Non-alcoholic fatty liver disease (NAFLD) is a low-grade systemic inflammatory condition, since liver and adipose tissue tumor necrosis factor-α (TNF-α) and TNF receptor 1 transcripts and serum TNF-α levels are inc...Non-alcoholic fatty liver disease (NAFLD) is a low-grade systemic inflammatory condition, since liver and adipose tissue tumor necrosis factor-α (TNF-α) and TNF receptor 1 transcripts and serum TNF-α levels are increased and IL-6-/-mice are less prone to NAFLD. Fatty liver damage caused by high-fat diets is associated with the generation of pro-inflammatory prostaglandin E2 (PGE2). A decrease in the levels of arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the usefulness of EPA and DHA both in the prevention and management of NAFLD has been reported. AA, EPA and DHA and their anti-inflammatory products lipoxins (LXs), resolvins and protectins suppress IL-6 and TNF-α and PGE2 production. These results suggest that the activities of △6 and △5 desaturases are reduced in NAFLD and hence, the dietary essential fatty acids, linoleic acid (LA) and α-linolenic acid (ALA) are not metabolized to their long-chain products AA, EPA and DHA, the precursors of anti-inflammatory molecules, LXs, resolvins and protectins that could prevent NAFLD. This suggests that an imbalance between proand anti-inflammatory bioactive lipids contribute to NAFLD. Hence, it is proposed that plasma and tissue levels of AA, EPA, DHA and LXs, resolvins and protectins could be used as predictors and prognostic biomarkers of NAFLD. It is suggested that the synthesis and use of more stable analogues of LXs, resolvins and protectins need to be explored in the prevention and management of NAFLD.展开更多
Background Protectin D1 （PD1）,derived from docosahexaenoic acid,has been shown to control and resolve inflammation in some experimental models of inflammatory disorders.We investigated the protective roles of protec...Background Protectin D1 （PD1）,derived from docosahexaenoic acid,has been shown to control and resolve inflammation in some experimental models of inflammatory disorders.We investigated the protective roles of protectin D1 in pulmonary inflammation and lung injury induced by lipopolysaccharide （LPS）.Methods Mice were randomly assigned to six groups （n=6 per group）：sham-vehicle group,sham-PD1 group,shamzVAD-fmk group,LPS-vehicle group,LPS-PD1 group,and LPS-PD1-zVAD-fmk group.Mice were injected intratracheally with 3 mg/kg LPS or saline,followed 24 hours later by intravenous injection of 200 μg/mouse PD1 or vehicle.At the same time,some mice were also injected intraperitoneally with the pan-caspase inhibitor zVAD-fmk.Seventy-two hours after LPS challenge,samples of pulmonary tissue and bronchoalveolar lavage fluid were collected.Optical microscopy was used to examine pathological changes in lungs.Cellularity and protein concentration in bronchoalveolar lavage fluid were analyzed.Lung wet/dry ratios and myeloperoxidase activity were measured.Apoptosis of neutrophils in bronchoalveolar lavage fluid （BALF） was also evaluated by flow cytometry.Results Intratracheal instillation of LPS increased neutrophil counts,protein concentration in bronchoalveolar lavage fluid and myeloperoxidase activity,it induced lung histological injury and edema,and also suppressed apoptosis of neutrophils in BALF.Posttreatment with PD1 inhibited LPS-evoked changes in BALF neutrophil counts and protein concentration and lung myeloperoxidase activity,with the outcome of decreased pulmonary edema and histological injury.In addition,PD1 promoted apoptosis of neutrophils in BALF.The beneficial effects of PD1 were blocked by zVAD-fmk.Conclusion Posttreatment with PD1 enhances resolution of lung inflammation during LPS-induced acute lung injury by enhancing apoptosis in emigrated neutrophils,which is,at least in part,caspase-dependent.展开更多
Background：Acute lung injury （ALI） is a severe disease with high mortality and poor prognosis.Protectin DX （PDX）,a pro-resolving lipid mediator,exhibits protective effects in ALI.Our experiment aimed to explore t...Background：Acute lung injury （ALI） is a severe disease with high mortality and poor prognosis.Protectin DX （PDX）,a pro-resolving lipid mediator,exhibits protective effects in ALI.Our experiment aimed to explore the effects and related mechanisms of PDX in mice with ALI induced by lipopolysaccharide （LPS）.Methods：BALB/c mice were randomly divided into five groups：sham,LPS,LPS plus 1 ng ofPDX （LPS ＋ PDX-1 ng）,LPS plus 10 ng ofPDX （LPS ＋ PDX-10 ng）,and LPS plus 100 ng ofPDX （LPS ＋ PDX-100 ng）.Bronchoalveolar lavage fluids （BALFs） were collected after 24 h,and total cells,polymorphonuclear leukocytes,monocyte-macrophages,and lymphocytes in BALF were enumerated.The concentration of interleukin （IL）-1 β3,IL-6,IL-10,tumor necrosis factor-alpha （TNF-α）,macrophage inflammatory protein （MIP）-1 cα,and MIP-2 in BALF was determined,and histopathological changes of the lung were observed.The concentration of protein in BALF and lung wet/dry weight ratios were detected to evaluate pulmonary edema.After determining the optimal dose of PDX,neutrophil-platelet interactions in whole blood were evaluated by flow cytometry.Results：The highest dose of PDX （100 ng/mouse） failed to provide pulmonary protective effects,whereas lower doses of PDX （1 ng/mouse and 10 ng/mouse）,especially 1 ng PDX,alleviated pulmonary histopathological changes,mitigated LPS-induced ALI and pulmonary edema,inhibited neutrophil infiltration,and reduced pro-inflammatory mediator （IL-1β,IL-6,TNF-α,and MIP-lα） levels.Meanwhile,1 ng PDX exhibited pro-resolving functions in ALI including upregulation of monocyte-macrophage numbers and anti-inflammatory mediator IL-l 0 levels.The flow cytometry results showed that PDX could inhibit neutrophil-platelet interactions in ALI.Conclusion：PDX exerts protective effects in LPS-inducedALI by mitigating pulmonary inflammation and abrogating neutrophil-platelet interactions.展开更多
基金Supported by Ramalingaswami Fellowship of the Department of Biotechnology, Indiaa grant from the Defense Research and Development Organisation, New Delhi, India
文摘Non-alcoholic fatty liver disease (NAFLD) is a low-grade systemic inflammatory condition, since liver and adipose tissue tumor necrosis factor-α (TNF-α) and TNF receptor 1 transcripts and serum TNF-α levels are increased and IL-6-/-mice are less prone to NAFLD. Fatty liver damage caused by high-fat diets is associated with the generation of pro-inflammatory prostaglandin E2 (PGE2). A decrease in the levels of arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the usefulness of EPA and DHA both in the prevention and management of NAFLD has been reported. AA, EPA and DHA and their anti-inflammatory products lipoxins (LXs), resolvins and protectins suppress IL-6 and TNF-α and PGE2 production. These results suggest that the activities of △6 and △5 desaturases are reduced in NAFLD and hence, the dietary essential fatty acids, linoleic acid (LA) and α-linolenic acid (ALA) are not metabolized to their long-chain products AA, EPA and DHA, the precursors of anti-inflammatory molecules, LXs, resolvins and protectins that could prevent NAFLD. This suggests that an imbalance between proand anti-inflammatory bioactive lipids contribute to NAFLD. Hence, it is proposed that plasma and tissue levels of AA, EPA, DHA and LXs, resolvins and protectins could be used as predictors and prognostic biomarkers of NAFLD. It is suggested that the synthesis and use of more stable analogues of LXs, resolvins and protectins need to be explored in the prevention and management of NAFLD.
基金the Natural Science Foundation of Zhejing Province,China
文摘Background Protectin D1 （PD1）,derived from docosahexaenoic acid,has been shown to control and resolve inflammation in some experimental models of inflammatory disorders.We investigated the protective roles of protectin D1 in pulmonary inflammation and lung injury induced by lipopolysaccharide （LPS）.Methods Mice were randomly assigned to six groups （n=6 per group）：sham-vehicle group,sham-PD1 group,shamzVAD-fmk group,LPS-vehicle group,LPS-PD1 group,and LPS-PD1-zVAD-fmk group.Mice were injected intratracheally with 3 mg/kg LPS or saline,followed 24 hours later by intravenous injection of 200 μg/mouse PD1 or vehicle.At the same time,some mice were also injected intraperitoneally with the pan-caspase inhibitor zVAD-fmk.Seventy-two hours after LPS challenge,samples of pulmonary tissue and bronchoalveolar lavage fluid were collected.Optical microscopy was used to examine pathological changes in lungs.Cellularity and protein concentration in bronchoalveolar lavage fluid were analyzed.Lung wet/dry ratios and myeloperoxidase activity were measured.Apoptosis of neutrophils in bronchoalveolar lavage fluid （BALF） was also evaluated by flow cytometry.Results Intratracheal instillation of LPS increased neutrophil counts,protein concentration in bronchoalveolar lavage fluid and myeloperoxidase activity,it induced lung histological injury and edema,and also suppressed apoptosis of neutrophils in BALF.Posttreatment with PD1 inhibited LPS-evoked changes in BALF neutrophil counts and protein concentration and lung myeloperoxidase activity,with the outcome of decreased pulmonary edema and histological injury.In addition,PD1 promoted apoptosis of neutrophils in BALF.The beneficial effects of PD1 were blocked by zVAD-fmk.Conclusion Posttreatment with PD1 enhances resolution of lung inflammation during LPS-induced acute lung injury by enhancing apoptosis in emigrated neutrophils,which is,at least in part,caspase-dependent.
基金This work was supported by National Natural Science Foundation of China （No. 82372036,81671890）.
文摘Background：Acute lung injury （ALI） is a severe disease with high mortality and poor prognosis.Protectin DX （PDX）,a pro-resolving lipid mediator,exhibits protective effects in ALI.Our experiment aimed to explore the effects and related mechanisms of PDX in mice with ALI induced by lipopolysaccharide （LPS）.Methods：BALB/c mice were randomly divided into five groups：sham,LPS,LPS plus 1 ng ofPDX （LPS ＋ PDX-1 ng）,LPS plus 10 ng ofPDX （LPS ＋ PDX-10 ng）,and LPS plus 100 ng ofPDX （LPS ＋ PDX-100 ng）.Bronchoalveolar lavage fluids （BALFs） were collected after 24 h,and total cells,polymorphonuclear leukocytes,monocyte-macrophages,and lymphocytes in BALF were enumerated.The concentration of interleukin （IL）-1 β3,IL-6,IL-10,tumor necrosis factor-alpha （TNF-α）,macrophage inflammatory protein （MIP）-1 cα,and MIP-2 in BALF was determined,and histopathological changes of the lung were observed.The concentration of protein in BALF and lung wet/dry weight ratios were detected to evaluate pulmonary edema.After determining the optimal dose of PDX,neutrophil-platelet interactions in whole blood were evaluated by flow cytometry.Results：The highest dose of PDX （100 ng/mouse） failed to provide pulmonary protective effects,whereas lower doses of PDX （1 ng/mouse and 10 ng/mouse）,especially 1 ng PDX,alleviated pulmonary histopathological changes,mitigated LPS-induced ALI and pulmonary edema,inhibited neutrophil infiltration,and reduced pro-inflammatory mediator （IL-1β,IL-6,TNF-α,and MIP-lα） levels.Meanwhile,1 ng PDX exhibited pro-resolving functions in ALI including upregulation of monocyte-macrophage numbers and anti-inflammatory mediator IL-l 0 levels.The flow cytometry results showed that PDX could inhibit neutrophil-platelet interactions in ALI.Conclusion：PDX exerts protective effects in LPS-inducedALI by mitigating pulmonary inflammation and abrogating neutrophil-platelet interactions.
