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Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability
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| Zeitschriftentitel: | Hepatology Communications |
|---|---|
| Personen und Körperschaften: | , , , , , , , , |
| In: | Hepatology Communications, 3, 2019, 11, S. 1435-1449 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Ovid Technologies (Wolters Kluwer Health)
|
| Schlagwörter: |
| author_facet |
Chopyk, Daniel M. Stuart, Johnasha D. Zimmerman, Matthew G. Wen, Jing Gumber, Sanjeev Suthar, Mehul S. Thapa, Manoj Czaja, Mark J. Grakoui, Arash Chopyk, Daniel M. Stuart, Johnasha D. Zimmerman, Matthew G. Wen, Jing Gumber, Sanjeev Suthar, Mehul S. Thapa, Manoj Czaja, Mark J. Grakoui, Arash |
|---|---|
| author |
Chopyk, Daniel M. Stuart, Johnasha D. Zimmerman, Matthew G. Wen, Jing Gumber, Sanjeev Suthar, Mehul S. Thapa, Manoj Czaja, Mark J. Grakoui, Arash |
| spellingShingle |
Chopyk, Daniel M. Stuart, Johnasha D. Zimmerman, Matthew G. Wen, Jing Gumber, Sanjeev Suthar, Mehul S. Thapa, Manoj Czaja, Mark J. Grakoui, Arash Hepatology Communications Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability Hepatology |
| author_sort |
chopyk, daniel m. |
| spelling |
Chopyk, Daniel M. Stuart, Johnasha D. Zimmerman, Matthew G. Wen, Jing Gumber, Sanjeev Suthar, Mehul S. Thapa, Manoj Czaja, Mark J. Grakoui, Arash 2471-254X 2471-254X Ovid Technologies (Wolters Kluwer Health) Hepatology http://dx.doi.org/10.1002/hep4.1406 <jats:p>Acetaminophen (APAP)‐induced liver injury is the most common cause of acute liver failure (ALF) in the Western world. APAP toxicity progresses to multiorgan dysfunction and thus has broader whole‐body implications. Importantly, greater 30‐day mortality has been observed in liver transplant recipients following ALF due to APAP‐related versus non‐APAP‐related causes. Reasons for this discrepancy have yet to be determined. Extrahepatic toxicities of APAP overdose may represent underappreciated and unaddressed comorbidities within this patient population. In the present study, rapid induction of apoptosis following APAP overdose was observed in the intestine, an organ that greatly influences the physiology of the liver. Strikingly, apoptotic cells appeared to be strictly restricted to the intestinal crypts. The use of leucine‐rich repeat‐containing G protein–coupled receptor 5 (<jats:italic toggle="yes">LGR5</jats:italic>) reporter mice confirmed that the <jats:italic toggle="yes">LGR5</jats:italic>‐positive (<jats:italic toggle="yes">+)</jats:italic> crypt base stem cells were disproportionately affected by APAP‐induced cell death. Although the apoptotic cells were cleared within 24 hours after APAP treatment, potentially long‐lived consequences on the intestine due to APAP exposure were indicated by prolonged deficits in gut barrier function. Moreover, small intestinal cell death was found to be independent of tumor necrosis factor receptor signaling and may represent a direct toxic insult to the intestine by exposure to high concentrations of APAP. <jats:italic toggle="yes">Conclusion:</jats:italic> APAP induces intestinal injury through a regulated process of apoptotic cell death that disproportionately affects <jats:italic toggle="yes">LGR5+ </jats:italic> stem cells. This work advances our understanding of the consequences of APAP toxicity in a novel organ that was not previously considered as a significant site of injury and thus presents potential new considerations for patient management.</jats:p> Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability Hepatology Communications |
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10.1002/hep4.1406 |
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Hepatology Communications |
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49 |
| title |
Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability |
| title_unstemmed |
Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability |
| title_full |
Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability |
| title_fullStr |
Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability |
| title_full_unstemmed |
Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability |
| title_short |
Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability |
| title_sort |
acetaminophen intoxication rapidly induces apoptosis of intestinal crypt stem cells and enhances intestinal permeability |
| topic |
Hepatology |
| url |
http://dx.doi.org/10.1002/hep4.1406 |
| publishDate |
2019 |
| physical |
1435-1449 |
| description |
<jats:p>Acetaminophen (APAP)‐induced liver injury is the most common cause of acute liver failure (ALF) in the Western world. APAP toxicity progresses to multiorgan dysfunction and thus has broader whole‐body implications. Importantly, greater 30‐day mortality has been observed in liver transplant recipients following ALF due to APAP‐related versus non‐APAP‐related causes. Reasons for this discrepancy have yet to be determined. Extrahepatic toxicities of APAP overdose may represent underappreciated and unaddressed comorbidities within this patient population. In the present study, rapid induction of apoptosis following APAP overdose was observed in the intestine, an organ that greatly influences the physiology of the liver. Strikingly, apoptotic cells appeared to be strictly restricted to the intestinal crypts. The use of leucine‐rich repeat‐containing G protein–coupled receptor 5 (<jats:italic toggle="yes">LGR5</jats:italic>) reporter mice confirmed that the <jats:italic toggle="yes">LGR5</jats:italic>‐positive (<jats:italic toggle="yes">+)</jats:italic> crypt base stem cells were disproportionately affected by APAP‐induced cell death. Although the apoptotic cells were cleared within 24 hours after APAP treatment, potentially long‐lived consequences on the intestine due to APAP exposure were indicated by prolonged deficits in gut barrier function. Moreover, small intestinal cell death was found to be independent of tumor necrosis factor receptor signaling and may represent a direct toxic insult to the intestine by exposure to high concentrations of APAP. <jats:italic toggle="yes">Conclusion:</jats:italic> APAP induces intestinal injury through a regulated process of apoptotic cell death that disproportionately affects <jats:italic toggle="yes">LGR5+
</jats:italic> stem cells. This work advances our understanding of the consequences of APAP toxicity in a novel organ that was not previously considered as a significant site of injury and thus presents potential new considerations for patient management.</jats:p> |
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| author | Chopyk, Daniel M., Stuart, Johnasha D., Zimmerman, Matthew G., Wen, Jing, Gumber, Sanjeev, Suthar, Mehul S., Thapa, Manoj, Czaja, Mark J., Grakoui, Arash |
| author_facet | Chopyk, Daniel M., Stuart, Johnasha D., Zimmerman, Matthew G., Wen, Jing, Gumber, Sanjeev, Suthar, Mehul S., Thapa, Manoj, Czaja, Mark J., Grakoui, Arash, Chopyk, Daniel M., Stuart, Johnasha D., Zimmerman, Matthew G., Wen, Jing, Gumber, Sanjeev, Suthar, Mehul S., Thapa, Manoj, Czaja, Mark J., Grakoui, Arash |
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| description | <jats:p>Acetaminophen (APAP)‐induced liver injury is the most common cause of acute liver failure (ALF) in the Western world. APAP toxicity progresses to multiorgan dysfunction and thus has broader whole‐body implications. Importantly, greater 30‐day mortality has been observed in liver transplant recipients following ALF due to APAP‐related versus non‐APAP‐related causes. Reasons for this discrepancy have yet to be determined. Extrahepatic toxicities of APAP overdose may represent underappreciated and unaddressed comorbidities within this patient population. In the present study, rapid induction of apoptosis following APAP overdose was observed in the intestine, an organ that greatly influences the physiology of the liver. Strikingly, apoptotic cells appeared to be strictly restricted to the intestinal crypts. The use of leucine‐rich repeat‐containing G protein–coupled receptor 5 (<jats:italic toggle="yes">LGR5</jats:italic>) reporter mice confirmed that the <jats:italic toggle="yes">LGR5</jats:italic>‐positive (<jats:italic toggle="yes">+)</jats:italic> crypt base stem cells were disproportionately affected by APAP‐induced cell death. Although the apoptotic cells were cleared within 24 hours after APAP treatment, potentially long‐lived consequences on the intestine due to APAP exposure were indicated by prolonged deficits in gut barrier function. Moreover, small intestinal cell death was found to be independent of tumor necrosis factor receptor signaling and may represent a direct toxic insult to the intestine by exposure to high concentrations of APAP. <jats:italic toggle="yes">Conclusion:</jats:italic> APAP induces intestinal injury through a regulated process of apoptotic cell death that disproportionately affects <jats:italic toggle="yes">LGR5+ </jats:italic> stem cells. This work advances our understanding of the consequences of APAP toxicity in a novel organ that was not previously considered as a significant site of injury and thus presents potential new considerations for patient management.</jats:p> |
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| spelling | Chopyk, Daniel M. Stuart, Johnasha D. Zimmerman, Matthew G. Wen, Jing Gumber, Sanjeev Suthar, Mehul S. Thapa, Manoj Czaja, Mark J. Grakoui, Arash 2471-254X 2471-254X Ovid Technologies (Wolters Kluwer Health) Hepatology http://dx.doi.org/10.1002/hep4.1406 <jats:p>Acetaminophen (APAP)‐induced liver injury is the most common cause of acute liver failure (ALF) in the Western world. APAP toxicity progresses to multiorgan dysfunction and thus has broader whole‐body implications. Importantly, greater 30‐day mortality has been observed in liver transplant recipients following ALF due to APAP‐related versus non‐APAP‐related causes. Reasons for this discrepancy have yet to be determined. Extrahepatic toxicities of APAP overdose may represent underappreciated and unaddressed comorbidities within this patient population. In the present study, rapid induction of apoptosis following APAP overdose was observed in the intestine, an organ that greatly influences the physiology of the liver. Strikingly, apoptotic cells appeared to be strictly restricted to the intestinal crypts. The use of leucine‐rich repeat‐containing G protein–coupled receptor 5 (<jats:italic toggle="yes">LGR5</jats:italic>) reporter mice confirmed that the <jats:italic toggle="yes">LGR5</jats:italic>‐positive (<jats:italic toggle="yes">+)</jats:italic> crypt base stem cells were disproportionately affected by APAP‐induced cell death. Although the apoptotic cells were cleared within 24 hours after APAP treatment, potentially long‐lived consequences on the intestine due to APAP exposure were indicated by prolonged deficits in gut barrier function. Moreover, small intestinal cell death was found to be independent of tumor necrosis factor receptor signaling and may represent a direct toxic insult to the intestine by exposure to high concentrations of APAP. <jats:italic toggle="yes">Conclusion:</jats:italic> APAP induces intestinal injury through a regulated process of apoptotic cell death that disproportionately affects <jats:italic toggle="yes">LGR5+ </jats:italic> stem cells. This work advances our understanding of the consequences of APAP toxicity in a novel organ that was not previously considered as a significant site of injury and thus presents potential new considerations for patient management.</jats:p> Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability Hepatology Communications |
| spellingShingle | Chopyk, Daniel M., Stuart, Johnasha D., Zimmerman, Matthew G., Wen, Jing, Gumber, Sanjeev, Suthar, Mehul S., Thapa, Manoj, Czaja, Mark J., Grakoui, Arash, Hepatology Communications, Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability, Hepatology |
| title | Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability |
| title_full | Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability |
| title_fullStr | Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability |
| title_full_unstemmed | Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability |
| title_short | Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability |
| title_sort | acetaminophen intoxication rapidly induces apoptosis of intestinal crypt stem cells and enhances intestinal permeability |
| title_unstemmed | Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability |
| topic | Hepatology |
| url | http://dx.doi.org/10.1002/hep4.1406 |