ObjectiveTo assesse the association of an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) with the risk and the mortality of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS).
MethodsWe searched electronic databases through April 2014 for the terms "angiotensin-converting enzyme gene", "acute lung injury" and "acute respiratory distress syndrome", and reviewed all studies that reported the relationship of the I/D polymorphism in ACE with ALI/ARDS in adults. Eight studies met the inclusion criteria, comprising 498 ALI/ARDS patients, 3220 healthy controls and 1137 patients without ALI/ARDS. Three genetic models were used: the allele, dominant and recessive models. The meta-analysis was performed with RevMan 5.2 software.
ResultsThe ACE I/D polymorphism was not associated with susceptibility to ALI/ARDS compared with the healthy controls and the patient controls for any genetic model. The ACE I/D polymorphism was associated with the mortality risk of ALI/ARDS in Asian subjects, and OR was 2.99 (95% CI 1.87-4.76, P < 0.05), 0.36 (95% CI 0.20-0.67, P < 0.05), 4.62 (95% CI 1.71-12.45, P < 0.05) for allele I/D, genotype II/II+ID and genotype DD/II+ID, respectively.
ConclusionThere is a possible association between the ACE I/D polymorphism genotype and the mortality risk of ALI/ARDS in Asians.
Objective To investigate the serumlevel of endothelin-1 ( ET-1) in patients with acute lung injury/acute respiratory distress syndrome ( ALI/ARDS) and its clinical significance. Methods Thirty-one ALI/ARDS patients received mechanical ventilation in ICUand 25 normal subjects were recruited in the study. The patients who died in two weeks fell in death group, and the patients who did not died in two weeks fell in survival group. The serum level of ET-1 measured by EIA method were compared between thepatients with different severity of lung injury [ evaluated by American-European Consensus Conference on ARDS ( AECC) criteria and lung injury score( LIS) ] , and between the patients with different prognosis ( death or survival ) . The correlation was analyzed between the level of ET-1 and clinical parameters.Results The ET-1 level was higher in the ALI/ARDS patients than that in the control subjects [ ( 6. 18 ±4. 48) ng/L vs. ( 2. 68 ±1. 34) ng/L, P lt;0. 05] . There was no significant difference in the patients with different severity [ ALI vs. ARDS, ( 5. 43 ±4. 39) ng/L vs. ( 7. 01 ±4. 51) ng/L, P gt; 0. 05; LIS≤2. 5 vs.LISgt;2. 5, ( 5. 93 ±5. 21) ng/L vs. ( 6. 68 ±2. 76) ng/L, P gt; 0. 05] . The ET-1 level in the death group continued to increase, and higher than that in the survival group on the 5th day [ ( 7. 96 ±3. 30) ng/L vs.( 4. 36 ±3. 29) ng/L, P lt; 0. 05] . The ET-1 level was positively correlated with SIRS, SAPSⅡ and APACHEⅡ ( r = 0. 359, 0. 369 and 0. 426, respectively, P lt; 0. 05 ) , and negatively correlated with PaO2 /FiO2 and AaDO2 ( r = - 0. 286 and - 0. 300, respectively, P lt;0. 05) . Conclusion The measurementof serum ET-1 can help to evaluate the severity and prognosis of ALI/ARDS patients.
ObjectiveTo observe the effects of aquaporin 1 (AQP1) on the proliferation and migration of endothelial progenitor-endothelial progenitor cells (EPC).MethodsBone marrow cells of AQP1 wild-type (WT) (n=6) and knockout-type (KO) mice (n=6) were isolated and differentiated into EPC in vitro. Immunofluorescence was used to detect cell surface antigens to identify EPC. Live cell kinetic imaging and quantification technology, transwell migration assays, as well as scratch test were used to compare the function of EPC between AQP1 WT and KO mice.ResultsEPC culture showed that cells were initially suspended and gradually adhered to typical mesenchymal stem cells within 7 days. After cultured on special medium for endothelial cells they were adhered and differentiated, and fusiform or polygonal, paving stone-like EPC were observed around 14 days. When cultured by special medium of EPC, CD133 and CD31 were positively detected after 7 days, and CD34 and Flk-1 were positively detected after 14 days. Positive expression of AQP1 was only detected in EPC of AQP1 WT mice. Functional studies of EPC revealed there was no significant difference in the proliferation of EPC between AQP1 WT and KO group mice. Transwell assay showed that EPC migration ability of AQP1 KO mice was significantly weaker than that of WT mice. The scratch healing ability of EPC in AQP1 KO mice was significantly lower than that of WT mice.ConclusionsEPC initially shows the characteristics of stem cells and with the prolongation of culture time, EPC gradually shows the characteristics of endothelial cells. AQP1 affects the EPC migration rather than proliferation.
ObjectiveTo investigate the effect and mechanism of microRNA (miR)-146a-3p on acute lung injury (ALI) and inflammation induced by lipopolysaccharide (LPS) in mice.MethodsThirty-two BALB/c mice were randomly divided into sham group, ALI group, ALI+agomiR-negative control (NC) group, ALI+miR-146a-3p agonist (agomiR-146a-3p) group, with 8 mice in each group. The ALI model was established by instilling 5 mg/kg LPS into the lungs through the trachea, and the same amount of saline was instilled slowly in the sham group. The mice in the ALI+agomiR-146a-3p group/NC group were injected with 8 mg/kg agomiR-146a-3p or agomiR-NC respectively through the tail vein, once a day, for 3 days. The sham group and the model group were given the same amount of normal saline injection through the tail vein. After 24 hours, they were sacrificed and lung tissues were collected. The expressions of miR-146a-3p and toll-like receptor 4 (TLR4) mRNA in lung tissue were detected by RT-qPCR, the expression levels of TLR4, cleaved caspase-3, Bcl-2 related X protein (Bax), B cell lymphoma-2 (Bcl-2) protein in lung tissue were detected by Western blot. The changes of lung pathology were observed by hematoxylin-eosin staining. The apoptosis of lung tissue was detected by TdT-mediated dUTP nick-end labeling. The expression levels of IL-1β, IL-6 and TNF-α in lung tissue were detected by enzyme-linked immunosorbent assay (ELISA). The dual luciferase reporting system verified the targeting relationship between miR-146a-3p and TLR4 in MRC-5 cells. MRC-5 cells were divided into control group, LPS group, LPS+miR-146a-3p mimic group, LPS+pcDNA3.1(pc)-TLR4 group, LPS+miR-146a-3p mimic+pc-TLR4 group. 100 nmol/L miR-146a-3p mimic and pc-TLR4 plasmids were transfected into MRC-5 cells separately or jointly for 24 hours, and then treated with 1000 ng/mL LPS or normal saline for 72 hours. The apoptosis rate was detected by flow cytometry. The expression levels of TLR4, cleaved caspase-3, Bax, and Bcl-2 proteins were detected by Western blot. The levels of IL-1β, IL-6 and TNF-α were detected by ELISA.ResultsCompared with the ALI group, the expression of miR-146a-3p was up-regulated, the expressions of TLR4 mRNA and protein were down-regulated, the apoptotic rate was decreased, the expressions of cleaved caspase-3 and Bax protein was down-regulated, the expression of Bcl-2 protein was up-regulated, and the levels of TNF-α, IL-6 and IL-1β in lung tissue were decreased in the lung tissues of the ALI+agomiR-146a-3p group (P<0.05). Dual-luciferase reporter assay confirmed that miR-146a-3p regulates transcription by targeting TLR4 3’UTR sequence (P<0.05). Compared with the LPS group, the expression of TLR4 protein in MRC-5 cells of the LPS+miR-146a-3p mimic group was down-regulated, the apoptosis was reduced, the expressions of cleaved caspase-3 and Bax protein were down-regulated, and the levels of TNF-α, IL-6 and IL-1β in lung tissue were decreased (P<0.05). Overexpression of TLR4 reversed the effect of miR-146a-3p mimic overexpression on LPS-induced apoptosis and inflammation of MRC-5 cells (P<0.05).ConclusionmiR-146a-3p alleviates LPS-induced ALI in mice by down-regulating TLR4.
【Abstract】Objective To investigate the role of VEGF and its soluble VEGF receptor ( sVEGFR-1) in pathogenesis of acute lung injury ( ALI) induced by immersion in seawater after open chest trauma. Methods Sixteen hybridized adult dogs were randomly divided into control group and seawater group. The control group only suffered from open chest trauma, whereas the seawater group were exposed to seawater after open chest trauma. Blood samples were collected at the 0, 2, 4, 6, 8 h after trauma for measurement of white blood cell count, arterial blood gas, plasma osmotic pressure ( POP) , electrolyte concentration, IL-8, vWF, VEGF and sVEGFR-1 levels. The lungs tissue and BALF was collected at 8 h after trauma. Pathological changes of the lung was observed under light microscope by HE staining. Meanwhile VEGF and sVEGFR-1 levels were measured in BALF and lung tissue homogenate. Total protein concentrations in plasma and BALF were measured to calculate the pulmonary penetration index ( PPI) . Results The lung of the seawater group showed interstitial mononuclear cell and neutrophil infiltration, interstitial edema, and vascular congestion. VEGF and sVEGFR-1 were significantly increased in the plasma, while VEGF was significantly reduced in the lung tissues and BALF. The levels of IL-1β, IL-8 and vWF, just as the level of VEGF, were significantly increased in the plasma. Meanwhile, the POP and electrolyte concentration were significantly increased. In the plasma, the responses of VEGFs during the early onset of ALI induced by immersion in seawater after open chest trauma were consistent with the POP and PPI. Conclusions High plasma levels and low BALF/ lung tissue levels of VEGFs is a distinguishing characteristic during the early onset of ALI induced by immersion in seawater after open chest trauma. VEGF may be a novel biomarker which has an important role in the development of ALI.
Objective To observe the level of vascular endothelium growth factor A( VEGF-A) in exhaled breath condensate ( EBC) of patients with acute lung injury/acute respiratory distress syndrome ( ALI/ARDS) , and investigate its clinical significance. Methods EBC of 23 patients with ALI/ARDS by mechanical ventilation in intensive care unit ( ICU) were collected with improved EcoScreen condenser. EBC of 17 normal control subjects were collected with EcoScreen condensor. The level of VEGF-A was measured by ELISA in EBC and serum. The levels of VEGF-A in EBC of patients with different grades of lung injuries were compared, and the correlation was analyzed between the level of VEGF-A and clinical indicators. Results The level of VEGF-A in EBC was lower in the patients with ALI/ARDS than that of control subjects [ ( 49. 88 ±6. 32) ng/L vs. ( 56. 50 ±6. 323) ng/L, P lt;0. 01] , the level of VEGF-A was higher in the ALI patients than that of ARDS patients [ ( 53. 56 ±5. 56) ng/L vs. ( 45. 86 ±4. 45) ng/L, P lt;0. 01] ,and higher in the survival patients than that of the died patients [ ( 51. 92 ±6. 28) ng/L vs. ( 46. 05 ± 4. 58) ng/L, P lt;0. 05] . The level of VEGF-A in EBC was negatively correlated with lung injury score and A-aDO2 /PaO2 ( r = - 0. 426 and - 0. 510, respectively, P lt;0. 05) , and positively correlated with PaO2 /FiO2 and PaO2 ( r =0. 626 and 0. 655, respectively, P lt; 0. 05) . The level of VEGF-A in serum was not different between the ALI/ARDS patients and the control subjects, between the ALI and ARDS patients, or between the survival and the died patients ( all P gt;0. 05) . The level of VEGF-A in serumhad no correlation with lung injury score, A-aDO2 /PaO2 , PaO2 /FiO2 , or PaO2 ( all P gt;0. 05) . Conclusion The changes of VEGF-A in EBC of patients with ALI/ARDSmay serve as an indicator for severity and prognosis evaluation.
Objective To explore the role of renin-angiotensin system( RAS) in acute lung injury( ALI) /acute respiratory dysfunction syndrome( ARDS) by using amouse cecal ligation and puncture ( CLP)model.Methods The ALI/ARDS animal models were assessed bymeasuring blood gas, wet/dry lung weight ratio( W/D) , and lung tissue histology 18 hours after CLP operation. After the ALI/ARDS models was successfully established, immunohistochemistry, western blotting and radioimmunity were used to investigate the changes of several key enzymes of RAS, such as ACE, ACE2 and Ang Ⅱ. In addition, two groups of animals received a separate intraperitoneal injection of angiotensin-converting enzyme ( ACE) inhibitor captopril or recombinant mouse ACE2 ( rmACE2) after CLP, then the changes of RAS in ALI/ARDS modelswere observed. Results The extensive lung injuries can be observed in the lung tissues from CLP-treated animals 18 hours after operation. The CLP-induced ALI/ARDS led to an increase in the wet/dry weight ratio of the lung tissues, and a decrease in the PaO2 /FiO2 [ ( 194. 3 ±23. 9) mm Hg vs ( 346. 7 ±20. 5) mm Hg,P lt;0. 01] . Immunohistochemistry and western blotting tests of the lung tissues from CLP-treated animals showed a decrease in the ACE2 protein level. However, in both the CLP and sham mice there were no significant differences between the two groups. CLP markedly increased Ang Ⅱ level in lungs and plasma of mice, and RAS drugs significantly impacted the Ang Ⅱ levels of mice. Compared with the CLP group,captopril or rmACE2 led to a decrease of the Ang Ⅱ level in mice [ Lung: ( 1. 58 ±0. 16) fmol /mg,( 1. 65 ±0. 21) fmol /mg vs ( 2. 38 ±0. 41) fmol /mg; Plasma: ( 178. 04 ±17. 87) fmol /mL, ( 153. 74 ±10. 24) fmol /mL vs ( 213. 38 ± 25. 44) fmol /mL] . Conclusions RAS activation is one of the characteristics of CLP-induced ALI/ARDS in mice models. ACE and ACE2 in RAS have a different role in the regulation of AngⅡ synthesis, while ACE has a positive effect in generating AngⅡ, and ACE2 shows a negative effect.
ObjectiveTo evaluate systematically the relationship between obesity and clinical prognosis in acute respiratory distress syndrome (ARDS) patients.MethodsA systematic search was performed in Pubmed, EMBASE, Cochrane databases, Wiley, Ovid, Medline, CNKI, VIP and Wanfang. All studies that reported obesity in the clinical prognosis of ARDS and acute lung injury were included. A meta-analysis was performed using RevMan 5.0 and Stata 10.0.ResultsA total of 28 368 patients from 9 studies were included in this meta-analysis. The combined results showed that obesity was associated with the decreased mortality of ARDS [odds ratio(OR)=0.63, 95% confidence intervals (95%CI) 0.41 to 0.98, P=0.04]. In subgroup analysis, the result showed no obvious relationship between obesity and 28-day mortality in ARDS/ALI (OR=0.92, 95%CI 0.55 to 1.54, P=0.76). However, obesity was associated with lower risk of 60days and 90-day mortality in ARDS/ALI (60-day: OR=0.84, 95%CI 0.75 to 0.94, P=0.002; 90-day: OR=0.38, 95%CI 0.22 to 0.66, P=0.000 5). Compared with normal weight patients with ARDS, hospital length of stay, ICU length of stay, and duration of mechanical ventilation did not differ significantly [hospital length of stay: weighted mean difference (WMD)=3.61, 95%CI –0.36 to 7.57, P=0.07; intensive care unit (ICU) length of stay: WMD=1.52, 95%CI –0.22 to 3.26, P=0.09; duration of mechanical ventilation: WMD=–0.50, 95%CI –2.18 to 1.19, P=0.56], but ventilator-free days was significantly longer in obese patients (WMD=2.68, 95%CI 0.86 to 4.51, P=0.004).ConclusionsObesity is not associated with hospital length of stay, ICU length of stay, and duration of mechanical ventilation in patients with ARDS. However, obesity is associated with a reduction of long-term mortality and increased ventilator-free days in the patients with ARDS. Additional larger randomized controlled studies are needed to confirm the possible role of obesity in the clinical prognosis of ARDS.
Objective To investigate the effects of noninvasive ventilation for the treatment of acute respiratory failure secondary to severe acute respiratory syndrome ( SARS) . Methods 127 patients with complete information were collected from the database of SARS in Guangdong province, who were all consistent with the ALI/ARDS diagnostic criteria. The patients were divided into three groups depending on ventilation status, ie. a no-ventilation group, a noninvasive ventilation group, and a mechanical ventilation group. The outcome of ventilation treatmentwas followed up.Multi-factor regression analysis was conducted to analyze the relations of ventilation treatment with ARDS and mortality, and factors associated with success of noninvasive ventilation. Results As soon as the patients met the diagnostic criteria of ALI/ARDS, the patients in the noninvasive ventilation group were in more serious condition and had a higher proportion of ARDS compared with the no-ventilation group ( P lt;0. 01) . The patients in the mechanical ventilation group had a higher mortality rate ( P lt;0.01) . 6 and 7 patients in the no-ventilation group had noninvasive ventilation and invasive ventilation thereafter, respectively. 15 patients in the noninvasive group switched to invasive ventilation. Compared with the patients without ventilation ( n =45) , the patients receiving noninvasive ventilation ( n = 61) were in more serious condition and at higher risk of developing ARDS ( P lt;0. 01) , but the mortality was not different between them ( P gt; 0. 05) . The patients who continued to receive noninvasive ventilation ( n = 40) were in more serious condition, and at higher risk of developing ARDS compared with the patients without ventilation ( n = 45) ( P lt; 0. 01) . 15 patients in the noninvasive group who switched to invasive ventilation were older than those patients continuing noninvasive ventilation.Conclusions For SARS patients fulfilling the ALI/ARDS criteria, the patients underwent noninvasive ventilation are more severe, run a higher probability of developing ARDS from ALI. But earlier initiation of noninvasive ventilation has no impact on mortality. The patients who tolerate noninvasive ventilation can avoid intubation, especially for young patients. However, the time and indication of shifting from noninvasive ventilation to invasive ventilation should be emphasized.
ObjectiveTo estimate whether alpha 1-antitrypsin (AAT) can reduce ventilator-induced lung injury (VILI) in acute respiratory distress syndrome (ARDS) rats after mechanical ventilation.MethodsThe rats were randomly divided into 3 groups: a sham (S) group, a mechanical ventilation (V) group and a mechanical ventilation/AAT (VA) group. The rats in the S group only received anesthesia, and the rats in the V and VA groups received endotoxin to simulate ARDS followed by mechanical ventilation for 4 hours. At the beginning of ventilation, the rats in the V group received saline, and the rats in the VA group received AAT. The PaO2/FiO2 ratio and the lung wet/dry (W/D) weight ratio were tested. The total protein and neutrophil elastase concentrations and the neutrophil and macrophage counts in bronchoalveolar lavage fluid (BALF) were tested. Proinflammatory factors in BALF and intercellular cell adhesion molecule-1 (ICAM-1) and microphage inflammatoryprotein-2 (MIP-2) in the serum were also detected. Furthermore, the oxidative stress response was detected, and histological injury and apoptosis were evaluated.ResultsCompared with the S group, PaO2/FiO2 was significantly decreased in the V group and the VA group, the protein concentration in the BALF and the lung W/D weight ratio were significantly increased, the concentration of inflammatory factors in BALF and peripheral blood was significantly increased, and inflammatory cells in BALF also increased. Meanwhile, malondialdehyde (MDA) concentration, myeloperoxidase (MPO) and nicotinamide adeninedinucleotide phosphate (NADPH) activity increased significantly. The V group and VA group were severely damaged, and the number of apoptotic cells increased significantly. Compared with the V group, the PaO2/FiO2 in the VA group significantly increased; the W/D weight ratio and the BALF protein concentration decreased; the number of macrophages and neutrophils in the BALF, and the concentration of elastase significantly decreased; tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in BALF decreased, IL-10 increased; ICAM-1 and MIP-2 in peripheral blood decreased. At the same time, the MDA concentration, MPO and NADPH activities in the VA group were significantly lower than those in the V group; the tissue damage was significantly reduced, and the number of apoptosis was significantly reduced. In addition, compared with the V group, the expression of Bax, gelsolin and cleaved caspase-3 decreased in the VA group, but the expression of Bcl-2 was increased (all P<0.05).ConclusionsAAT can relieve VILI in ARDS rats. The protection conferred by AAT may be associated with the anti-inflammatory, antioxidative stress response and antiapoptotic effect of AAT.
