OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a pote...OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a potential strategy for the treatment of ALI or IPF,we identified potent inhibitors of Leukotriene A4 hydrolase(LTA4H),a key enzyme in the biosynthesis of LTB4.METHODS In this study,we identified two known histone deacetylase(HDAC)inhibitors,suberanilohydroxamic acid(SAHA)and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide(M344),as effective inhibitors of LTA4H using enzymatic assay,thermofluor assay,and X-ray crystallographic investigation.We next tested the effect of SAHA and M344 on endogenous LTB4 biosynthesis in neutrophils by ELISA and neutrophil migration by transwell migration assay.A murine experimental model of ALI was induced by lipopolysaccharide(LPS)inhalation.Histopathological analysis of lung tissue using H&E staining revealed the serious pulmonary damage caused by LPS treatment and the effect of the SAHA.We next examined m RNA and protein levels of pro-inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid using q RT-PCR and ELISA to further investigate the underlying mechanisms of anti-inflammatory activities by SAHA.We also investigated the effects of SAHA and M344 on a murine experimental model of bleomycin(BLM)-induced IPF model.RESULTS The results of enzymatic assay and X-ray crystallography showed that both SAHA and M344 bind to LTA4H,significantly decrease LTB4 levels in neutrophil,and markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose.CONCLUSION Collectively,SAHA and M344 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.展开更多
Aim To study the effects of baicalein （BC）, a phenolic flavonoid extracted mainly from Scutellaria ba- icalensis Georgi, on lipopolysaccharide （LPS）-induced acute lung injury （ALI） in mice and the molecular mech...Aim To study the effects of baicalein （BC）, a phenolic flavonoid extracted mainly from Scutellaria ba- icalensis Georgi, on lipopolysaccharide （LPS）-induced acute lung injury （ALI） in mice and the molecular mecha- nisms underlying. Methods Mice were administrated intranasally with LPS （20 mg · kg^-1/body weight） to estab- lish the ALI model. Then the mice were treated twice with BC （50,100 and 200 mg · kg^-1, p. o. ） 0. 5 hour and 12 hours after LPS stimulation, following another 12 hours, the lungs were collected for histological study. Results LPS caused marked inflammatory cell infiltration and myeloperoxidase activation in lungs, accompanied by significantly in- creased lung W/D ratio, from 7.97±0. 60 in normal group to 12. 49 ± 1.49 in the model. 77.88% reduction in the lung W/D ratio was observed in 200 mg· kg^-1 dose of baicalein. The myeloperoxidase activity was reduced to 40. 14% in mice treated with 200 mg · kg^-1. The number of total cells, neutrophils, and macrophages in BALF de- creased with increasing concentration of baicalein. Inflammatory cytokines level in serum declined significantly while insignificant changes of the same in BALF was observed in mice treated with 50,100 and 200 mg · kg^-1 doses of ba- icalein. Furthermore, LPS induced markedly the expression of inflammasomes and other inflammation-related genes in lung tissue. Treatment of LPS-exposed mice with BC significantly reduced the expression levels of these genes and al- leviated the pathological changes in lungs. Moreover, 1 μmol · L^-1 and 10 μmol · L^-1 BC inhibited remarkably the nuclear translocation of NF-kappaB p65 in Raw264.7 cells. Conclusion Baicalein alleviates LPS-induced acute lung injury in mice by suppressing NF-KB-mediated inflammatory responses and downregulation of inflammasomes.展开更多
Objective:To investigate the effect of salvia miltiorrhiza on expression of the MMP-2、9 and TIMP-1、TIMP-2 in tissue of acute lung injury of severe acute pancreatitis(SAP).Methods:MMP-2、9 expression and changes of t...Objective:To investigate the effect of salvia miltiorrhiza on expression of the MMP-2、9 and TIMP-1、TIMP-2 in tissue of acute lung injury of severe acute pancreatitis(SAP).Methods:MMP-2、9 expression and changes of the lung were measured after the SAP rats were induced by retrograde injection of 5%sodium tauocholate into hepatopancreatic duct.The changes of those parameters were also measured after salvia miltiorrhiza was injected intramuscularly just after induction of SAP.Results:The level of MMP-2、9 in pancreas and lung in SAP group were significantly higher than those in sham;The level of MMP-2、9 in salvia miltiorrhiza group were significantly lower than those in SAP group. Conclusion:MMP-2、9 were overexpressed in Acute lung injury (ALI) induced by SAP, salvia miltiorrhiza downregulates MMP-2、9 expression and decreased injury of lung tissue.展开更多
The model of acute lung injury(ALI)was established by intraperitoneal administration,but there was no time-point observation and comparison.ALI model was established by intraperitoneal injection of lipopolysaccharide(...The model of acute lung injury(ALI)was established by intraperitoneal administration,but there was no time-point observation and comparison.ALI model was established by intraperitoneal injection of lipopolysaccharide(LPS)at the concentration of 10 mg·kg^-1 (10 mg LPS dissolved in 1 mL normal saline to prepare 1 mL·kg^-1solution)in rats.The control group(CG)was intraperitoneally injected with saline of the same dose.In the LPS group,lung tissues were collected at 4,6,8,12 and 24 h after administration.Then,the morphology changes,the ratio of wet-to-dry weight(W/D),the expression of interleukin-1β(IL-1β)and tumor necrosis factor-α(TNF-α)proteins,the levels of malondialdehyde(MDA),the activities of superoxide dismutase(SOD),glutathione peroxidase(GSH)were measured.To verify the success of the model,the degrees of lung injury via Western blot,RT-PCR,ELISA and other techniques were detected at different time points,and the severe time of the ALI model established was deterimined by intraperitoneal administration,which provided a stable model basis for the study of the pathogenesis of ALI in the future.The results showed that the lung injury occurred in LPS group.W/D and lung pathological changes at 12 and 24 h of LPS group were significantly different from those in the CG.Compared with the CG,the expression of IL-1βand TNF-αproteins and the content of MDA in lung tissues of LPS group increased and most significant difference was found at 12 and 24 h(p<0.01).Compared with the CG,the activities of SOD and GSH in LPS 12 h group decreased significantly(p<0.01).In conclusion,inflammation and oxidative damage were the main causes of the ALI in rats.Lung injury was most obvious 12 h after intraperitoneal injection of 10 mg·kg^-1 LPS.展开更多
目的分析脓毒症肺损伤患者中医证型分布状况与肺损伤相关指标及序贯性器官衰竭评分(sequential organ failure assessment,SOFA)、急性生理和慢性健康状况Ⅱ(Acute Physiology and Chronic Health EvaluationⅡ,APACHEⅡ)评分的相关性...目的分析脓毒症肺损伤患者中医证型分布状况与肺损伤相关指标及序贯性器官衰竭评分(sequential organ failure assessment,SOFA)、急性生理和慢性健康状况Ⅱ(Acute Physiology and Chronic Health EvaluationⅡ,APACHEⅡ)评分的相关性。方法选取2022年1月—2023年1月医院收治的脓毒症肺损伤患者80例,收集患者的一般资料、肺损伤相关指标[动脉血氧合指数(ratio of partial pressure of O_(2) in arterial blood to fraction of inspired oxygen,PaO_(2)/FiO_(2))、肺泡动脉氧分压差(alveolar-arterial oxygen gradient,P(A-a)O_(2))]及SOFA、APACHEⅡ评分情况,根据中医分型标准对脓毒症肺损伤患者进行分型,比较不同分型的脓毒症肺损伤患者以上各观察指标情况并分析相关性。结果脓毒症肺损伤患者以肺热壅痹证型占比最高、35.00%(28/80),其次为瘀血阻肺型27.50%(22/80),肺塞腑实型23.75%(19/80),水饮郁肺型13.75%(11/80)。不同证型的患者在性别、年龄方面差异均无统计学意义(P>0.05);不同证型的患者肺损伤指标PaO_(2)/FiO_(2)、P(A-a)O_(2)差异均有统计学意义(P<0.05);不同证型的患者SOFA、APACHEⅡ评分差异均有统计学意义(P<0.05)。肺热壅痹、瘀血阻肺、肺塞腑实、水饮郁肺证型与PaO_(2)/FiO_(2)呈显著负相关(P<0.05),与P(A-a)O_(2)、SOFA评分、APACHEⅡ评分呈显著正相关(P<0.05)。结论脓毒症肺损伤患者中医证型主要为肺热壅痹、瘀血阻肺、肺塞腑实、水饮郁肺,与肺损伤相关指标及SOFA、APACHEⅡ评分密切相关,掌握脓毒症肺损伤辨证分型特点并观察患者肺损伤相关指标及SOFA、APACHEⅡ评分变化,对疾病诊治及预后评估具有较高价值。展开更多
基金supported by National Natural Science Foundation of China(81402482,91313303)
文摘OBJECTIVE Leukotriene B4(LTB4)biosynthesis and subsequently neutrophilic inflammation may provide a potential strategy for the treatment of acute lung injury(ALI)or idiopathic pulmonary fibrosis(IPF).To provide a potential strategy for the treatment of ALI or IPF,we identified potent inhibitors of Leukotriene A4 hydrolase(LTA4H),a key enzyme in the biosynthesis of LTB4.METHODS In this study,we identified two known histone deacetylase(HDAC)inhibitors,suberanilohydroxamic acid(SAHA)and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide(M344),as effective inhibitors of LTA4H using enzymatic assay,thermofluor assay,and X-ray crystallographic investigation.We next tested the effect of SAHA and M344 on endogenous LTB4 biosynthesis in neutrophils by ELISA and neutrophil migration by transwell migration assay.A murine experimental model of ALI was induced by lipopolysaccharide(LPS)inhalation.Histopathological analysis of lung tissue using H&E staining revealed the serious pulmonary damage caused by LPS treatment and the effect of the SAHA.We next examined m RNA and protein levels of pro-inflammatory cytokines in lung tissue and bronchoalveolar lavage fluid using q RT-PCR and ELISA to further investigate the underlying mechanisms of anti-inflammatory activities by SAHA.We also investigated the effects of SAHA and M344 on a murine experimental model of bleomycin(BLM)-induced IPF model.RESULTS The results of enzymatic assay and X-ray crystallography showed that both SAHA and M344 bind to LTA4H,significantly decrease LTB4 levels in neutrophil,and markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose.CONCLUSION Collectively,SAHA and M344 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.
文摘Aim To study the effects of baicalein （BC）, a phenolic flavonoid extracted mainly from Scutellaria ba- icalensis Georgi, on lipopolysaccharide （LPS）-induced acute lung injury （ALI） in mice and the molecular mecha- nisms underlying. Methods Mice were administrated intranasally with LPS （20 mg · kg^-1/body weight） to estab- lish the ALI model. Then the mice were treated twice with BC （50,100 and 200 mg · kg^-1, p. o. ） 0. 5 hour and 12 hours after LPS stimulation, following another 12 hours, the lungs were collected for histological study. Results LPS caused marked inflammatory cell infiltration and myeloperoxidase activation in lungs, accompanied by significantly in- creased lung W/D ratio, from 7.97±0. 60 in normal group to 12. 49 ± 1.49 in the model. 77.88% reduction in the lung W/D ratio was observed in 200 mg· kg^-1 dose of baicalein. The myeloperoxidase activity was reduced to 40. 14% in mice treated with 200 mg · kg^-1. The number of total cells, neutrophils, and macrophages in BALF de- creased with increasing concentration of baicalein. Inflammatory cytokines level in serum declined significantly while insignificant changes of the same in BALF was observed in mice treated with 50,100 and 200 mg · kg^-1 doses of ba- icalein. Furthermore, LPS induced markedly the expression of inflammasomes and other inflammation-related genes in lung tissue. Treatment of LPS-exposed mice with BC significantly reduced the expression levels of these genes and al- leviated the pathological changes in lungs. Moreover, 1 μmol · L^-1 and 10 μmol · L^-1 BC inhibited remarkably the nuclear translocation of NF-kappaB p65 in Raw264.7 cells. Conclusion Baicalein alleviates LPS-induced acute lung injury in mice by suppressing NF-KB-mediated inflammatory responses and downregulation of inflammasomes.
基金supported mainly by Chinese traditionalmedicines and drugs administrative agent(92B093)
文摘Objective:To investigate the effect of salvia miltiorrhiza on expression of the MMP-2、9 and TIMP-1、TIMP-2 in tissue of acute lung injury of severe acute pancreatitis(SAP).Methods:MMP-2、9 expression and changes of the lung were measured after the SAP rats were induced by retrograde injection of 5%sodium tauocholate into hepatopancreatic duct.The changes of those parameters were also measured after salvia miltiorrhiza was injected intramuscularly just after induction of SAP.Results:The level of MMP-2、9 in pancreas and lung in SAP group were significantly higher than those in sham;The level of MMP-2、9 in salvia miltiorrhiza group were significantly lower than those in SAP group. Conclusion:MMP-2、9 were overexpressed in Acute lung injury (ALI) induced by SAP, salvia miltiorrhiza downregulates MMP-2、9 expression and decreased injury of lung tissue.
基金Supported by the National Key Research and Development Program of China(2016YED0501008)the National Natural Science Foundation of China(31772806)the Natural Science Foundation of Heilongjiang Province(C2017022)。
文摘The model of acute lung injury(ALI)was established by intraperitoneal administration,but there was no time-point observation and comparison.ALI model was established by intraperitoneal injection of lipopolysaccharide(LPS)at the concentration of 10 mg·kg^-1 (10 mg LPS dissolved in 1 mL normal saline to prepare 1 mL·kg^-1solution)in rats.The control group(CG)was intraperitoneally injected with saline of the same dose.In the LPS group,lung tissues were collected at 4,6,8,12 and 24 h after administration.Then,the morphology changes,the ratio of wet-to-dry weight(W/D),the expression of interleukin-1β(IL-1β)and tumor necrosis factor-α(TNF-α)proteins,the levels of malondialdehyde(MDA),the activities of superoxide dismutase(SOD),glutathione peroxidase(GSH)were measured.To verify the success of the model,the degrees of lung injury via Western blot,RT-PCR,ELISA and other techniques were detected at different time points,and the severe time of the ALI model established was deterimined by intraperitoneal administration,which provided a stable model basis for the study of the pathogenesis of ALI in the future.The results showed that the lung injury occurred in LPS group.W/D and lung pathological changes at 12 and 24 h of LPS group were significantly different from those in the CG.Compared with the CG,the expression of IL-1βand TNF-αproteins and the content of MDA in lung tissues of LPS group increased and most significant difference was found at 12 and 24 h(p<0.01).Compared with the CG,the activities of SOD and GSH in LPS 12 h group decreased significantly(p<0.01).In conclusion,inflammation and oxidative damage were the main causes of the ALI in rats.Lung injury was most obvious 12 h after intraperitoneal injection of 10 mg·kg^-1 LPS.
文摘目的分析脓毒症肺损伤患者中医证型分布状况与肺损伤相关指标及序贯性器官衰竭评分(sequential organ failure assessment,SOFA)、急性生理和慢性健康状况Ⅱ(Acute Physiology and Chronic Health EvaluationⅡ,APACHEⅡ)评分的相关性。方法选取2022年1月—2023年1月医院收治的脓毒症肺损伤患者80例,收集患者的一般资料、肺损伤相关指标[动脉血氧合指数(ratio of partial pressure of O_(2) in arterial blood to fraction of inspired oxygen,PaO_(2)/FiO_(2))、肺泡动脉氧分压差(alveolar-arterial oxygen gradient,P(A-a)O_(2))]及SOFA、APACHEⅡ评分情况,根据中医分型标准对脓毒症肺损伤患者进行分型,比较不同分型的脓毒症肺损伤患者以上各观察指标情况并分析相关性。结果脓毒症肺损伤患者以肺热壅痹证型占比最高、35.00%(28/80),其次为瘀血阻肺型27.50%(22/80),肺塞腑实型23.75%(19/80),水饮郁肺型13.75%(11/80)。不同证型的患者在性别、年龄方面差异均无统计学意义(P>0.05);不同证型的患者肺损伤指标PaO_(2)/FiO_(2)、P(A-a)O_(2)差异均有统计学意义(P<0.05);不同证型的患者SOFA、APACHEⅡ评分差异均有统计学意义(P<0.05)。肺热壅痹、瘀血阻肺、肺塞腑实、水饮郁肺证型与PaO_(2)/FiO_(2)呈显著负相关(P<0.05),与P(A-a)O_(2)、SOFA评分、APACHEⅡ评分呈显著正相关(P<0.05)。结论脓毒症肺损伤患者中医证型主要为肺热壅痹、瘀血阻肺、肺塞腑实、水饮郁肺,与肺损伤相关指标及SOFA、APACHEⅡ评分密切相关,掌握脓毒症肺损伤辨证分型特点并观察患者肺损伤相关指标及SOFA、APACHEⅡ评分变化,对疾病诊治及预后评估具有较高价值。
