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
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
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
In land warfare,trenches serve as vital defensive fortifications,offering protection to soldiers while engaging in combat.However,despite their protective function,soldiers often sustain injuries within these trenches...In land warfare,trenches serve as vital defensive fortifications,offering protection to soldiers while engaging in combat.However,despite their protective function,soldiers often sustain injuries within these trenches.The lack of corresponding blast data alongside empirical injury reports presents a significant knowledge gap,particularly concerning the blast pressures propagating within trench spaces following nearby explosions.This absence hinders the correlation between blast parameters,trench geometry,and reported injury cases,limiting our understanding of blast-related risks within trenches.This paper addresses the critical aspect of blast propagation within trench systems,essential for evaluating potential blast injury risks to individuals within these structures.Through advanced computational fluid dynamics(CFD)simulations,the study comprehensively investigates blast injury risks resulting from explosions near military trenches.Employing a sophisticated computational model,the research analyzes the dynamic blast effects within trenches,considering both geometrical parameters and blast characteristics influenced by explosive weight and scaled distance.The numerical simulations yield valuable insights into the impact of these parameters on blast injury risks,particularly focusing on eardrum rupture,lung injury,and traumatic brain injury levels within the trench.The findings elucidate distinct patterns of high-risk zones,highlighting unique characteristics of internal explosions due to confinement and venting dynamics along the trench.This study underscores the significance of detailed numerical modeling in assessing blast injury risks and provides a novel knowledge base for understanding risks associated with explosives detonating near military trenches.The insights gained contribute to enhancing safety measures in both military and civilian contexts exposed to blast events near trench structures.展开更多
The fraction of horse chestnut seeds was named escins,which mainly consists of A,B,C,and D escin.Accumulating evidence suggests that escin exerts potent anti-inflammatory and anti-edematous effects.The effects of esci...The fraction of horse chestnut seeds was named escins,which mainly consists of A,B,C,and D escin.Accumulating evidence suggests that escin exerts potent anti-inflammatory and anti-edematous effects.The effects of escin on inflammation and edema have been confirmed in various models.In a study in 1961,intravenous administration of escin was found to reduce acute edema in a rat paw.In the same study,escin was found to inhibit the increase in vascular permeability induced by egg white injection.Escin dose-dependently reduced the capillary permeability in chloroform-induced local inflammation in the abdominal skin surface of rabbits.The anti-inflammatory and anti-edematous effects of external use of escin were studied in carrageenan-induced paw edema and histamine-induced capillary permeability in rats.Escin gel decreased the contents of PGE2,TNF-α,and IL^(-1)β,and reduced the raw edema and capillary permeability.The carrageenan-induced paw edema and pleuritis in bilaterally adrenalectomized rats were used to investigate the anti-inflammatory effects of escin and glucocorticoid alone or combined.Co-administration of escin with cortisone significantly reduced the volume of exudates and the number of white blood cells of exudates.The findings suggest escin can synergize with glucocorticoids to enhance their anti-inflammatory effect.The anti-inflammatory effect of escin was investigated in carrageenan-induced paw edema and acetic acid-induced capillary permeability in mice.Escin showed an anti-inflammatory effect,which is similar to that seen with dexamethasone treatment.However,escin showed a longer duration of the anti-inflammatory response than that of dexamethasone.Furthermore,escin had no significant effects on spleen index,thymus index,proliferative capacity of splenocytes,lymphocyte count,and phagocytic rate.The findings suggest that escin is a potent anti-inflammatory drug with long-lasting anti-inflammatory effects without any immunosuppressive effects.Traditionally the mechanism of anti-inflammatory effect of escin is supposed to be relative to release of PGF2αand corticosterone.The early studies showed that escin might promote the release of PGF2αand affect the pituitary adrenal system,stimulate the release of adrenocorticotropic hormone(ACTH)and glucocorticoid,which may explain its anti-inflammatory and anti-edema effects.Escin has glucocorticoid-like anti-inflammatory effect.However,escin did not exhibit an anti-inflammatory effect in low dose.Combination of suboptimal concentrations of escin with corticosterone inhibited the release of inflammatory factors including NO,TNF-αand IL^(-1)βin the LPS-stimulated macrophage cells.Previous studies demonstrate that escin combined with glucocorticoid produced synergistic anti-inflammatory effects.The potential synergistic mechanisms may be associated with the property which escin regulates the glucocorticoid receptor(GR)signaling pathway.Escin can upregulate the expression of GR,promote the combination of glucocorticoid and GR,then promote the activated GR transfer into the nucleus.Activated GR will inhibit the activation of NF-κB directly,thus further inhibiting the expression of TNF-αand IL^(-1)βand other inflammatory factors.Escin could inhibit 11β-HSD2 but not 11β-HSD1,thus decrease the metabolism of glucocorticoid.Escin and glucocorticoids have similar chemical structures.This indicate that one of the anti-inflammatory mechanisms of escin may be due to its stimulating GR by binding to it.Eacin might be a partial agonist of GR.A good many of researches have demonstrated the anti-inflammatory properties of escin,and shed light on the underlying mechanisms by which escin exerts these effects.Escin,as an oral or intravenous formulation,or a topical gel,inhibits inflammation,producing measurable improvements in edema and acute lung injury.Further clinical studies of escin are needed to demonstrate these properties in larger patient populations.展开更多
OBJECTIVE To investigate whether Renqing Changjue has a protective effect on acute respiratory distress syndrome(ARDS)induced by endotoxin lipopolysaccharide(LPS)in rabbits.METHODS Thirty-six healthy male New Zealand ...OBJECTIVE To investigate whether Renqing Changjue has a protective effect on acute respiratory distress syndrome(ARDS)induced by endotoxin lipopolysaccharide(LPS)in rabbits.METHODS Thirty-six healthy male New Zealand white rabbits were randomly divided into six groups:normal control group,model group,dexamethasone group,Renqing Changjue high,middle and low dose group,with six rabbits in each group.LPS was used to replicate the ARDS model after five consecutive days of gavage.Arterial pressure,respiratory rate and anal temperature blood were recorded for arterial blood gas analysis at 0,0.5,1,2 and 4 h,respectively.At the end of the four-hour experiment,rabbits were killed by bloodletting,and the lung tissue was quickly removed to determine the cytokines,SOD,MDA and pathological examination of rabbit lung.RESULTS Renqing Changjue can significantly reduce the pathological changes of lung in ARDS model group.The expression of AQP1 and MPO in rabbit lung was significantly decreased by immunohistochemistry(P<0.05),reduce the lung wet/dry weight ratio,increase the ratio of PaO_(2)/FiO_(2),inhibit the release of inflammatory factors and scavenge free radicals and antioxidant effects.CONCLUSION Renqing Changjue can effectively protect rabbits with acute respiratory distress syndrome induced by LPS,and may protect the lung by inhibiting the release of cytokines and anti-oxidation.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.
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.
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.
文摘In land warfare,trenches serve as vital defensive fortifications,offering protection to soldiers while engaging in combat.However,despite their protective function,soldiers often sustain injuries within these trenches.The lack of corresponding blast data alongside empirical injury reports presents a significant knowledge gap,particularly concerning the blast pressures propagating within trench spaces following nearby explosions.This absence hinders the correlation between blast parameters,trench geometry,and reported injury cases,limiting our understanding of blast-related risks within trenches.This paper addresses the critical aspect of blast propagation within trench systems,essential for evaluating potential blast injury risks to individuals within these structures.Through advanced computational fluid dynamics(CFD)simulations,the study comprehensively investigates blast injury risks resulting from explosions near military trenches.Employing a sophisticated computational model,the research analyzes the dynamic blast effects within trenches,considering both geometrical parameters and blast characteristics influenced by explosive weight and scaled distance.The numerical simulations yield valuable insights into the impact of these parameters on blast injury risks,particularly focusing on eardrum rupture,lung injury,and traumatic brain injury levels within the trench.The findings elucidate distinct patterns of high-risk zones,highlighting unique characteristics of internal explosions due to confinement and venting dynamics along the trench.This study underscores the significance of detailed numerical modeling in assessing blast injury risks and provides a novel knowledge base for understanding risks associated with explosives detonating near military trenches.The insights gained contribute to enhancing safety measures in both military and civilian contexts exposed to blast events near trench structures.
文摘The fraction of horse chestnut seeds was named escins,which mainly consists of A,B,C,and D escin.Accumulating evidence suggests that escin exerts potent anti-inflammatory and anti-edematous effects.The effects of escin on inflammation and edema have been confirmed in various models.In a study in 1961,intravenous administration of escin was found to reduce acute edema in a rat paw.In the same study,escin was found to inhibit the increase in vascular permeability induced by egg white injection.Escin dose-dependently reduced the capillary permeability in chloroform-induced local inflammation in the abdominal skin surface of rabbits.The anti-inflammatory and anti-edematous effects of external use of escin were studied in carrageenan-induced paw edema and histamine-induced capillary permeability in rats.Escin gel decreased the contents of PGE2,TNF-α,and IL^(-1)β,and reduced the raw edema and capillary permeability.The carrageenan-induced paw edema and pleuritis in bilaterally adrenalectomized rats were used to investigate the anti-inflammatory effects of escin and glucocorticoid alone or combined.Co-administration of escin with cortisone significantly reduced the volume of exudates and the number of white blood cells of exudates.The findings suggest escin can synergize with glucocorticoids to enhance their anti-inflammatory effect.The anti-inflammatory effect of escin was investigated in carrageenan-induced paw edema and acetic acid-induced capillary permeability in mice.Escin showed an anti-inflammatory effect,which is similar to that seen with dexamethasone treatment.However,escin showed a longer duration of the anti-inflammatory response than that of dexamethasone.Furthermore,escin had no significant effects on spleen index,thymus index,proliferative capacity of splenocytes,lymphocyte count,and phagocytic rate.The findings suggest that escin is a potent anti-inflammatory drug with long-lasting anti-inflammatory effects without any immunosuppressive effects.Traditionally the mechanism of anti-inflammatory effect of escin is supposed to be relative to release of PGF2αand corticosterone.The early studies showed that escin might promote the release of PGF2αand affect the pituitary adrenal system,stimulate the release of adrenocorticotropic hormone(ACTH)and glucocorticoid,which may explain its anti-inflammatory and anti-edema effects.Escin has glucocorticoid-like anti-inflammatory effect.However,escin did not exhibit an anti-inflammatory effect in low dose.Combination of suboptimal concentrations of escin with corticosterone inhibited the release of inflammatory factors including NO,TNF-αand IL^(-1)βin the LPS-stimulated macrophage cells.Previous studies demonstrate that escin combined with glucocorticoid produced synergistic anti-inflammatory effects.The potential synergistic mechanisms may be associated with the property which escin regulates the glucocorticoid receptor(GR)signaling pathway.Escin can upregulate the expression of GR,promote the combination of glucocorticoid and GR,then promote the activated GR transfer into the nucleus.Activated GR will inhibit the activation of NF-κB directly,thus further inhibiting the expression of TNF-αand IL^(-1)βand other inflammatory factors.Escin could inhibit 11β-HSD2 but not 11β-HSD1,thus decrease the metabolism of glucocorticoid.Escin and glucocorticoids have similar chemical structures.This indicate that one of the anti-inflammatory mechanisms of escin may be due to its stimulating GR by binding to it.Eacin might be a partial agonist of GR.A good many of researches have demonstrated the anti-inflammatory properties of escin,and shed light on the underlying mechanisms by which escin exerts these effects.Escin,as an oral or intravenous formulation,or a topical gel,inhibits inflammation,producing measurable improvements in edema and acute lung injury.Further clinical studies of escin are needed to demonstrate these properties in larger patient populations.
基金2020 Project of Tibetan Medicine Administration of Tibet Autonomous Region(JJKT202004)and 2020 Reform and Development Special Project(324042000101)。
文摘OBJECTIVE To investigate whether Renqing Changjue has a protective effect on acute respiratory distress syndrome(ARDS)induced by endotoxin lipopolysaccharide(LPS)in rabbits.METHODS Thirty-six healthy male New Zealand white rabbits were randomly divided into six groups:normal control group,model group,dexamethasone group,Renqing Changjue high,middle and low dose group,with six rabbits in each group.LPS was used to replicate the ARDS model after five consecutive days of gavage.Arterial pressure,respiratory rate and anal temperature blood were recorded for arterial blood gas analysis at 0,0.5,1,2 and 4 h,respectively.At the end of the four-hour experiment,rabbits were killed by bloodletting,and the lung tissue was quickly removed to determine the cytokines,SOD,MDA and pathological examination of rabbit lung.RESULTS Renqing Changjue can significantly reduce the pathological changes of lung in ARDS model group.The expression of AQP1 and MPO in rabbit lung was significantly decreased by immunohistochemistry(P<0.05),reduce the lung wet/dry weight ratio,increase the ratio of PaO_(2)/FiO_(2),inhibit the release of inflammatory factors and scavenge free radicals and antioxidant effects.CONCLUSION Renqing Changjue can effectively protect rabbits with acute respiratory distress syndrome induced by LPS,and may protect the lung by inhibiting the release of cytokines and anti-oxidation.
