The Experts below are selected from a list of 282 Experts worldwide ranked by ideXlab platform
R A Zager - One of the best experts on this subject based on the ideXlab platform.
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toll like receptor tlr4 shedding and depletion acute proximal tubular cell responses to hypoxic and Toxic Injury
American Journal of Physiology-renal Physiology, 2007Co-Authors: R A Zager, Ali C M Johnson, Steve Lund, Julie RandolphhabeckerAbstract:Acute renal failure (ARF) induces tubular hyperresponsiveness to TLR4 ligands, culminating in exaggerated renal cytokine/chemokine production. However, the fate of TLR4 protein during acute tubular...
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Renal cortical ceramide patterns during ischemic and Toxic Injury: assessments by HPLC-mass spectrometry
American Journal of Physiology-Renal Physiology, 1999Co-Authors: T Kalhorn, R A ZagerAbstract:Ceramides are a class of signaling molecules that can acutely accumulate in tissues as part of a “stress response.” They are classically measured by the diacylglycerol kinase assay, which, in general, measures total ceramide rather than individual moieties within the diverse ceramide family. The present study was undertaken to 1) adapt current HPLC-mass spectrometry technology for measuring individual renal ceramides, and 2) use this technique to more fully characterize the nature of the renal ceramide “stress” reaction. Renal cortical tissues were obtained from CD-1 mice under control conditions and 2 or 18 h after renal Injury (ischemia-reperfusion and glycerol-mediated myohemoglobinuria). C24, C22, and C16 ceramides were identified in normal renal cortex, constituting 70, 10, and 20% of the total ceramide pool, respectively. Within each of these families, heterogeneity was apparent because of differing degrees of unsaturation (0–3 double bonds) in the constituent fatty acid of ceramide. Renal Injury dramatically changed ceramide profiles: 1) total ceramide increased by ∼300%; 2) although all ceramides participated in this reaction, they did so to differing degrees; 3) this caused pronounced changes in ceramide distribution patterns; 4) Injury induced a striking shift toward unsaturated (vs. saturated) fatty acids within the C22 and C24 (but not the C16) ceramide pools; and 5) the extent of these qualitative changes differed according to the etiology of the initiating renal damage. Thus we conclude that ceramide stress response involves major qualitative (and not simply quantitative) changes in ceramide expression that are partially disease dependent. These findings underscore the fact that simply measuring total renal ceramide content (e.g., by diacylglycerol kinase assay) substantially oversimplifies the nature and, hence, the potential implications of the ceramide stress reaction.
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Renal cortical ceramide patterns during ischemic and Toxic Injury: assessments by HPLC-mass spectrometry.
The American journal of physiology, 1999Co-Authors: T Kalhorn, R A ZagerAbstract:Ceramides are a class of signaling molecules that can acutely accumulate in tissues as part of a "stress response." They are classically measured by the diacylglycerol kinase assay, which, in general, measures total ceramide rather than individual moieties within the diverse ceramide family. The present study was undertaken to 1) adapt current HPLC-mass spectrometry technology for measuring individual renal ceramides, and 2) use this technique to more fully characterize the nature of the renal ceramide "stress" reaction. Renal cortical tissues were obtained from CD-1 mice under control conditions and 2 or 18 h after renal Injury (ischemia-reperfusion and glycerol-mediated myohemoglobinuria). C24, C22, and C16 ceramides were identified in normal renal cortex, constituting 70, 10, and 20% of the total ceramide pool, respectively. Within each of these families, heterogeneity was apparent because of differing degrees of unsaturation (0-3 double bonds) in the constituent fatty acid of ceramide. Renal Injury dramatically changed ceramide profiles: 1) total ceramide increased by approximately 300%; 2) although all ceramides participated in this reaction, they did so to differing degrees; 3) this caused pronounced changes in ceramide distribution patterns; 4) Injury induced a striking shift toward unsaturated (vs. saturated) fatty acids within the C22 and C24 (but not the C16) ceramide pools; and 5) the extent of these qualitative changes differed according to the etiology of the initiating renal damage. Thus we conclude that ceramide stress response involves major qualitative (and not simply quantitative) changes in ceramide expression that are partially disease dependent. These findings underscore the fact that simply measuring total renal ceramide content (e.g., by diacylglycerol kinase assay) substantially oversimplifies the nature and, hence, the potential implications of the ceramide stress reaction.
Nelson Fausto - One of the best experts on this subject based on the ideXlab platform.
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Transforming growth factor‐α expression during liver regeneration after partial hepatectomy and Toxic Injury, and potential interactions between transforming growth factor‐α and hepatocyte growth factor
Hepatology, 1993Co-Authors: Eric M. Webber, Pamela I. Brown, Molly H. Bartlett, Mark J Fitzgerald, Nelson FaustoAbstract:Transforming growth factor-α and hepatocyte growth factor are important stimulators of hepatocyte proliferation. In this series of experiments we sought to measure the expression of transforming growth factor-α mRNA by hepatocytes in response to Toxic liver Injury produced by carbon tetrachloride or galactosamine and to perform a more detailed analysis of transforming growth factor-α expression after partial hepatectomy. We also explored the interactions of transforming growth factor-α and hepatocyte growth factor in their effects on hepatocytes in vitro and tested the ability of these factors to stimulate endogenous transforming growth factor-α production by hepatocytes. In previous work we have used oligonucleotide probes to measure transforming growth factor-α mRNA expression after partial hepatectomy. In this study we used a rat transforming growth factor-α cDNA probe and found that the level of liver transforming growth factor-α mRNA increases 4 hr after partial hepatectomy, shows peak expression at 18 hr and returns to the normal level by 36 to 48 hr. Measurement of the corresponding peptide in the liver by means of radioimmunoassay shows that the level of transforming growth factor-α rises by 12 hr, peaks at 24 hr and remains significantly increased at 48 hr compared with the levels in sham-operated rats. Carbon tetrachloride and galactosamine are known to produce different patterns of acute liver Injury, with maximal hepatocyte DNA synthesis at 48 hr and 5 days, respectively. After carbon tetrachloride administration the profiles of the transforming growth factor-α and hepatocyte growth factor mRNA expression are similar, each showing two peaks: the first at 12 hr and the second at 48 hr. In contrast, after galactosamineinduced liver Injury the expression patterns of transforming growth factor-α and hepatocyte growth factor mRNAs differ: hepatocyte growth factor shows a major peak at 24 hr, with a smaller increase at 5 days, whereas transforming growth factor-α begins to increase after 2 days, with a single peak occurring at 5 days. In primary hepatocyte cultures, transforming growth factor-α and hepatocyte growth factor appear to have complementary effects. The maximal hepatocyte nuclear labeling index induced by hepatocyte growth factor was 42%; the addition of transforming growth factor-α increased this to 74%. Exogenous transforming growth factor-α, but not hepatocyte growth factor, stimulates the production of the transforming growth factor-α peptide by hepatocytes. However, when hepatocyte growth factor is added to cultures already containing transforming growth factor-α it further increases the amount of transforming growth factor-α-stimulated transforming growth factor-α synthesis by approximately 40%. These results strengthen the view that transforming growth factor-α is an important physiological stimulator of hepatocyte replication in liver growth induced by partial hepatectomy and Toxic Injury and that hepatocyte growth factor may modulate hepatocyte transforming growth factor-α secretion. (HEPATOLOGY 1993;18:1422–1431.)
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transforming growth factor α expression during liver regeneration after partial hepatectomy and Toxic Injury and potential interactions between transforming growth factor α and hepatocyte growth factor
Hepatology, 1993Co-Authors: Eric M. Webber, Pamela I. Brown, Molly H. Bartlett, Mark J Fitzgerald, Nelson FaustoAbstract:Transforming growth factor-α and hepatocyte growth factor are important stimulators of hepatocyte proliferation. In this series of experiments we sought to measure the expression of transforming growth factor-α mRNA by hepatocytes in response to Toxic liver Injury produced by carbon tetrachloride or galactosamine and to perform a more detailed analysis of transforming growth factor-α expression after partial hepatectomy. We also explored the interactions of transforming growth factor-α and hepatocyte growth factor in their effects on hepatocytes in vitro and tested the ability of these factors to stimulate endogenous transforming growth factor-α production by hepatocytes. In previous work we have used oligonucleotide probes to measure transforming growth factor-α mRNA expression after partial hepatectomy. In this study we used a rat transforming growth factor-α cDNA probe and found that the level of liver transforming growth factor-α mRNA increases 4 hr after partial hepatectomy, shows peak expression at 18 hr and returns to the normal level by 36 to 48 hr. Measurement of the corresponding peptide in the liver by means of radioimmunoassay shows that the level of transforming growth factor-α rises by 12 hr, peaks at 24 hr and remains significantly increased at 48 hr compared with the levels in sham-operated rats. Carbon tetrachloride and galactosamine are known to produce different patterns of acute liver Injury, with maximal hepatocyte DNA synthesis at 48 hr and 5 days, respectively. After carbon tetrachloride administration the profiles of the transforming growth factor-α and hepatocyte growth factor mRNA expression are similar, each showing two peaks: the first at 12 hr and the second at 48 hr. In contrast, after galactosamineinduced liver Injury the expression patterns of transforming growth factor-α and hepatocyte growth factor mRNAs differ: hepatocyte growth factor shows a major peak at 24 hr, with a smaller increase at 5 days, whereas transforming growth factor-α begins to increase after 2 days, with a single peak occurring at 5 days. In primary hepatocyte cultures, transforming growth factor-α and hepatocyte growth factor appear to have complementary effects. The maximal hepatocyte nuclear labeling index induced by hepatocyte growth factor was 42%; the addition of transforming growth factor-α increased this to 74%. Exogenous transforming growth factor-α, but not hepatocyte growth factor, stimulates the production of the transforming growth factor-α peptide by hepatocytes. However, when hepatocyte growth factor is added to cultures already containing transforming growth factor-α it further increases the amount of transforming growth factor-α-stimulated transforming growth factor-α synthesis by approximately 40%. These results strengthen the view that transforming growth factor-α is an important physiological stimulator of hepatocyte replication in liver growth induced by partial hepatectomy and Toxic Injury and that hepatocyte growth factor may modulate hepatocyte transforming growth factor-α secretion. (HEPATOLOGY 1993;18:1422–1431.)
Eric M. Webber - One of the best experts on this subject based on the ideXlab platform.
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Transforming growth factor‐α expression during liver regeneration after partial hepatectomy and Toxic Injury, and potential interactions between transforming growth factor‐α and hepatocyte growth factor
Hepatology, 1993Co-Authors: Eric M. Webber, Pamela I. Brown, Molly H. Bartlett, Mark J Fitzgerald, Nelson FaustoAbstract:Transforming growth factor-α and hepatocyte growth factor are important stimulators of hepatocyte proliferation. In this series of experiments we sought to measure the expression of transforming growth factor-α mRNA by hepatocytes in response to Toxic liver Injury produced by carbon tetrachloride or galactosamine and to perform a more detailed analysis of transforming growth factor-α expression after partial hepatectomy. We also explored the interactions of transforming growth factor-α and hepatocyte growth factor in their effects on hepatocytes in vitro and tested the ability of these factors to stimulate endogenous transforming growth factor-α production by hepatocytes. In previous work we have used oligonucleotide probes to measure transforming growth factor-α mRNA expression after partial hepatectomy. In this study we used a rat transforming growth factor-α cDNA probe and found that the level of liver transforming growth factor-α mRNA increases 4 hr after partial hepatectomy, shows peak expression at 18 hr and returns to the normal level by 36 to 48 hr. Measurement of the corresponding peptide in the liver by means of radioimmunoassay shows that the level of transforming growth factor-α rises by 12 hr, peaks at 24 hr and remains significantly increased at 48 hr compared with the levels in sham-operated rats. Carbon tetrachloride and galactosamine are known to produce different patterns of acute liver Injury, with maximal hepatocyte DNA synthesis at 48 hr and 5 days, respectively. After carbon tetrachloride administration the profiles of the transforming growth factor-α and hepatocyte growth factor mRNA expression are similar, each showing two peaks: the first at 12 hr and the second at 48 hr. In contrast, after galactosamineinduced liver Injury the expression patterns of transforming growth factor-α and hepatocyte growth factor mRNAs differ: hepatocyte growth factor shows a major peak at 24 hr, with a smaller increase at 5 days, whereas transforming growth factor-α begins to increase after 2 days, with a single peak occurring at 5 days. In primary hepatocyte cultures, transforming growth factor-α and hepatocyte growth factor appear to have complementary effects. The maximal hepatocyte nuclear labeling index induced by hepatocyte growth factor was 42%; the addition of transforming growth factor-α increased this to 74%. Exogenous transforming growth factor-α, but not hepatocyte growth factor, stimulates the production of the transforming growth factor-α peptide by hepatocytes. However, when hepatocyte growth factor is added to cultures already containing transforming growth factor-α it further increases the amount of transforming growth factor-α-stimulated transforming growth factor-α synthesis by approximately 40%. These results strengthen the view that transforming growth factor-α is an important physiological stimulator of hepatocyte replication in liver growth induced by partial hepatectomy and Toxic Injury and that hepatocyte growth factor may modulate hepatocyte transforming growth factor-α secretion. (HEPATOLOGY 1993;18:1422–1431.)
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transforming growth factor α expression during liver regeneration after partial hepatectomy and Toxic Injury and potential interactions between transforming growth factor α and hepatocyte growth factor
Hepatology, 1993Co-Authors: Eric M. Webber, Pamela I. Brown, Molly H. Bartlett, Mark J Fitzgerald, Nelson FaustoAbstract:Transforming growth factor-α and hepatocyte growth factor are important stimulators of hepatocyte proliferation. In this series of experiments we sought to measure the expression of transforming growth factor-α mRNA by hepatocytes in response to Toxic liver Injury produced by carbon tetrachloride or galactosamine and to perform a more detailed analysis of transforming growth factor-α expression after partial hepatectomy. We also explored the interactions of transforming growth factor-α and hepatocyte growth factor in their effects on hepatocytes in vitro and tested the ability of these factors to stimulate endogenous transforming growth factor-α production by hepatocytes. In previous work we have used oligonucleotide probes to measure transforming growth factor-α mRNA expression after partial hepatectomy. In this study we used a rat transforming growth factor-α cDNA probe and found that the level of liver transforming growth factor-α mRNA increases 4 hr after partial hepatectomy, shows peak expression at 18 hr and returns to the normal level by 36 to 48 hr. Measurement of the corresponding peptide in the liver by means of radioimmunoassay shows that the level of transforming growth factor-α rises by 12 hr, peaks at 24 hr and remains significantly increased at 48 hr compared with the levels in sham-operated rats. Carbon tetrachloride and galactosamine are known to produce different patterns of acute liver Injury, with maximal hepatocyte DNA synthesis at 48 hr and 5 days, respectively. After carbon tetrachloride administration the profiles of the transforming growth factor-α and hepatocyte growth factor mRNA expression are similar, each showing two peaks: the first at 12 hr and the second at 48 hr. In contrast, after galactosamineinduced liver Injury the expression patterns of transforming growth factor-α and hepatocyte growth factor mRNAs differ: hepatocyte growth factor shows a major peak at 24 hr, with a smaller increase at 5 days, whereas transforming growth factor-α begins to increase after 2 days, with a single peak occurring at 5 days. In primary hepatocyte cultures, transforming growth factor-α and hepatocyte growth factor appear to have complementary effects. The maximal hepatocyte nuclear labeling index induced by hepatocyte growth factor was 42%; the addition of transforming growth factor-α increased this to 74%. Exogenous transforming growth factor-α, but not hepatocyte growth factor, stimulates the production of the transforming growth factor-α peptide by hepatocytes. However, when hepatocyte growth factor is added to cultures already containing transforming growth factor-α it further increases the amount of transforming growth factor-α-stimulated transforming growth factor-α synthesis by approximately 40%. These results strengthen the view that transforming growth factor-α is an important physiological stimulator of hepatocyte replication in liver growth induced by partial hepatectomy and Toxic Injury and that hepatocyte growth factor may modulate hepatocyte transforming growth factor-α secretion. (HEPATOLOGY 1993;18:1422–1431.)
Mark J Fitzgerald - One of the best experts on this subject based on the ideXlab platform.
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Transforming growth factor‐α expression during liver regeneration after partial hepatectomy and Toxic Injury, and potential interactions between transforming growth factor‐α and hepatocyte growth factor
Hepatology, 1993Co-Authors: Eric M. Webber, Pamela I. Brown, Molly H. Bartlett, Mark J Fitzgerald, Nelson FaustoAbstract:Transforming growth factor-α and hepatocyte growth factor are important stimulators of hepatocyte proliferation. In this series of experiments we sought to measure the expression of transforming growth factor-α mRNA by hepatocytes in response to Toxic liver Injury produced by carbon tetrachloride or galactosamine and to perform a more detailed analysis of transforming growth factor-α expression after partial hepatectomy. We also explored the interactions of transforming growth factor-α and hepatocyte growth factor in their effects on hepatocytes in vitro and tested the ability of these factors to stimulate endogenous transforming growth factor-α production by hepatocytes. In previous work we have used oligonucleotide probes to measure transforming growth factor-α mRNA expression after partial hepatectomy. In this study we used a rat transforming growth factor-α cDNA probe and found that the level of liver transforming growth factor-α mRNA increases 4 hr after partial hepatectomy, shows peak expression at 18 hr and returns to the normal level by 36 to 48 hr. Measurement of the corresponding peptide in the liver by means of radioimmunoassay shows that the level of transforming growth factor-α rises by 12 hr, peaks at 24 hr and remains significantly increased at 48 hr compared with the levels in sham-operated rats. Carbon tetrachloride and galactosamine are known to produce different patterns of acute liver Injury, with maximal hepatocyte DNA synthesis at 48 hr and 5 days, respectively. After carbon tetrachloride administration the profiles of the transforming growth factor-α and hepatocyte growth factor mRNA expression are similar, each showing two peaks: the first at 12 hr and the second at 48 hr. In contrast, after galactosamineinduced liver Injury the expression patterns of transforming growth factor-α and hepatocyte growth factor mRNAs differ: hepatocyte growth factor shows a major peak at 24 hr, with a smaller increase at 5 days, whereas transforming growth factor-α begins to increase after 2 days, with a single peak occurring at 5 days. In primary hepatocyte cultures, transforming growth factor-α and hepatocyte growth factor appear to have complementary effects. The maximal hepatocyte nuclear labeling index induced by hepatocyte growth factor was 42%; the addition of transforming growth factor-α increased this to 74%. Exogenous transforming growth factor-α, but not hepatocyte growth factor, stimulates the production of the transforming growth factor-α peptide by hepatocytes. However, when hepatocyte growth factor is added to cultures already containing transforming growth factor-α it further increases the amount of transforming growth factor-α-stimulated transforming growth factor-α synthesis by approximately 40%. These results strengthen the view that transforming growth factor-α is an important physiological stimulator of hepatocyte replication in liver growth induced by partial hepatectomy and Toxic Injury and that hepatocyte growth factor may modulate hepatocyte transforming growth factor-α secretion. (HEPATOLOGY 1993;18:1422–1431.)
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transforming growth factor α expression during liver regeneration after partial hepatectomy and Toxic Injury and potential interactions between transforming growth factor α and hepatocyte growth factor
Hepatology, 1993Co-Authors: Eric M. Webber, Pamela I. Brown, Molly H. Bartlett, Mark J Fitzgerald, Nelson FaustoAbstract:Transforming growth factor-α and hepatocyte growth factor are important stimulators of hepatocyte proliferation. In this series of experiments we sought to measure the expression of transforming growth factor-α mRNA by hepatocytes in response to Toxic liver Injury produced by carbon tetrachloride or galactosamine and to perform a more detailed analysis of transforming growth factor-α expression after partial hepatectomy. We also explored the interactions of transforming growth factor-α and hepatocyte growth factor in their effects on hepatocytes in vitro and tested the ability of these factors to stimulate endogenous transforming growth factor-α production by hepatocytes. In previous work we have used oligonucleotide probes to measure transforming growth factor-α mRNA expression after partial hepatectomy. In this study we used a rat transforming growth factor-α cDNA probe and found that the level of liver transforming growth factor-α mRNA increases 4 hr after partial hepatectomy, shows peak expression at 18 hr and returns to the normal level by 36 to 48 hr. Measurement of the corresponding peptide in the liver by means of radioimmunoassay shows that the level of transforming growth factor-α rises by 12 hr, peaks at 24 hr and remains significantly increased at 48 hr compared with the levels in sham-operated rats. Carbon tetrachloride and galactosamine are known to produce different patterns of acute liver Injury, with maximal hepatocyte DNA synthesis at 48 hr and 5 days, respectively. After carbon tetrachloride administration the profiles of the transforming growth factor-α and hepatocyte growth factor mRNA expression are similar, each showing two peaks: the first at 12 hr and the second at 48 hr. In contrast, after galactosamineinduced liver Injury the expression patterns of transforming growth factor-α and hepatocyte growth factor mRNAs differ: hepatocyte growth factor shows a major peak at 24 hr, with a smaller increase at 5 days, whereas transforming growth factor-α begins to increase after 2 days, with a single peak occurring at 5 days. In primary hepatocyte cultures, transforming growth factor-α and hepatocyte growth factor appear to have complementary effects. The maximal hepatocyte nuclear labeling index induced by hepatocyte growth factor was 42%; the addition of transforming growth factor-α increased this to 74%. Exogenous transforming growth factor-α, but not hepatocyte growth factor, stimulates the production of the transforming growth factor-α peptide by hepatocytes. However, when hepatocyte growth factor is added to cultures already containing transforming growth factor-α it further increases the amount of transforming growth factor-α-stimulated transforming growth factor-α synthesis by approximately 40%. These results strengthen the view that transforming growth factor-α is an important physiological stimulator of hepatocyte replication in liver growth induced by partial hepatectomy and Toxic Injury and that hepatocyte growth factor may modulate hepatocyte transforming growth factor-α secretion. (HEPATOLOGY 1993;18:1422–1431.)
Pamela I. Brown - One of the best experts on this subject based on the ideXlab platform.
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Transforming growth factor‐α expression during liver regeneration after partial hepatectomy and Toxic Injury, and potential interactions between transforming growth factor‐α and hepatocyte growth factor
Hepatology, 1993Co-Authors: Eric M. Webber, Pamela I. Brown, Molly H. Bartlett, Mark J Fitzgerald, Nelson FaustoAbstract:Transforming growth factor-α and hepatocyte growth factor are important stimulators of hepatocyte proliferation. In this series of experiments we sought to measure the expression of transforming growth factor-α mRNA by hepatocytes in response to Toxic liver Injury produced by carbon tetrachloride or galactosamine and to perform a more detailed analysis of transforming growth factor-α expression after partial hepatectomy. We also explored the interactions of transforming growth factor-α and hepatocyte growth factor in their effects on hepatocytes in vitro and tested the ability of these factors to stimulate endogenous transforming growth factor-α production by hepatocytes. In previous work we have used oligonucleotide probes to measure transforming growth factor-α mRNA expression after partial hepatectomy. In this study we used a rat transforming growth factor-α cDNA probe and found that the level of liver transforming growth factor-α mRNA increases 4 hr after partial hepatectomy, shows peak expression at 18 hr and returns to the normal level by 36 to 48 hr. Measurement of the corresponding peptide in the liver by means of radioimmunoassay shows that the level of transforming growth factor-α rises by 12 hr, peaks at 24 hr and remains significantly increased at 48 hr compared with the levels in sham-operated rats. Carbon tetrachloride and galactosamine are known to produce different patterns of acute liver Injury, with maximal hepatocyte DNA synthesis at 48 hr and 5 days, respectively. After carbon tetrachloride administration the profiles of the transforming growth factor-α and hepatocyte growth factor mRNA expression are similar, each showing two peaks: the first at 12 hr and the second at 48 hr. In contrast, after galactosamineinduced liver Injury the expression patterns of transforming growth factor-α and hepatocyte growth factor mRNAs differ: hepatocyte growth factor shows a major peak at 24 hr, with a smaller increase at 5 days, whereas transforming growth factor-α begins to increase after 2 days, with a single peak occurring at 5 days. In primary hepatocyte cultures, transforming growth factor-α and hepatocyte growth factor appear to have complementary effects. The maximal hepatocyte nuclear labeling index induced by hepatocyte growth factor was 42%; the addition of transforming growth factor-α increased this to 74%. Exogenous transforming growth factor-α, but not hepatocyte growth factor, stimulates the production of the transforming growth factor-α peptide by hepatocytes. However, when hepatocyte growth factor is added to cultures already containing transforming growth factor-α it further increases the amount of transforming growth factor-α-stimulated transforming growth factor-α synthesis by approximately 40%. These results strengthen the view that transforming growth factor-α is an important physiological stimulator of hepatocyte replication in liver growth induced by partial hepatectomy and Toxic Injury and that hepatocyte growth factor may modulate hepatocyte transforming growth factor-α secretion. (HEPATOLOGY 1993;18:1422–1431.)
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transforming growth factor α expression during liver regeneration after partial hepatectomy and Toxic Injury and potential interactions between transforming growth factor α and hepatocyte growth factor
Hepatology, 1993Co-Authors: Eric M. Webber, Pamela I. Brown, Molly H. Bartlett, Mark J Fitzgerald, Nelson FaustoAbstract:Transforming growth factor-α and hepatocyte growth factor are important stimulators of hepatocyte proliferation. In this series of experiments we sought to measure the expression of transforming growth factor-α mRNA by hepatocytes in response to Toxic liver Injury produced by carbon tetrachloride or galactosamine and to perform a more detailed analysis of transforming growth factor-α expression after partial hepatectomy. We also explored the interactions of transforming growth factor-α and hepatocyte growth factor in their effects on hepatocytes in vitro and tested the ability of these factors to stimulate endogenous transforming growth factor-α production by hepatocytes. In previous work we have used oligonucleotide probes to measure transforming growth factor-α mRNA expression after partial hepatectomy. In this study we used a rat transforming growth factor-α cDNA probe and found that the level of liver transforming growth factor-α mRNA increases 4 hr after partial hepatectomy, shows peak expression at 18 hr and returns to the normal level by 36 to 48 hr. Measurement of the corresponding peptide in the liver by means of radioimmunoassay shows that the level of transforming growth factor-α rises by 12 hr, peaks at 24 hr and remains significantly increased at 48 hr compared with the levels in sham-operated rats. Carbon tetrachloride and galactosamine are known to produce different patterns of acute liver Injury, with maximal hepatocyte DNA synthesis at 48 hr and 5 days, respectively. After carbon tetrachloride administration the profiles of the transforming growth factor-α and hepatocyte growth factor mRNA expression are similar, each showing two peaks: the first at 12 hr and the second at 48 hr. In contrast, after galactosamineinduced liver Injury the expression patterns of transforming growth factor-α and hepatocyte growth factor mRNAs differ: hepatocyte growth factor shows a major peak at 24 hr, with a smaller increase at 5 days, whereas transforming growth factor-α begins to increase after 2 days, with a single peak occurring at 5 days. In primary hepatocyte cultures, transforming growth factor-α and hepatocyte growth factor appear to have complementary effects. The maximal hepatocyte nuclear labeling index induced by hepatocyte growth factor was 42%; the addition of transforming growth factor-α increased this to 74%. Exogenous transforming growth factor-α, but not hepatocyte growth factor, stimulates the production of the transforming growth factor-α peptide by hepatocytes. However, when hepatocyte growth factor is added to cultures already containing transforming growth factor-α it further increases the amount of transforming growth factor-α-stimulated transforming growth factor-α synthesis by approximately 40%. These results strengthen the view that transforming growth factor-α is an important physiological stimulator of hepatocyte replication in liver growth induced by partial hepatectomy and Toxic Injury and that hepatocyte growth factor may modulate hepatocyte transforming growth factor-α secretion. (HEPATOLOGY 1993;18:1422–1431.)
