【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 investigate whether p38 mitogen activated protein kinase (p38MAPK) inhibitor can reduce acute lung injury (ALI) caused by lipopolysaccharide (LPS) by regulating Th17/Treg balance. Methods Balb/c mice were randomly divided into a control group, an ALI group and an intervention group. The mice in the control group were injected with phosphate-buffered saline, the mice in the ALI group were intraperitoneally injected with 40 mg/kg LPS, and the mice in the intervention group were injected with SB203580 (0.5 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg) intraperitoneally 1 h prior to the intraperitoneal injection of LPS. All mice were killed on 12 h later respectively. Hematoxylin-eosinstin staining was used to observe the pathological changes of lung tissue, and cell classification, counting, and total protein levels in bronchoalveolar lavage fluid (BALF) were detected. Transcript expression of forkhead box p3 (Foxp3) and retinoic acid receptor-related orphan receptor-γt (RORγt) was detected by real-time polymerase chain reaction. Interleukin (IL)-6, IL-10, IL-17, IL-23 and transforming growth factor-β (TGF-β) in lung tissue and IL-6, tumor necrosis factor-α (TNF-α) in serum were measured by enzyme-linked immunosorbent assay. The Th17 and Treg subset distribution in spleen was determined by flow cytometry. Results Histopathological examination showed that LPS induced inflammatory cell infiltration in lung tissue, increased cell count and protein levels in BALF (P<0.05), and increased proportion of neutrophils and monocytes in the ALI mice. SB203580 significantly attenuated tissue injury of the lungs in LPS-induced ALI mice. Serum levels of IL-6 and TNF-α in the ALI group were significantly higher than those in the control group, and inflammatory cytokines were decreased after SB203580 intervention. Compared with the ALI group, the production of inflammatory cytokines associate with Th17, including IL-17, IL-23, RORγt was inhibited, and the production of cytokines associate with Treg, such as IL-10 and Foxp3 in lung tissue was increased in the intervention group in a concentration-dependent manner with SB203580. After SB203580 intervention, Th17/Treg ratio was significantly decreased compared with the LPS group (P<0.05). Conclusion p38MAPK inhibitor can reduce LPS-induced ALI by regulating the imbalance of Treg cells and Th17 cells.
Objective To investigate the changes in osteoprotegerin (OPG) / receptor activator of nuclear factor-κB ligand (RANKL) ratio in sepsis-associated acute lung injury (SA-ALI) and the role of regulation of this ratio on the inflammatory response in SA-ALI. Methods Eighteen C57BL/6 male mice were randomly divided into sham operation group, cecal ligation and perforation (CLP) group and RANKL group, with 6 mice in each group. Before the experiment, the RANKL group was intraperitoneally injected with 5 μg (0.2 mL) of recombinant RANKL antibody, whereas both the sham operation group and the CLP group were intraperitoneally injected with a volume-matched normal saline. One hour later, the sham operation group underwent only abdominal exploration and repositioning, while the other groups underwent the CLP surgery to induce the SA-ALI model. After 24 h of modelling, all mice were sacrificed and samples were collected. Pathological evaluation of lung tissues was performed by haematoxylin-eosin staining; enzyme-linked immunosorbent assay was used to detect serum concentrations of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β; while the mRNA and protein expression of OPG and RANKL, along with their ratio values, were detected by real-time polymerase chain reaction for quantitative analysis and protein immunoblotting. Results The SA-ALI mouse model was successfully established. Compared with the sham operation group, mice in the CLP group showed disturbed alveolar structure, obvious alveolar and interstitial haemorrhage and inflammatory cell infiltration, elevated serum levels of IL-6, TNF-α and IL-1β (P<0.05), significantly increased mRNA and protein expression of OPG and elevated OPG/RANKL ratio in lung tissue (P<0.05), whereas RANKL mRNA and protein expression was significantly decreased (P<0.05). Compared with the CLP group, the pathological damage of lung tissue in the RANKL group was reduced, the infiltration of alveolar and interstitial inflammatory cells was significantly improved, and the alveolar structure and morphology were more regular, with lower serum levels of IL-6, TNF-α and IL-1β (P<0.05), significantly lower mRNA and protein expression of OPG and OPG/RANKL ratio in lung tissue (P<0.05), and significantly higher mRNA and protein expression of RANKL in lung tissue (P<0.05). Conclusion The alteration of OPG/RANKL ratio may be related to the pathophysiological process of SA-ALI, and the decrease in its level may reflect the attenuation of the inflammatory response in SA-ALI.
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 explore the anti-inflammatory mechanism of the proteasome inhibitor MG-132 on rats with acute lung injury (ALI). Methods54 male SD rats were randomly divided into a control group,an ALI group,and a MG-132 group. LPS (5 mg/kg) was injected via tail vein in the ALI group and the MG-132 grouop,while the normal saline was given instead in the control group. MG-132 (10 mg/kg) was injected intraperitoneally at 30 min before LPS administration in the MG-132 group. Six rats in each group were sacrificed at 2,4,and 8h after normal saline or LPS administration. Then the following parameters were observed including pathology changes of lung tissue,wet to dry weight ratio of lung tissue (W/D),the levels of ICAM-1 and TNF-α in bronchoalveolar lavage fluid (BALF) by ELISA,and the protein level of nuclear factor-kappa B P65 (NF-κB P65) in lung tissue by Western blot. ResultsThe pathological observation showed the typical ALI performance,as obvious pulmonary tissue congestion,edema,a large number of inflammatory cells infiltration in the ALI group. These inflammatory performance were obviously alleviated in the MG-132 group. Compared with the control group,the W/D,the levels of ICAM-1 and TNF-α in BALF,and the expression of the protein NF-κB P65 in lung tissue at 2,4 and 6h in the ALI group were significantly increased(P<0.05). Above parameters were significantly decreased in the MG-132 group compared with the ALI group. The expression of the protein NF-κB P65 was significantly positively related with the levels of ICAM-1 and TNF-α in BALF(P<0.01). ConclusionMG-132 can suppress inflammatory response in endotoxin-induced acute lung injury,which may be related to inhibition of NF-κB activation.
Objective To investigate the effects of different levels of intra-abdominal pressure ( IAP) on respiration and hemodynamics in a porcine model of acute lung injury( ALI) .Methods A total of 8 domestic swine received mechanical ventilation. Following baseline observations, oleic acid 0. 1mL/kg in 20mL of normal saline was infused via internal jugular vein. Using a nitrogen gas pneumoperitongum, the IAP increased from0 to 15 and 25mmHg, and the groups were named IAP0 , IAP15 and IAP25 , respectively. During the experimental period, hemodynamic parameters including heart rate ( HR) , cardiac output ( CO) , mean arterial pressure( MAP) , central venous pressure( CVP) , intrathoracic blood volume index( ITBVI) and so on were obtained by using thermodilution technique of pulse induced continuous cardiac output( PiCCO) . The esophageal pressure( Pes) was dynamicly monitored by the esophageal catheter. Results Pes and peak airway pressure( Ppeak) increased and static lung compliance( Cstat) decreased significantly in IAP15 and IAP25 groups compared with IAP0 group( all P lt;0. 01) . Transpulmonary pressure( Ptp) showed a downward trend( P gt;0. 05) . PO2 and oxygenation index showed a downward trend while PCO2 showed a upward trend ( P gt;0. 05) . HR and CVP increased significantly, cardiac index( CI) and ITBV index decreased significantly ( all P lt;0. 05) ,MAP didn′t change significantly( P gt;0. 05) . The changes in Pes were negatively correlated with the changes in CI( r = - 0. 648, P = 0. 01) . Conclusion In the porcine model of ALI, Pes increases because of a rise in IAP which decreased pulmonary compliance and CI.
Objective To investigate the protective effect of annexin A1 (ANXA1) derived from human umbilical cord mesenchymal stem cells (HucMSCs) on lipopolysaccharide (LPS) -induced acute lung injury (ALI). Methods Six-week-old male C57BL/6 mice were randomly divided into a sham group, a LPS group, a LPS+HucMSC-cm (LPS+cm) group, a LPS+nc-cm group, and a LPS+si-cm group, with 6 mice in each group. LPS (5 mg/kg) was intratracheally injected to induce ALI model. Then, normal saline, HucMSC-cm (HucMSC conditioned medium), HucMSC-nc-cm (normal ANXA1 expression) and HucMSC-si-cm (knockout of ANXA1) were injected intratracheally with 50 μL each after LPS treatment for 4 hours. After 72 hours of LPS administration, the mice were killed, and the blood and lung tissues were retained. After corresponding treatment, the blood and lung tissues were preserved. The expression of IL-6 in peripheral blood of mice was detected by enzyme-linked immunosorbnent assay, the pathological changes of lung tissues were observed by hematoxylin-eosin staining, and the expressions of interleukin-6 (IL-6) and vascular cell adhesion molecule-1 (VCAM-1) in lung tissues of each group were detected by Western blot and immunohistochemistry. Results Compared with the sham group, the lung histopathology of mice in the LPS group showed significantly increased inflammatory factor infiltration, alveolar collapse, and lung tissue structure destruction as well as lung tissue injury score and wet/dry weight ratio (W/D) increased (all P<0.05). Accordingly, IL-6 and VCAM-1 protein levels in lung tissue and IL-6 expression in peripheral blood were increased (all P<0.05). Compared with the LPS group, the pathological injury of lung tissue in the LPS+cm group was improved, the lung tissue injury score and the W/D ratio decreased while IL-6, VCAM-1 protein levels in lung tissue and IL-6 expression in peripheral blood were decreased (all P<0.05). But there were no significant differences between the LPS+cm group and the LPS+ nc-cm group (all P>0.05). Compared with the LPS+nc-cm group, lung tissue pathological injury was aggravated again, lung tissue injury score and W/D were also increased in the LPS+si-cm group (all P<0.05). IL-6 and VCAM-1 protein levels in lung tissue and IL-6 expression in peripheral blood were increased again (all P<0.05). Conclusion ANXA1 derived from HucMSCs has certain protective effect in LPS-induced ALI model.
ObjectiveTo explore the clinical value of three early predictive scale of lung injury (ALI) in patients with high risk of acute lung injury (ALI) after lung cancer surgery.MethodsA convenient sampling method was used in this study. A retrospective analysis was performed on patients with lung cancer underwent lung surgery. The patients were divided into an ALI group and a non-ALI group according to ALI diagnostic criteria. Three kinds of lung injury predictive scoring methods were used, including lung injury prediction score (LIPS), surgical lung injury prediction (SLIP) and SLIP-2. The differences in the scores of the two groups were compared. The correlation between the three scoring methods was also analyzed. The diagnostic value was analyzed by drawing receiver operating characteristic (ROC) curves.ResultsA total of 400 patients underwent lung cancer surgery, and 38 patients (9.5%) developed ALI after operation. Among them, 2 cases progressed to acute respiratory distress syndrome and were treated in intensive care unit. There were no deaths. The predictive scores of the patients in the ALI group were higher than those in the non-ALI group, and the difference was statistically significant (all P<0.001). There was a good correlation between the three scoring methods (allP<0.001). The three scoring methods had better diagnostic value for early prediction of high risk ALI patients after lung cancer surgery and their area under ROC curve (AUC) were larger than 0.8. LIPS score performed better than others, with an AUC of 0.833, 95%CI (0.79, 0.87).ConclusionThree predictive scoring methods may be applied to early prediction of high risk ALI patients after lung cancer surgery, in which LIPS performs better than others.
Objective To explore the effect of early short-term use of low-dose steroids on early acute lung injury (EALI) after video-assisted thoracoscopic lobectomy. Methods Patients who underwent video-assisted thoracoscopic lobectomy in our department from January 2019 to January 2022 were selected for this retrospective cohort study. They were divided into an early steroid treatment group and a control group based on whether steroids were used in the early postoperative period. In the early steroid treatment group, in addition to routine postoperative treatment, low-dose methylprednisolone was administered intravenously, at 80-120 mg/d for 3 consecutive days. In the control group, routine postoperative treatment was given, but no steroids were used in the first 3 days. A chest computed tomography (CT) scan was performed on postoperative day (POD) 1, and POD3 or POD4 to assess lung injury. Chest CT scores, the EALI incidence, the length of hospital stay, and the incidence of poor incision healing were recorded. ResultsA total of 521 patients were included, consisting of 255 males and 266 females, aged 11-80 years. There were 203 patients in the early steroid treatment group and 318 patients in the control group. On POD1, the incidence of EALI was 16.0% in the control group and 13.8% in the steroid group, with no significant difference between the two groups (P>0.05). There was also no significant difference in the CT scores of patients with EALI in the two groups (P>0.05). On POD3/4, the incidence of EALI was 33.6% in the control group and 22.7% in the steroid group, showing a significant difference (P=0.007). When comparing the CT scores of patients with EALI in both groups, the scores were lower in the steroid group, but the difference was not significant (P>0.05). The overall incidence of EALI on POD1-4 was 37.4% in the control group and 26.1% in the steroid group, showing a significant difference (P=0.007). Of these, 28.9% of patients in the control group showed radiological progression, which means new EALI occurred or existing EALI progressed, while the progression rate was 14.8% in the steroid group (P<0.001). The length of hospital stay was significantly shorter in the steroid group compared to the control group (P<0.001), but the incidence of poor incision healing was not (P>0.05). Conclusion Early use of corticosteroids cannot reduce the incidence and severity of EALI on POD1, but it can reduce the incidence of EALI on POD3/4 and decrease the risk of radiological progression, and also lower the overall risk of EALI after surgery, without extended postoperative hospital stays or increased incidence of poor incision healing. Therefore, early postoperative use of low-dose corticosteroids can help to inhibit the occurrence and progression of EALI. It is suggested to use as early as possible especially in patients with high risks of postoperative EALI.
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.