The influence of peripheral muscle strength on prognosis after extubation and subsequent functional outcomes is not evident. The objectives of this study were to determine (1) whether peripheral ...muscle strength can be used as a predictor for patients' prognoses after extubation, and (2) whether the peripheral muscle strength before extubation is correlated with patients' subsequent ambulation ability and in-hospital mortality. This study was a prospective observational cohort study. A hand-held dynamometer was used for evaluated the muscle strength of the biceps and quadriceps right before extubation. Besides, after the patients had been transferred from the ICU to the general ward, a 2-minute walk test was performed. A total of 52 patients were enrolled in this study, and the rate of extubation failure was 15%. The muscle strength of the quadriceps was significantly correlated with the prognosis after extubation, 48% of the patients were able to ambulate after being transferred to the general ward. The overall mortality rate was 11%, and there was a significant correlation between the biceps muscle strength and in-hospital mortality. Peripheral muscle strength may serve as an important predictor of a patients' prognoses after extubation. Poor peripheral muscle strength is indicative of not only a higher risk of re-intubation but also higher in-hospital mortality and poorer functional outcomes.Trial registration: ISRCTN16370134. Registered 30 May 2019, prospectively registered. https://www.isrctn.com/ISRCTN16370134 .
Acute lung injury (ALI) is characterized by severe hypoxemia and has significantly high mortality rates. Acute hyperglycemia occurs in patients with conditions such as sepsis or trauma, among others, ...and it results in aggravated inflammation and induces damage in patients with ALI. Regulation of alveolar fluid is essential for the development and resolution of pulmonary edema in lung injury. Pulmonary sodium-potassium-chloride co-transporter 1 (NKCC1) regulates the net influx of ions and water into alveolar cells. The activation of with-no-lysine kinase 4 (WNK4), STE20/SPS1-related proline/alanine rich kinase (SPAK) and the NKCC1 pathway lead to an increase in the expression of NKCC1 and aggravation of ALI. Moreover, hyperglycemia is known to induce NKCC1 expression via the activation of the serum-glucocorticoid kinase 1 (SGK1)-NKCC1 pathway. We aim to evaluate the influence of acute hyperglycemia on the SGK1-NKCC1 pathway in ALI. ALI was induced using a high tidal volume for four hours in a rat model. Acute hyperglycemia was induced by injection with 0.5 mL of 40% glucose solution followed by continuous infusion at 2 mL/h. The animals were divided into sham, sham+ hyperglycemia, ALI, ALI + hyperglycemia, ALI + inhaled bumetanide (NKCC1 inhibitor) pretreatment, ALI + hyperglycemia + inhalational bumetanide pretreatment, and ALI + hyperglycemia + post-ALI inhalational bumetanide groups. Severe lung injury along with pulmonary edema, alveolar protein leakage, and lung inflammation was observed in ALI with hyperglycemia than in ALI without hyperglycemia. This was concurrent with the higher expression of pro-inflammatory cytokines, infiltration of neutrophils and alveolar macrophages (AM) 1, and NKCC1 expression. Inhalational NKCC1 inhibitor significantly inhibited the SGK1-NKCC1, and WNK4-SPAK-NKCC1 pathways. Additionally, it reduced pulmonary edema, inflammation, levels of pro-inflammatory cytokines, neutrophils and AM1 and increased AM2. Therefore, acute hyperglycemia aggravates lung injury via the further activation of the SGK1-NKCC1 pathway. The NKCC1 inhibitor can effectively attenuate lung injury aggravated by acute hyperglycemia.
Non-small cell lung cancers carrying epidermal growth factor receptor (EGFR) mutations respond well to EGFR tyrosine kinase inhibitors (TKIs), but patients ultimately develop drug resistance and ...relapse. Although epithelial-mesenchymal transition (EMT) can predict resistance to EGFR TKIs, the molecular mechanisms are still unknown.
To examine the role of EMT regulators in resistance to gefitinib.
The expression level of EMT regulators in gefitinib-sensitive cells (PC9) and gefitinib-resistant cells (PC9/gef) was determined using quantitative real-time reverse transcription-polymerase chain reaction and Western blot analysis. Molecular manipulations (silencing or overexpression) were performed to investigate the effects of EMT regulators on gefitinib resistance in vitro, and a xenograft mouse model was used for in vivo confirmation. In addition, cancer cells from 44 patients with malignant pleural effusions of lung adenocarcinoma were collected for analysis of EMT regulator mRNA by quantitative real-time reverse transcription-polymerase chain reaction.
Slug expression, but not that of snail, twist, or zeb-1, was significantly increased in PC9/gef compared with PC9 cells. Slug knockdown in PC9/gef cells reversed resistance to gefitinib, and overexpression of Slug in PC9 cells protected cells from gefitinib-induced apoptosis. Silencing of Slug in gefitinib-resistant cells restored gefitinib-induced apoptosis primarily through Bim up-regulation and activation of caspase-9. Slug enhanced tumor growth in a xenograft mouse model, even with gefitinib treatment. In clinical samples, Slug expression was significantly higher in cancer cells with resistance to EGFR TKIs than in treatment-naive cancer cells.
Slug contributes to the resistance to gefitinib and may be a potential therapeutic target for treating resistance to EGFR TKIs.
Axl is a cell surface receptor tyrosine kinase, and activation of the Axl attenuates inflammation induced by various stimuli. Growth arrest-specific 6 (Gas6) has high affinity for Axl receptor. The ...role of Gas6/Axl signaling in ischemia-reperfusion-induced acute lung injury (IR-ALI) has not been explored previously. We hypothesized that Gas6/Axl signaling regulates IR-induced alveolar inflammation via a pathway mediated by suppressor of cytokine signaling 3 (SOCS3).
IR-ALI was induced by producing 30 min of ischemia followed by 90 min of reperfusion in situ in an isolated and perfused rat lung model. The rats were randomly allotted to a control group and IR groups, which were treated with three different doses of Gas6. Mouse alveolar epithelium MLE-12 cells were cultured in control and hypoxia-reoxygenation (HR) conditions with or without Gas6 and Axl inhibitor R428 pretreatment.
We found that Gas6 attenuated IR-induced lung edema, the production of proinflammatory cytokines in perfusates, and the severity of ALI ex vivo. IR down-regulated SOCS3 expression and up-regulated NF-κB, and Gas6 restored this process. In the model of MLE-12 cells with HR, Gas6 suppressed the activation of TRAF6 and NF-κB by up-regulating SOCS3. Axl expression of alveolar epithelium was suppressed in IR-ALI but Gas6 restored phosphorylation of Axl. The anti-inflammatory effect of Gas6 was antagonized by R428, which highlighted that phosphorylation of Axl mediated the protective role of Gas6 in IR-ALI.
Gas6 up-regulates phosphorylation of Axl on alveolar epithelium in IR-ALI. The Gas6/Axl signaling activates the SOCS3-mediated pathway and attenuates IR-related inflammation and injury.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Extubation failure can lead to a longer intensive care unit (ICU) stay, higher mortality rate, and higher risk of requiring tracheostomy. Chest physiotherapy (CPT) can help patients in ...reducing the accumulation of airway secretion, preventing collapsed lung, improving lung compliance, and reducing comorbidities. Much research has investigated the correlation between CPT and respiratory system clearance. However, few studies have investigated the correlation between CPT and failed ventilator extubation. Therefore, this study aimed to investigate the use of CPT for reducing the rate of failed removal from mechanical ventilators.
Methods
This study was an intervention study with mechanical control. Subjects were divided into two groups. The control group, which received routine nursing chest care, was selected from a retrospective chart review. The intervention group was prospectively taken into the chest physiotherapy program. The chest physiotherapy treatment protocol consisted of inspiratory muscle training, manual hyperinflation, chest wall mobilization, secretion removal, cough function training, and early mobilization.
Results
A total of 439 subjects were enrolled in the intervention and control groups, with a mean age of 69 years. APACHE II score (P = .09) and GCS scores (P = .54) were similar between the two groups. Compared to the control group, patients in the intervention group had a significantly lower reintubation rate (8% vs 16%; P = .01).
Conclusions
The results indicate that intensive chest physiotherapy could decrease extubation failure in mechanically ventilated patients in the ICU. In addition, chest physiotherapy could also significantly improve the rapid shallow breathing index score.
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Bumetanide is a potent loop diuretic that acts as an inhibitor of sodium-potassium-chloride cotransporter 2 (NKCC2) and its isoform NKCC1. Although the expression of NKCC2 is limited ...to the kidney, NKCC1 is widely expressed in various cells, where it participates in a variety of physiological functions including ion transport, alveolar fluid secretion, and cell volume regulation. We investigated the role of NKCC1 in modulation of host immunity. Lipopolysaccharide (LPS) stimulated the expression and phosphorylation of NKCC1 in RAW264.7 cells in vitro and activated these cells to produce inflammatory cytokines. Enlarging the cell volume in a low-osmotic microenvironment amplified the LPS-induced inflammatory responses and phagocytosis activity of RAW264.7 cells. Pretreatment with the NKCC1 inhibitor bumetanide attenuated LPS-induced activation of inflammatory cells and cell volume-related function. Mice treated with an intratracheal bumetanide spray showed greater resistance to LPS-induced tissue inflammation and acute lung injury in vivo. Our studies suggest that NKCC1 plays a unique role as an amplifier of LPS-induced macrophage functions and that NKCC1 might be a novel target for treating sepsis-related acute respiratory distress syndrome.
Ischemia–reperfusion acute lung injury is characterized by increased vascular permeability, lung edema, and neutrophil sequestration. Ischemia–reperfusion acute lung injury occurs in lung ...transplantation and other major surgical procedures. Effective regulation of alveolar fluid balance is critical for pulmonary edema. Sodium-potassium-chloride co-transporter regulates alveolar fluid and is associated with inflammation. We hypothesized that sodium-potassium-chloride co-transporter is important in ischemia–reperfusion acute lung injury. Bumetanide, a sodium-potassium-chloride co-transporter inhibitor, is used to treat pulmonary edema clinically. We studied the effect of bumetanide in ischemia–reperfusion acute lung injury.
Isolated perfusion of mouse lungs in situ was performed. The main pulmonary artery and left atrium were catheterized for lung perfusion and effluent collection for recirculation, respectively, with perfusate consisting of 1 mL blood and 9 mL physiologic solution. Ischemia–reperfusion was induced by 120 minutes of ischemia (no ventilation or perfusion) and reperfused for 60 minutes. Wild-type, SPAK knockout (SPAK−/−), and WNK4 knockin (WNK4D561A/+) mice were divided into control, ischemia–reperfusion, and ischemia–reperfusion + bumetanide groups (n = 6 per group). Bumetanide was administered via perfusate during reperfusion. Measurements were taken of lung wet/dry weight, microvascular permeability, histopathology, cytokine concentrations, and activity of the nuclear factor-κB pathway.
In wild-type mice, ischemia–reperfusion caused lung edema (wet/dry weight 6.30 ± 0.36) and hyperpermeability (microvascular permeability, 0.29 ± 0.04), neutrophil sequestration (255.0 ± 55.8 cells/high-power field), increased proinflammatory cytokines, and nuclear factor-κB activation (1.33 ± 0.13). Acute lung injury was more severe in WNK4 mice with more lung edema, permeability, neutrophil sequestration, and nuclear factor-κB activation. Severity of acute lung injury was attenuated in SPAK−/−mice. Bumetanide decreased pulmonary edema (wild-type: wet/dry weight 5.05 ± 0.44, WNK4: wet/dry weight 5.13 ± 0.70), neutrophil sequestration (wild-type: 151.7 ± 27.8 cells/high-power field, WNK4: 135.3 ± 19.1 cells/high-power field), permeability (wild-type: 0.19 ± 0.01, WNK4: 0.21 ± 0.03), cytokines, and nuclear factor-κB activation after ischemia–reperfusion.
Functional reduction of sodium-potassium-chloride co-transporter by genetic or pharmacologic treatment to inhibit sodium-potassium-chloride co-transporter resulted in lower severity of acute lung injury induced by ischemia–reperfusion. Sodium-potassium-chloride co-transporter may present a promising target for therapeutic interventions in a clinical setting.
Ischemia-reperfusion (IR)-induced acute lung injury (ALI) is implicated in several clinical conditions like lung transplantation, acute pulmonary embolism after thrombolytic therapy, re-expansion of ...collapsed lung from pneumothorax or pleural effusion, cardiopulmonary bypass and etc. Because mortality remains high despite advanced medical care, prevention and treatment are important clinical issues for IR-induced ALI. Vascular endothelial growth factor (VEGF) has a controversial role in ALI. We therefore conducted this study to determine the effects of anti-VEGF antibody in IR-induced ALI. In the current study, the IR-induced ALI was conducted in a rat model of isolated-perfused lung in situ in the chest. The animals were divided into the control, control + preconditioning anti-VEGF antibody (bevacizumab, 5mg/kg), IR, IR + preconditioning anti-VEGF antibody (1mg/kg), IR+ preconditioning anti-VEGF antibody (5mg/kg) and IR+ post-IR anti-VEGF antibody (5mg/kg) group. There were eight adult male Sprague-Dawley rats in each group. The IR caused significant pulmonary micro-vascular hyper-permeability, pulmonary edema, neutrophilic infiltration in lung tissues, increased tumor necrosis factor-α, and total protein concentrations in bronchoalveolar lavage fluid. VEGF and extracellular signal-regulated kinase (ERK) were increased in IR-induced ALI. Administration of preconditioning anti-VEGF antibody significantly suppressed the VEGF and ERK expressions and attenuated the IR-induced lung injury. This study demonstrates the important role of VEGF in early IR-induced ALI. The beneficial effects of preconditioning anti-VEGF antibody in IR-induced ALI include the attenuation of lung injury, pro-inflammatory cytokines, and neutrophilic infiltration into the lung tissues.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ischemia-reperfusion (IR)-induced acute lung injury (ALI) is implicated in several clinical conditions including lung transplantation, cardiopulmonary bypass surgery, re-expansion of collapsed lung ...from pneumothorax or pleural effusion and etc. IR-induced ALI remains a challenge in the current treatment. Carbonic anhydrase has important physiological function and influences on transport of CO2. Some investigators suggest that CO2 influences lung injury. Therefore, carbonic anhydrase should have the role in ALI. This study was undertaken to define the effect of a carbonic anhydrase inhibitor, acetazolamide (AZA), in IR-induced ALI, that was conducted in a rat model of isolated-perfused lung with 30 minutes of ischemia and 90 minutes of reperfusion. The animals were divided into six groups (n = 6 per group): sham, sham + AZA 200 mg/kg body weight (BW), IR, IR + AZA 100 mg/kg BW, IR + AZA 200 mg/kg BW and IR+ AZA 400 mg/kg BW. IR caused significant pulmonary micro-vascular hyper-permeability, pulmonary edema, pulmonary hypertension, neutrophilic sequestration, and an increase in the expression of pro-inflammatory cytokines. Increases in carbonic anhydrase expression and perfusate pCO2 levels were noted, while decreased Na-K-ATPase expression was noted after IR. Administration of 200mg/kg BW and 400mg/kg BW AZA significantly suppressed the expression of pro-inflammatory cytokines (TNF-α, IL-1, IL-6 and IL-17) and attenuated IR-induced lung injury, represented by decreases in pulmonary hyper-permeability, pulmonary edema, pulmonary hypertension and neutrophilic sequestration. AZA attenuated IR-induced lung injury, associated with decreases in carbonic anhydrase expression and pCO2 levels, as well as restoration of Na-K-ATPase expression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Excessive amounts of air can enter the lungs and cause air embolism (AE)-induced acute lung injury (ALI). Pulmonary AE can occur during diving, aviation, and iatrogenic invasive procedures. ...AE-induced lung injury presents with severe hypoxia, pulmonary hypertension, microvascular hyper-permeability, and severe inflammatory responses. Pulmonary AE-induced ALI is a serious complication resulting in significant morbidity and mortality. Surfactant is abundant in the lungs and its function is to lower surface tension. Earlier studies have explored the beneficial effects of surfactant in ALI; however, none have investigated the role of surfactant in pulmonary AE-induced ALI. Therefore, we conducted this study to determine the effects of surfactant in pulmonary AE-induced ALI. Isolated-perfused rat lungs were used as a model of pulmonary AE. The animals were divided into four groups (
n
= 6 per group): sham, air embolism (AE), AE + surfactant (0.5 mg/kg), and AE+ surfactant (1 mg/kg). Surfactant pretreatment was administered before the induction of pulmonary AE. Pulmonary AE was induced by the infusion of 0.7 cc air through a pulmonary artery catheter. After induction of air, pulmonary AE was presented with pulmonary edema, pulmonary microvascular hyper-permeability, and lung inflammation with neutrophilic sequestration. Activation of NF-κB was observed, along with increased expression of pro-inflammatory cytokines, and Na-K-Cl cotransporter isoform 1 (NKCC1). Surfactant suppressed the activation of NF-κB and decreased the expression of pro-inflammatory cytokines and NKCC1, thereby attenuating AE-induced lung injury. Therefore, AE-induced ALI presented with pulmonary edema, microvascular hyper-permeability, and lung inflammation. Surfactant suppressed the expressions of NF-κB, pro-inflammatory cytokines, and NKCC1, thereby attenuating AE-induced lung injury.
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