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.
Objective To explore the protective effects of liver X receptor-αactivator ( LXRα)T0901317 on rats with acute lung injury ( ALI) . Methods Seventy-two male Wistar rats were randomly divided into three goups, ie. a control group, a LPS group, and a T0901317 group. Artery blood gas analysis,lung tissue wet/dry weight ratio,myeloperoxidase activity, and lung histopathological changes were measured.The expressions of LXRαand TNF-αmRNA in lung tissue were detected by RT-PCR. The protein levels ofTNF-αand LXRαwere examined with ELISA and immunohistochemistry, respectively. Results In the ALI rats, PaO2 decreased, lung W/D weight ratio and myeloperoxidase activity increased significantly compared with the control group ( P lt; 0. 05) . Histopathological examination also revealed obvious lung injury. In theLPS group, the expression of TNF-αmRNA in lung tissue and the level of TNF-αprotein in lung homogenate and serum increased markedly( all P lt; 0. 05) while the expression of LXR-αmRNA declined significantly ( P lt; 0. 05) . Immunohistochemical staining showed that lung tissues of the normal rats expressed LXRαsignificantly but in the LPS group the expression of TNF-αand LXR-αin lung tissue decreased markedly ( P lt;0. 05) . After the treatment with T0901317, the expressions of LXR-αin lung tissues were significantly higher than those in the LPS group both at the mRNA and the protein level ( P lt; 0. 05) . Conclusion T0901317 plays an anti-inflammatory effect through up-regulating the expression of LXR-αand suppressing the expression of TNF-α, thus reduces the infiltration and aggregation of inflammatory cells in lung tissue.
Objective To assess the efficacy of ambroxol on acute lung injury/acute respiratory distress syndrome ( ALI/ARDS) . Methods The randomized controlled study involving ambroxol on ALI/ARDS were searched and identified from Cochrane Library, PubMed, China Academic Journals Full-text Database, Chinese Biomedical Literature Database, WanFang Resource Database, and Chinese Journal Fulltext Database. The quality of the chosen randomized controlled studies was evaluated, and then the valid data was extracted for meta-analysis. Results Ten articles were included, all in Chinese, including 459 cases ofpatients ( 233 cases in experimental group,226 cases in control group) , with baseline comparability between the various experiments. Systematic review showed that in ALI/ARDS patients, high-dose ambroxol was in favor to improve PaO2 [ WMD =12. 23, 95% ( 9. 62, 14. 84) , P lt; 0. 0001] and PaO2 /FiO2 [ WMD = 32. 75,95% ( 30. 00, 35. 51) , P lt;0. 0001] , reduce lung injury score [ WMD = - 0. 49, 95% ( - 0. 66, - 0. 33) ,P lt;0. 0001] , decrease the duration of mechanical ventilation [ WMD = - 2. 70, 95% ( - 3. 24, - 1. 12) ,P lt;0. 0001] and the length of ICU stay [ WMD= - 2. 70, 95% ( - 3. 37, - 2. 04) , P lt;0. 0001] , and lower mortality [ OR=0. 46,95%( 0. 22, 1. 00) , P = 0. 05] . Conclusions The existing clinical evidence shows that, compared with conventional therapy, high-dose ambroxol plus can significantly improve PaO2 , PaO2 /FiO2 , lung injury score, duration of mechanical ventilation, length of ICU stay and mortality in ALI/ARDS patients. Due to the quality of research and the limitations of the study sample, there likely to exist a bias,and may affect the strength of result, so we expect more high-quality, large-scale randomized controlled clinical trial to verify.
Objective To compare three approaches of lipopolysaccharides ( LPS) administration for inducing acute lung injury ( ALI) in mice. Methods LPS ( 5 mg/kg) was intratracheally aerosol administered ( ITA group) , intratracheally instilled ( ITI group) , or intraperitoneally injected ( IPI group) to induce ALI in BLAB/ c mice. Evans Blue instead of LPS was intratracheally administered to observe the liquid distribution in the lungs. Two hours after LPS administration, the mice were sacrificed and the lungs were removed to determine wet-to-dry lung weight ratio ( W/D) , and the histological changes were evaluated by HE staining. Phosphorylation level of IκB-αand NF-κB p65 in lung tissue were investigated by Western blot. Transcription intensity of TNF-α and IL-1β mRNA in lung tissue were detected by real-time quantitative PCR. Results Evans Blue distributed more uniformly in the ITA group than the ITI group. The lung W/D ratio and histological changes score in three LPS administration groups were all significantly higher than the normal control group ( P lt;0. 01) , with the ITA group being the highest. The phosphorylation levels of IκB-αand NF-κB p65 were significantly higher in the ITA group than the ITI group ( P lt;0. 05) , and were significantly higher in the ITI group than the IPI group ( P lt; 0. 05) . Transcription intensity of TNF-αand IL-1βmRNA was significantly higher in the ITA group than the ITI group ( P lt;0. 05) , and were significantly higher in the ITI group than the IPI group ( P lt;0. 05) . Conclusion Being non-invasive and convenient,intratracheal LPS aerosol inhalation is an optimal method to induce ALI in mice because it induces more extensive and uniformly distributed injuries in lung.
ObjectiveTo investigate the effect of ambroxol hydrochloride on c-Jun N-terminal kinase (JNK) signal pathway in gastric aspiration lung injury. MethodsForty healthy male Sprague Dawley rats were randomly divided into a control group, an injury group, a SP600125 (JNK specific inhibitor) group and an ambroxol group. The model of gastric aspiration lung injury was established by aspiration of gastric contents. The rats in the SP600125 group preoperatively received intravenous injection of JNK specific inhibitor SP600125 (3 mg/100 g). The rats in the ambroxol group received intravenous injection of ambroxol hydrochloride (50 mg/kg) 2 hours after the damage occurred. The neutrophil count and malondialdehyde (MDA) activity in bronchoalveolar lavage fluid (BALF), the lung wet weight/dry weight ratio (W/D), and myeloperoxidase (MPO) activity were measured. The protein expressions of JNK and phosphorylated JNK (p-JNK) and inducible nitric oxide synthase (iNOS) in lung tissue were detected by Western blot method. The changes of lung tissue structure were observed under light microscope. ResultsIn the injury group, the neutrophil counts and MDA activity in BALF, W/D, MPO activity, p-JNK and iNOS protein expression increased significantly, lung tissue appeared obvious histopathological injury compared with the control group. In the SP600125 group and the ambroxol group, neutrophil count and MDA activity in BALF, lung W/D, MPO activity, p-JNK and iNOS protein expression were significantly decreased compared with the injury group (P < 0.05), and the damage of the lung tissue pathology was reduced. The expression of JNK protein in lung tissue was not different in all groups (P > 0.05). ConclusionsJNK is involved in inflammatory reaction of gastric aspiration lung injury. The protective effect of ambroxol may be related to the inhibition of JNK signaling pathway and the inhibition of iNOS expression.
Objective To investigate the effect of aerosolized perfluorocarbon (PFC) (FC77) on gas exchange，histopathological changes of lung in acute lung injury and pulmonary expression of tumor necrosis factor-α (TNF-α) mRNA.Methods After acute lung injury (ALI) was induced by oleic acid (OA)，16 rabbits were assigned randomly into 2 groups,ie.aerosolized perfluorocarbon group (PFC group) and conventional mechanical ventilation group (CMV group).Gas exchange parameters were measured before and after ALI，at 1，2，3，4 h after treatment.Histological sections taken from 6 different parts of lung were stained by hematoxylin and eosion.The express of TNF-α mRNA in the 2 different parts of lung were detected by in situ hybridization (ISH).Results Compared with CMV group，the PaO2 and static lung compliance (CLst) were significantly increased (Plt;0.05)，the histopathological lesions of lung were attenuated，and the TNF-α mRNA expression was decreased significantly in PFC group (all Plt;0.05).There was more expression of TNF-α mRNA in backside than that in foreside of lung in two groups (Plt;0.05).Conclusion Aerosolized perfluorocarbon (PFC) can decrease expression of tumor necrosis factor-α mRNA in the lung，and improve the CLst and oxygenation during acute lung injury.
Objective To review the effects of pulmonary surfactant in adult patients with acute lung injury ( ALI) /acute respiratory distress syndrome ( ARDS) . Methods Randomized controlled trials ( RCTs) were recruited from PubMed ( 1966.1-2011.3) , ISI Web of Knowledge ( all the years) and Wanfang Database ( 1982-2011) . Related published data and attached references were hand searched. All the RCTs about pulmonary surfactant for the adult patients with ALI/ARDS were included, then a meta-analysis was performed. Results Eight eligible trials were enrolled. Pooled analysis showed that treatment with pulmonary surfactant was not associated with reduction in 28 or 30-day mortality compared with the control group [ OR 1.05, 95% CI ( 0.90, 1.22 ) , P = 0.55] , neither did subgroup analysis in the pneumoia/ aspiration, sepsis, and trauma/ surgery induced ALI/ARDS patients. Three RCTs showed the oxygenation was significantly improved in adult ALI/ARDS patients receiving pulmonary surfactant compared with the control group( Plt;0.05) . Shorter mechanical ventilation days was shown in the ALI/ARDS patients receiving pulmonary surfactant in one RCT(Plt;0.05) . Conclusions Meta-analysis showed pulmonary surfactant did not reduce the 28 or 30-day mortality of adult patients with ALI/ARDS, however, improved the oxygenation. Pulmonary surfactant can be considered a therapy in ALI/ARDS.
Ojective To establish a rat model of hyperoxia induced acute lung injury. Methods Eighty healthy male SD rats were randomly divided into an air group and a hyperoxia group ( ≥95% O2 ) .Each group was further divided into 12 h, 24 h, 36 h, 48 h, 60 h subgroups. Arterial blood gas was monitored. Lung tissue was sampled for evaluation of lung wet to dry ratio, lung index, and pulmonary permeation index. Bronchoalveolar lavage fluid ( BALF) was collected for measurement of lactatedehydrogenase ( LDH) activity and white blood cell count ( WBC) . Results After hyperoxia exposure for 48 ～60 h, lung pathology showed alveolar structure disruption, lung parenchyma wrath bleeding and edema.Lung wet to dry ratio, lung index, pulmonary permeation index, LDH and WBC in BALF all increased significantly, peaked at 48 h and remained at high level at 60 h while PaO2 dropped progressively.Conclusion Exposure to ≥ 95% O2 for 48 ～60 h can successfully establish the rat model of hyperoxia induced acute lung injury.
Objective To explore the effects of different humidification and heating strategies during non-invasive positive pressure ventilation( NIPPV) in patients with ALI/ARDS. Methods A total of 45 patients with ALI/ARDS were randomly divided into three groups to receive NIPPV with different humidification and heating strategies, ie. Group A ( humidification with a 370 Humidifier without heating) ,group B ( humidification with a 370 Humidifier along with a MR410 Heater) , and group C ( humidification and heating with aMR850 Humidifier, and a RT308 circuit heater) . The changes of air temperature, absolute humidity, relative humidity, sputum thickness and patient comfort were compared between the three groups. Sputum thickness was evaluated with AWSS scoring system. Results After humidification and heating, the air temperature, absolute humidity and AWSS score improved significantly in group B [ elevated from ( 23. 9 ±1. 0) ℃, (9.8 ±1. 3) mg/L and 2. 0 ±0. 7 respectively to ( 30. 3 ±1. 7) ℃, ( 31. 0 ±2. 3)mg/L and ( 3. 0 ±0. 9) respectively, P lt; 0. 001] and group C [ elevated from( 23. 8 ±1. 0) , ( 9. 8 ±1. 5)mg/L and ( 2. 1 ±0. 7) respectively to ( 34. 0 ±1. 1) ℃, ( 43.8 ±2. 5) mg /L and 3. 5 ±1. 0 respectively,P lt; 0. 001] . Air temperature and absolute humidity were significantly higher in group C than those in group B( P lt; 0. 001) . Of all the parameters, only absolute humidity showed a significant improvment in group A [ elevated from( 9. 9 ±1. 6) mg/L to ( 11. 9 ±0. 9) mg/L, P lt; 0. 001] . The degree of comfort in group C was significantly higher than that in group A and B [ 8. 0 ±1. 7 vs 5. 0 ±1. 2 and 3. 0 ±0. 4, respectively, P lt;0. 001] . In group A seven patients were switched to group C because of discomfort, four accepted NIPPV continuously, and two avoided invasive mechanical ventilation eventually. In group B three patients were switched to group C because of intolerance of too much condensed water in the breathing circuit, all of them accepted NIPPV continuously, and one avoided invasive mechanical ventilation eventually. Conclusions Compared with mere humidification or humidification with heating humidifier, humidification with heating humidifier and circuit heating during NIPPV can improve the absolute humidity, air temperature and patient comfort,meanwhile decreasing the sputumthickness of patients with ALI/ARDS.
Objective To investigate the effects and mechanisms of pentoxifylline ( PTX )pretreatment on acute lung injury ( ALI) induced by hemorrhagic shock in mice. Methods Ninety mice were randomly divided into three groups, ie. a control group, a hemorrhagic shock group, and a PTX group.Lung histological changes were examined by HE staining. Meanwhile, the wet-to-dry weight ratio ( W/D) and myeloperoxidase ( MPO) activity in lung were measured. The levels of TNF-αand IL-1βin lung homogenatewere measured by ELISA. The expressions of TLR4 mRNA and TLR4 protein in lung were detected by reverse transcription-polymerase chain reaction ( RT-PCR ) and Western blot, respectively. Results Hemorrhagic shock induced obvious ALI changes in lungs of the hemorrhagic shock group. W/D and MPO activity were significantly higher in the hemorrhagic shock group than the control group( P lt; 0. 01) . The expressions of TNF-α, IL-1β, TLR4 mRNA and TLR4 protein were also significantly higher than the control group( P lt;0. 01) . PTX pretreatment could relieve ALI changes induced by hemorrhagic shock, and decrease W/D and MPO activity. The expressions of TNF-α, IL-1β, TLR4 mRNA and TLR4 protein were also decreased by PTX pretreatment. Conclusions PTX pretreatment shows protective effects on ALI afterhemorrhagic shock. Its possible mechanismmay relate to down-regulation of TLR4, thus inhibit the expression of pro-inflammatory cytokins.