Pub Date : 2018-06-25DOI: 10.1002/9781119433729.ch11
D. Benos
{"title":"Now what?","authors":"D. Benos","doi":"10.1002/9781119433729.ch11","DOIUrl":"https://doi.org/10.1002/9781119433729.ch11","url":null,"abstract":"","PeriodicalId":125752,"journal":{"name":"The American journal of physiology","volume":"19 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"120978848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1997-06-01DOI: 10.1152/AJPRENAL.1997.272.6.F816
T. Katsura, C. Gustafson, D. Ausiello, Dennis Brown
Vasopressin-dependent translocation of aquaporin-2 (AQP2) between intracellular vesicles and the plasma membrane has been demonstrated in vivo and in vitro. Furthermore, the vasopressin-induced increase in apical membrane water permeability of renal principal cells is dependent on a rise in intracellular adenosine 3',5'-cyclic monophosphate and activation of protein kinase A (PKA). To determine whether trafficking of AQP2 is dependent on PKA phosphorylation, we first examined the effect of the PKA-inhibitor N-(2[[3-(4-bromophenyl)-2-propenyl]-amino]-ethyl)-5-isoquinolinesulfonam ide (H-89) on AQP2 translocation in transfected LLC-PK1 cells. Vasopressin-induced membrane insertion of AQP2 was completely inhibited by pretreatment of the cells for 60 min with H-89. This reagent also caused a dense accumulation of AQP2 in the Golgi region. Next, LLC-PK1 cells were stably transfected with AQP2 cDNA in which the PKA phosphorylation site, Ser256, was replaced with alanine (S256A). S256A-AQP2 was not phosphorylated in vitro by PKA, and S256A-AQP2 was mainly localized to intracellular vesicles in the basal condition, similar to wild-type AQP2. However, after stimulation with vasopressin or forskolin, the cellular distribution of S256A-AQP2 remained unchanged. In addition, the usual vasopressin-induced increase in endocytosis seen in AQP2-transfected cells was not observed in S256A-AQP2-transfected cells. These results demonstrate that the Ser256 PKA phosphorylation site is possibly involved in the vasopressin-induced trafficking of AQP2 from intracellular vesicles to the plasma membrane and in the subsequent stimulation of endocytosis.
{"title":"Protein kinase A phosphorylation is involved in regulated exocytosis of aquaporin-2 in transfected LLC-PK1 cells.","authors":"T. Katsura, C. Gustafson, D. Ausiello, Dennis Brown","doi":"10.1152/AJPRENAL.1997.272.6.F816","DOIUrl":"https://doi.org/10.1152/AJPRENAL.1997.272.6.F816","url":null,"abstract":"Vasopressin-dependent translocation of aquaporin-2 (AQP2) between intracellular vesicles and the plasma membrane has been demonstrated in vivo and in vitro. Furthermore, the vasopressin-induced increase in apical membrane water permeability of renal principal cells is dependent on a rise in intracellular adenosine 3',5'-cyclic monophosphate and activation of protein kinase A (PKA). To determine whether trafficking of AQP2 is dependent on PKA phosphorylation, we first examined the effect of the PKA-inhibitor N-(2[[3-(4-bromophenyl)-2-propenyl]-amino]-ethyl)-5-isoquinolinesulfonam ide (H-89) on AQP2 translocation in transfected LLC-PK1 cells. Vasopressin-induced membrane insertion of AQP2 was completely inhibited by pretreatment of the cells for 60 min with H-89. This reagent also caused a dense accumulation of AQP2 in the Golgi region. Next, LLC-PK1 cells were stably transfected with AQP2 cDNA in which the PKA phosphorylation site, Ser256, was replaced with alanine (S256A). S256A-AQP2 was not phosphorylated in vitro by PKA, and S256A-AQP2 was mainly localized to intracellular vesicles in the basal condition, similar to wild-type AQP2. However, after stimulation with vasopressin or forskolin, the cellular distribution of S256A-AQP2 remained unchanged. In addition, the usual vasopressin-induced increase in endocytosis seen in AQP2-transfected cells was not observed in S256A-AQP2-transfected cells. These results demonstrate that the Ser256 PKA phosphorylation site is possibly involved in the vasopressin-induced trafficking of AQP2 from intracellular vesicles to the plasma membrane and in the subsequent stimulation of endocytosis.","PeriodicalId":125752,"journal":{"name":"The American journal of physiology","volume":"24 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114300566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1997-06-01DOI: 10.2957/KANZO.38.SUPL2_120
H. Kurosawa, F. Que, L. Roberts, Patricia J. Fesmier, G. Gores
Hepatocytes do not express Bcl-2, a repressor of apoptosis. In contrast, cholangiocytes, which are in direct contact with bile, do express Bcl-2. Because cholestasis results in the retention of bile within hepatocytes, we reasoned cholestasis may induce hepatocellular expression of Bcl-2. Thus our aim was to determine whether hepatocytes express Bcl-2 or alter expression of other Bcl-2 family members in cholestasis using the bile duct-ligated (BDL) rat as a model of cholestasis. De novo Bcl-2 expression was observed in hepatocytes of BDL rats assessed by reverse transcriptase-polymerase chain reaction and immunoblot analysis. Immunohistochemistry demonstrated that Bcl-2 expression in hepatocytes was greater in periportal hepatocytes than pericentral hepatocytes. Expression of Bcl-x (an antiapoptotic Bcl-2 family protein) was not altered by bile duct ligation, whereas expression of Bax (a proapoptotic Bcl-2 family protein) increased slightly as determined by Northern and Western blot analyses. Bcl-2-positive hepatocytes isolated from BDL rats were resistant to induction of apoptosis by 50 microM glycochenodeoxycholate. Our results demonstrate, for the first time, expression of Bcl-2 by hepatocytes during cholestasis. We suggest that hepatocellular expression of Bcl-2 during cholestasis is an adaptive phenomenon to resist apoptosis by toxic bile salts.
{"title":"Hepatocytes in the bile duct-ligated rat express Bcl-2.","authors":"H. Kurosawa, F. Que, L. Roberts, Patricia J. Fesmier, G. Gores","doi":"10.2957/KANZO.38.SUPL2_120","DOIUrl":"https://doi.org/10.2957/KANZO.38.SUPL2_120","url":null,"abstract":"Hepatocytes do not express Bcl-2, a repressor of apoptosis. In contrast, cholangiocytes, which are in direct contact with bile, do express Bcl-2. Because cholestasis results in the retention of bile within hepatocytes, we reasoned cholestasis may induce hepatocellular expression of Bcl-2. Thus our aim was to determine whether hepatocytes express Bcl-2 or alter expression of other Bcl-2 family members in cholestasis using the bile duct-ligated (BDL) rat as a model of cholestasis. De novo Bcl-2 expression was observed in hepatocytes of BDL rats assessed by reverse transcriptase-polymerase chain reaction and immunoblot analysis. Immunohistochemistry demonstrated that Bcl-2 expression in hepatocytes was greater in periportal hepatocytes than pericentral hepatocytes. Expression of Bcl-x (an antiapoptotic Bcl-2 family protein) was not altered by bile duct ligation, whereas expression of Bax (a proapoptotic Bcl-2 family protein) increased slightly as determined by Northern and Western blot analyses. Bcl-2-positive hepatocytes isolated from BDL rats were resistant to induction of apoptosis by 50 microM glycochenodeoxycholate. Our results demonstrate, for the first time, expression of Bcl-2 by hepatocytes during cholestasis. We suggest that hepatocellular expression of Bcl-2 during cholestasis is an adaptive phenomenon to resist apoptosis by toxic bile salts.","PeriodicalId":125752,"journal":{"name":"The American journal of physiology","volume":"88 3 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126103933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1997-04-01DOI: 10.1016/S0895-7061(97)89217-5
B. Csiky, G. Simon
{"title":"Synergistic vascular effects of dietary sodium supplementation and angiotensin II administration.","authors":"B. Csiky, G. Simon","doi":"10.1016/S0895-7061(97)89217-5","DOIUrl":"https://doi.org/10.1016/S0895-7061(97)89217-5","url":null,"abstract":"","PeriodicalId":125752,"journal":{"name":"The American journal of physiology","volume":"273 3 Pt 2 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1997-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131017361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1997-03-01DOI: 10.1097/00024382-199703001-00232
M. Uchiba, K. Okajima, K. Murakami, M. Johno, H. Okabe, K. Takatsuki
Acute respiratory distress syndrome (ARDS) is a serious complication of sepsis. Thrombomodulin, an important endothelial anticoagulant, binds thrombin to generate activated protein C (APC). We have previously demonstrated that APC prevents endotoxin (ET)-induced pulmonary vascular injury by inhibiting activated leukocytes. We therefore examined whether recombinant human soluble thrombomodulin (rhs-TM) prevents activated leukocyte-induced pulmonary vascular injury in rats receiving ET. Intravenous administration of rhs-TM prevented ET-induced pulmonary accumulation of leukocytes and increase in pulmonary vascular permeability, as well as ET-induced histological changes, such as leukocyte infiltration and pulmonary interstitial edema. Dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, did not prevent these effects of ET. rhs-TM did not prevent ET-induced pulmonary accumulation of leukocytes and pulmonary vascular injury in rats pretreated with DEGR-Xa. These results suggest that rhs-TM prevents ET-induced pulmonary vascular injury by inhibiting pulmonary accumulation of leukocytes and that this effect may be mediated primarily by APC generation.
{"title":"Recombinant thrombomodulin prevents endotoxin-induced lung injury in rats by inhibiting leukocyte activation.","authors":"M. Uchiba, K. Okajima, K. Murakami, M. Johno, H. Okabe, K. Takatsuki","doi":"10.1097/00024382-199703001-00232","DOIUrl":"https://doi.org/10.1097/00024382-199703001-00232","url":null,"abstract":"Acute respiratory distress syndrome (ARDS) is a serious complication of sepsis. Thrombomodulin, an important endothelial anticoagulant, binds thrombin to generate activated protein C (APC). We have previously demonstrated that APC prevents endotoxin (ET)-induced pulmonary vascular injury by inhibiting activated leukocytes. We therefore examined whether recombinant human soluble thrombomodulin (rhs-TM) prevents activated leukocyte-induced pulmonary vascular injury in rats receiving ET. Intravenous administration of rhs-TM prevented ET-induced pulmonary accumulation of leukocytes and increase in pulmonary vascular permeability, as well as ET-induced histological changes, such as leukocyte infiltration and pulmonary interstitial edema. Dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, did not prevent these effects of ET. rhs-TM did not prevent ET-induced pulmonary accumulation of leukocytes and pulmonary vascular injury in rats pretreated with DEGR-Xa. These results suggest that rhs-TM prevents ET-induced pulmonary vascular injury by inhibiting pulmonary accumulation of leukocytes and that this effect may be mediated primarily by APC generation.","PeriodicalId":125752,"journal":{"name":"The American journal of physiology","volume":"104 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1997-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122533748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1996-05-01DOI: 10.1097/00005768-199605001-01098
R. Hickson, L. Wegrzyn, D. Osborne, I. Karl
Skeletal muscle atrophy from glucocorticoids is prevented by glutamine infusion. Because the gene-encoding glutamine synthetase (GS) is glucocorticoid inducible, it represented an appropriate model for resting whether glucocorticoids and glutamine exert opposing actions on the expression of specific genes related to atrophy in muscle tissue. Rats were administered hydrocortisone 21-acetate or the dosing vehicle (carboxymethyl cellulose) and were infused with saline (Sal) or glutamine (Gln, 240 mM, 0.75 ml/h) for 7 days. Hormone treatment did not significantly lower glutamine levels in fast-twitch white or red regions of the quadriceps. Despite higher serum glutamine concentrations with amino acid infusion [1.52 +/- 0.03 (Gln) vs. 1.20 +/- 0.04 (Sal) mumol/ml], muscle glutamine concentrations were not markedly increased in these fiber types. In saline-infused animals, glucocorticoid treatment produced 200-300% increases in plantaris, fast-twitch white, and fast-twitch red muscle GS enzyme activity and mRNA. Moreover, in all muscle types studied, glutamine infusion diminished glucocorticoid effects on GS enzyme activity to 131-159% and on GS mRNA to 110-200% of the values in saline-treated controls. These data demonstrate that glutamine infusion results in inhibiting GS expression, but the absence of changes in muscle glutamine concentration suggests the interplay of additional regulators of the GS gene.
由糖皮质激素引起的骨骼肌萎缩可通过谷氨酰胺输注加以预防。由于编码谷氨酰胺合成酶(GS)的基因是糖皮质激素诱导的，因此它代表了一个合适的模型，用于研究糖皮质激素和谷氨酰胺是否对肌肉组织中与萎缩相关的特定基因的表达产生相反的作用。大鼠分别给予氢化可的松21-醋酸酯或给药载体(羧甲基纤维素)，并以生理盐水(Sal)或谷氨酰胺(Gln, 240 mM, 0.75 ml/h)灌胃7 d。激素治疗并没有显著降低快速收缩的股四头肌白色或红色区域的谷氨酰胺水平。尽管氨基酸输注提高了血清谷氨酰胺浓度[1.52 +/- 0.03 (Gln) vs. 1.20 +/- 0.04 (Sal) mumol/ml]，但这些纤维类型的肌肉谷氨酰胺浓度没有显著增加。在盐水灌注的动物中，糖皮质激素处理使跖肌、快抽搐白肌和快抽搐红肌GS酶活性和mRNA增加200-300%。此外，在所有研究的肌肉类型中，谷氨酰胺输注使糖皮质激素对GS酶活性的影响降低到盐水处理对照组的131-159%，GS mRNA降低到110-200%。这些数据表明，谷氨酰胺输注导致抑制GS表达，但肌肉谷氨酰胺浓度没有变化，这表明GS基因的其他调节因子相互作用。
{"title":"Glutamine interferes with glucocorticoid-induced expression of glutamine synthetase in skeletal muscle.","authors":"R. Hickson, L. Wegrzyn, D. Osborne, I. Karl","doi":"10.1097/00005768-199605001-01098","DOIUrl":"https://doi.org/10.1097/00005768-199605001-01098","url":null,"abstract":"Skeletal muscle atrophy from glucocorticoids is prevented by glutamine infusion. Because the gene-encoding glutamine synthetase (GS) is glucocorticoid inducible, it represented an appropriate model for resting whether glucocorticoids and glutamine exert opposing actions on the expression of specific genes related to atrophy in muscle tissue. Rats were administered hydrocortisone 21-acetate or the dosing vehicle (carboxymethyl cellulose) and were infused with saline (Sal) or glutamine (Gln, 240 mM, 0.75 ml/h) for 7 days. Hormone treatment did not significantly lower glutamine levels in fast-twitch white or red regions of the quadriceps. Despite higher serum glutamine concentrations with amino acid infusion [1.52 +/- 0.03 (Gln) vs. 1.20 +/- 0.04 (Sal) mumol/ml], muscle glutamine concentrations were not markedly increased in these fiber types. In saline-infused animals, glucocorticoid treatment produced 200-300% increases in plantaris, fast-twitch white, and fast-twitch red muscle GS enzyme activity and mRNA. Moreover, in all muscle types studied, glutamine infusion diminished glucocorticoid effects on GS enzyme activity to 131-159% and on GS mRNA to 110-200% of the values in saline-treated controls. These data demonstrate that glutamine infusion results in inhibiting GS expression, but the absence of changes in muscle glutamine concentration suggests the interplay of additional regulators of the GS gene.","PeriodicalId":125752,"journal":{"name":"The American journal of physiology","volume":"68 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1996-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116916244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1996-03-03DOI: 10.1097/00005768-199605001-00550
H. Nielsen, N. Secher, J. H. Kristensen, N. Christensen, K. Espersen, B. Pedersen
To evaluate the role of the spleen for the exercise-induced lymphocytosis, six splenectomized subjects and six matched control subjects cycled for 12 min at two submaximal work rates corresponding to 50 and 75% of their maximal work capacity, followed by a supramaximal intensity maintained until exhaustion (16 +/- 1 min; mean +/- SE). Venous blood samples were taken before, during, and 2 h after the maximal load. In both groups, the concentration of lymphocytes became elevated during exercise, but the increase from the level at rest was impaired in the splenectomized subjects compared with that of the controls (118 +/- 34 vs. 238 +/- 38%; P < 0.05). This was reflected in several lymphocyte subsets: cluster designation (CD) 3+ cells (pan T lymphocytes), 69 +/- 19 vs. 204 +/- 37%; CD8+ cells (T lymphocyte subset), 164 +/- 41 vs. 467 +/- 68%; CD16+ cells [natural killer (NK) cells], 291 +/- 88 vs. 870 +/- 177%; CD56+ cells (NK cells), 301 +/- 108 vs. 753 +/- 187%. Also, the specific NK cell lysis of target cells (NK cell activity) during exercise was lower for the splenectomized subjects (30 +/- 7%) than that of the control subjects (52 +/- 10%), but evaluation of lytic units indicates that this was due to a reduced number of NK cells in the assay rather than insufficient cell lysis. Plasma catecholamines reached the same level in the splenectomized subjects and control subjects, which was taken to reflect that the activity of the sympathetic nervous system was similar in the two groups of subjects. Thus the major finding of this study is that the spleen is important for lymphocytosis during exercise, accounting for two-thirds of the increase in T lymphocytes and NK cells.
{"title":"Splenectomy impairs lymphocytosis during maximal exercise.","authors":"H. Nielsen, N. Secher, J. H. Kristensen, N. Christensen, K. Espersen, B. Pedersen","doi":"10.1097/00005768-199605001-00550","DOIUrl":"https://doi.org/10.1097/00005768-199605001-00550","url":null,"abstract":"To evaluate the role of the spleen for the exercise-induced lymphocytosis, six splenectomized subjects and six matched control subjects cycled for 12 min at two submaximal work rates corresponding to 50 and 75% of their maximal work capacity, followed by a supramaximal intensity maintained until exhaustion (16 +/- 1 min; mean +/- SE). Venous blood samples were taken before, during, and 2 h after the maximal load. In both groups, the concentration of lymphocytes became elevated during exercise, but the increase from the level at rest was impaired in the splenectomized subjects compared with that of the controls (118 +/- 34 vs. 238 +/- 38%; P < 0.05). This was reflected in several lymphocyte subsets: cluster designation (CD) 3+ cells (pan T lymphocytes), 69 +/- 19 vs. 204 +/- 37%; CD8+ cells (T lymphocyte subset), 164 +/- 41 vs. 467 +/- 68%; CD16+ cells [natural killer (NK) cells], 291 +/- 88 vs. 870 +/- 177%; CD56+ cells (NK cells), 301 +/- 108 vs. 753 +/- 187%. Also, the specific NK cell lysis of target cells (NK cell activity) during exercise was lower for the splenectomized subjects (30 +/- 7%) than that of the control subjects (52 +/- 10%), but evaluation of lytic units indicates that this was due to a reduced number of NK cells in the assay rather than insufficient cell lysis. Plasma catecholamines reached the same level in the splenectomized subjects and control subjects, which was taken to reflect that the activity of the sympathetic nervous system was similar in the two groups of subjects. Thus the major finding of this study is that the spleen is important for lymphocytosis during exercise, accounting for two-thirds of the increase in T lymphocytes and NK cells.","PeriodicalId":125752,"journal":{"name":"The American journal of physiology","volume":"5 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1996-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116315491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1996-02-01DOI: 10.1016/S0735-1097(96)82191-7
J. Dupuis, C. Goresky, C. Rose, D. Stewart, P. Cernacek, A. Schwab, A. Simard
{"title":"Endothelin-1 myocardial clearance, production, and effect on capillary permeability in vivo.","authors":"J. Dupuis, C. Goresky, C. Rose, D. Stewart, P. Cernacek, A. Schwab, A. Simard","doi":"10.1016/S0735-1097(96)82191-7","DOIUrl":"https://doi.org/10.1016/S0735-1097(96)82191-7","url":null,"abstract":"","PeriodicalId":125752,"journal":{"name":"The American journal of physiology","volume":"273 3 Pt 2 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1996-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129736197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1995-10-01DOI: 10.1097/00005176-199510000-00123
C. Deutschman, B. Haber, K. Andrejko, D. E. Cressman, R. Harrison, E. Elenko, R. Taub
Hepatocellular dysfunction in sepsis may be neutrophil mediated. We therefore tested the hypothesis that sepsis-induced neutrophil accumulation is associated with increased expression of the chemokine, cytokine-induced neutrophil chemoattractant (CINC). In Sprague-Dawley rats made septic by cecal ligation and puncture, we demonstrate a time-dependent increase in CINC mRNA, which returns to baseline by 48 h. By in situ hybridization, this mRNA is present in hepatocytes and nonparenchymal cells. CINC protein levels in septic animals parallel mRNA levels and resolve by 48 h. Because CINC expression is induced by cytokines including tumor necrosis factor-alpha (TNF- alpha), we show, by immunohistochemistry, that sepsis elevates intrahepatic TNF-alpha. Finally, because the CINC promoter is transactivated by the transcription factor, nuclear factor kappa B (NF-kappa B), we determined that hepatic NF-kappa B DNA binding increases dramatically, peaking 16 h after cecal ligation and puncture. Thus activated NF-kappa B may mediate CINC induction in sepsis. This constellation of findings suggests a mechanism by which sepsis may induce neutrophil accumulation in the liver and may have implications regarding sepsis-induced hepatic dysfunction.
脓毒症的肝细胞功能障碍可能是中性粒细胞介导的。因此，我们验证了脓毒症诱导的中性粒细胞积累与趋化因子、细胞因子诱导的中性粒细胞趋化剂(CINC)的表达增加有关的假设。在通过盲肠结扎和穿刺导致脓毒症的Sprague-Dawley大鼠中，我们发现CINC mRNA呈时间依赖性增加，在48小时后恢复到基线水平。通过原位杂交，这种mRNA存在于肝细胞和非实质细胞中。脓毒症动物的CINC蛋白水平与mRNA水平平行，并在48小时后消退。由于CINC的表达是由包括肿瘤坏死因子- α (TNF- α)在内的细胞因子诱导的，我们通过免疫组织化学发现，脓毒症升高肝内TNF- α。最后，由于CINC启动子被转录因子核因子kappa B (NF-kappa B)反激活，我们确定肝脏NF-kappa B DNA结合显著增加，在盲肠结扎和穿刺后16小时达到峰值。因此活化的nf - κ B可能介导败血症的CINC诱导。这些发现提示了脓毒症可能诱导肝脏中性粒细胞积聚的机制，并可能与脓毒症引起的肝功能障碍有关。
{"title":"Increased expression of cytokine-induced neutrophil chemoattractant in septic rat liver.","authors":"C. Deutschman, B. Haber, K. Andrejko, D. E. Cressman, R. Harrison, E. Elenko, R. Taub","doi":"10.1097/00005176-199510000-00123","DOIUrl":"https://doi.org/10.1097/00005176-199510000-00123","url":null,"abstract":"Hepatocellular dysfunction in sepsis may be neutrophil mediated. We therefore tested the hypothesis that sepsis-induced neutrophil accumulation is associated with increased expression of the chemokine, cytokine-induced neutrophil chemoattractant (CINC). In Sprague-Dawley rats made septic by cecal ligation and puncture, we demonstrate a time-dependent increase in CINC mRNA, which returns to baseline by 48 h. By in situ hybridization, this mRNA is present in hepatocytes and nonparenchymal cells. CINC protein levels in septic animals parallel mRNA levels and resolve by 48 h. Because CINC expression is induced by cytokines including tumor necrosis factor-alpha (TNF- alpha), we show, by immunohistochemistry, that sepsis elevates intrahepatic TNF-alpha. Finally, because the CINC promoter is transactivated by the transcription factor, nuclear factor kappa B (NF-kappa B), we determined that hepatic NF-kappa B DNA binding increases dramatically, peaking 16 h after cecal ligation and puncture. Thus activated NF-kappa B may mediate CINC induction in sepsis. This constellation of findings suggests a mechanism by which sepsis may induce neutrophil accumulation in the liver and may have implications regarding sepsis-induced hepatic dysfunction.","PeriodicalId":125752,"journal":{"name":"The American journal of physiology","volume":"12 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1995-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116306087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1995-06-01DOI: 10.1097/00024382-199506000-00178
C. Lang
Previous studies have demonstrated that in vivo injection of lipopolysaccharide (LPS) acutely stimulates glucose uptake (GU) in skeletal muscle. The purpose of the present study was to determine whether this enhanced GU is neurally mediated. In the first group of rats, a unilateral sciatic nerve transection was performed 3 h before injection of LPS, and in vivo GU was assessed using 2-[14C]deoxy-D-glucose 40 min after LPS injection. At this time, LPS-treated rats were hyperglycemic (12 mM), and insulin levels were not different from control rats. In the innervated leg, LPS increased GU 43-228%, depending on the muscle type. In contrast, LPS failed to increase GU in muscles from the denervated limb. In other experiments, somatostatin was infused to produce an insulinopenic condition before the injection of LPS. Despite insulinopenia, muscle GU was still increased by LPS. In control rats, in which the euglycemic hyperinsulinemic clamp technique was used, acute muscle denervation was shown to impair insulin-mediated GU in the presence of pharmacological, but not physiological, insulin levels. Non-insulin-mediated GU (NIMGU) was assessed in rats that were insulinopenic and hyperglycemic. In innervated muscle, NIMGU was increased 56-126 and 118-145% when the plasma glucose was elevated to 9 and 12 mM, respectively. In contrast, hyperglycemia-induced increases in NIMGU were attenuated in denervated muscle. These data demonstrate that 1) the early LPS-induced stimulation of muscle GU is mediated via a non-insulin-mediated pathway and 2) the LPS-induced increase in NIMGU in muscle is neurally mediated.
先前的研究表明，体内注射脂多糖(LPS)会急性刺激骨骼肌的葡萄糖摄取(GU)。本研究的目的是确定这种增强的GU是否由神经介导。第一组大鼠在注射LPS前3小时行单侧坐骨神经横断术，注射LPS后40分钟用2-[14C]脱氧- d -葡萄糖测定体内GU。此时，lps处理大鼠高血糖(12 mM)，胰岛素水平与对照大鼠无差异。在神经支配的腿部，根据肌肉类型不同，LPS使GU增加43-228%。相比之下，LPS不能增加失神经肢体肌肉的GU。在其他实验中，在注射LPS之前注入生长抑素以产生胰岛素缺乏状态。尽管胰岛素缺乏，但LPS仍使肌肉GU升高。在使用正糖高胰岛素钳夹技术的对照大鼠中，急性肌肉去神经支配显示在药理学而非生理性胰岛素水平存在的情况下损害胰岛素介导的GU。在胰岛素缺乏和高血糖大鼠中评估非胰岛素介导的GU (NIMGU)。在神经支配肌中，当血浆葡萄糖升高至9和12 mM时，NIMGU分别升高56-126和118-145%。相反，高血糖引起的NIMGU升高在去神经支配肌肉中减弱。这些数据表明:1)lps诱导的肌肉GU的早期刺激是通过非胰岛素介导的途径介导的;2)lps诱导的肌肉NIMGU的增加是神经介导的。
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