmonar. Es una patología con una mortalidad mayor al 50% debido a la falta de una terapia específica más allá del manejo sintomático y soporte ventilatorio. Se expone el caso de un paciente masculino de 56 años quien se presenta con síntomas respiratorios inespecíficos, deterioro progresivo de la oxigenación y hallazgo de opacidades en vidrio esmerilado difusas bilaterales. Además, biopsia pulmonar en la que se evidencia daño alveolar difuso en fase fibroproliferativa en quien se descarta proceso infeccioso, enfermedades autoinmunes y toxicidad medicamentosa, por lo que se hace el diagnóstico. Recibió manejo con pulsos de metilprednisolona con recuperación completa del cuadro. MÉD.UIS.2021;34(3): 103-8.
Abstract Acute interstitial pneumonitis, also known as Hamman Rich syndrome, characterised by acute respiratory failure, bilateral lung infiltrates on radiographs and diffuse alveolar damage (DAD) on lung histopathology, is an exclusion diagnosis which requires a complete study of other possible etiologies of DAD. It is a pathology with a mortality greater than 50% due to not having a specific therapy beyond symptomatic management and ventilatory support. We present a case of a 56 year old male with respiratory symptoms, who has progressive worsening oxygen levels and bilateral ground glass opacities on chest images. Lung biopsy with diffuse alveolar damage, infection, autoimmune diseases, and drug adverse reaction were ruled out. Managed with mechanical ventilation and high dose systemic corticoids with complete recovery. MÉD.UIS.2021;34(3): 103-8.