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
Objective Hypoxemia is one of the main factors of pulmonary hypertension,and it can also be a complication of pulmonary hypertension,and it is a risk factor for many cardiovascular diseases,which increases the adverse...Objective Hypoxemia is one of the main factors of pulmonary hypertension,and it can also be a complication of pulmonary hypertension,and it is a risk factor for many cardiovascular diseases,which increases the adverse prognosis of patients.At present,there are some controversies about the diagnosis and treatment of sleep apnea disorder in patients with pulmonary hypertension.展开更多
根据脊柱侧凸研究会（Scoliosis Research Scociety,SRS）制定的标准,在10岁（不包括10岁）之前发生的所有类型脊柱侧凸畸形定义为早发性脊柱侧凸（early onset scoliosis,EOS）,包括特发性的（Idiopathic）和非特发性的（Non-idiopathi...根据脊柱侧凸研究会（Scoliosis Research Scociety,SRS）制定的标准,在10岁（不包括10岁）之前发生的所有类型脊柱侧凸畸形定义为早发性脊柱侧凸（early onset scoliosis,EOS）,包括特发性的（Idiopathic）和非特发性的（Non-idiopathic）脊柱侧凸。而早期文献[1]和著作[2]报道将早发性脊柱侧凸的年龄界限规定在5岁之前。正常情况下[3~6],0~5岁T1~S1高度平均增长10cm,T1~T12增长7cm;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Objective Hypoxemia is one of the main factors of pulmonary hypertension,and it can also be a complication of pulmonary hypertension,and it is a risk factor for many cardiovascular diseases,which increases the adverse prognosis of patients.At present,there are some controversies about the diagnosis and treatment of sleep apnea disorder in patients with pulmonary hypertension.
文摘根据脊柱侧凸研究会（Scoliosis Research Scociety,SRS）制定的标准,在10岁（不包括10岁）之前发生的所有类型脊柱侧凸畸形定义为早发性脊柱侧凸（early onset scoliosis,EOS）,包括特发性的（Idiopathic）和非特发性的（Non-idiopathic）脊柱侧凸。而早期文献[1]和著作[2]报道将早发性脊柱侧凸的年龄界限规定在5岁之前。正常情况下[3~6],0~5岁T1~S1高度平均增长10cm,T1~T12增长7cm;
