Acute pancreatitis induces cytokine production in endotoxin-resistant mice

James Eubanks, Omaima Sabek, Malak Kotb, Lillian W. Gaber, James Henry, Naoki Hijiya, Louis G. Britt, A. Osama Gaber, Sanna M. Goyert

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Objective: The purpose of this study was to determine whether pathologic progression and cytokine responses in acute pancreatitis (AP) are altered in the absence of endotoxemia. Summary Background Data: Previous studies have demonstrated that AP is characterized by rapid production and release of inflammatory cytokines, which play a major role in the local pancreatic and systemic complications of this disease. Infection and endotoxemia have been implicated as a major source of morbidity and death in AP and as possible stimuli for the overwhelming cytokine response seen in this disease. Methods: AP was induced by a choline-deficient and ethionine-supplemented diet for 4 days in normal C57BL/6J mice (controls, n = 23) and in CD14 knockout mice (CD14KO, n = 23), which cannot produce circulating cytokines in response to endotoxin. Control and endotoxin-resistant mice were killed at time 0, then at 24, 48, 72, and 96 hours after the start of the diet. At each time point serum was collected for amylase, glucose, and cytokine measurements (tumor necrosis factor-alpha [TNFα] and interleukin-1β [IL 1β]), and the pancreas was removed for histologic examination. TNFα was measured with a bioassay using WEHI-2F cells and IL1β with a bioassay using D10.G4.1 cells. Results: CD14KO mice developed biochemical manifestations of AP with alterations in amylase levels, hypoglycemia, weight loss, and histologic changes of pancreatitis similar to the pattern seen in control mice. TNFα and IL1 β production had similar kinetics in both groups, with significant peak TNFα serum levels at 72 hours and a progressive rise of IL1β levels throughout the study period. Histologic changes appeared earlier and were more pronounced in the control versus the CD14KO mice. However, the mortality rate was identical (20% at 96 hours) for both groups. Conclusions: These results demonstrate that the progression of AP, the cytokine response associated with the disease, and early death are independent of endotoxin action. These findings, which suggest that an uncharacterized stimulus is responsible for triggering the cytokine cascade in this disease, may have significant implications for the management of patients with AP.

Original languageEnglish (US)
Pages (from-to)904-911
Number of pages8
JournalAnnals of surgery
Volume227
Issue number6
DOIs
StatePublished - Jun 1 1998

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Endotoxins
Pancreatitis
Cytokines
Tumor Necrosis Factor-alpha
Endotoxemia
Amylases
Biological Assay
Ethionine
Diet
Choline
Serum
Interleukin-1
Inbred C57BL Mouse
Hypoglycemia
Knockout Mice
Weight Loss
Pancreas
Morbidity
Glucose
Mortality

All Science Journal Classification (ASJC) codes

  • Surgery

Cite this

Eubanks, J., Sabek, O., Kotb, M., Gaber, L. W., Henry, J., Hijiya, N., ... Goyert, S. M. (1998). Acute pancreatitis induces cytokine production in endotoxin-resistant mice. Annals of surgery, 227(6), 904-911. https://doi.org/10.1097/00000658-199806000-00014

Acute pancreatitis induces cytokine production in endotoxin-resistant mice. / Eubanks, James; Sabek, Omaima; Kotb, Malak; Gaber, Lillian W.; Henry, James; Hijiya, Naoki; Britt, Louis G.; Gaber, A. Osama; Goyert, Sanna M.

In: Annals of surgery, Vol. 227, No. 6, 01.06.1998, p. 904-911.

Research output: Contribution to journalArticle

Eubanks, J, Sabek, O, Kotb, M, Gaber, LW, Henry, J, Hijiya, N, Britt, LG, Gaber, AO & Goyert, SM 1998, 'Acute pancreatitis induces cytokine production in endotoxin-resistant mice', Annals of surgery, vol. 227, no. 6, pp. 904-911. https://doi.org/10.1097/00000658-199806000-00014
Eubanks, James ; Sabek, Omaima ; Kotb, Malak ; Gaber, Lillian W. ; Henry, James ; Hijiya, Naoki ; Britt, Louis G. ; Gaber, A. Osama ; Goyert, Sanna M. / Acute pancreatitis induces cytokine production in endotoxin-resistant mice. In: Annals of surgery. 1998 ; Vol. 227, No. 6. pp. 904-911.
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abstract = "Objective: The purpose of this study was to determine whether pathologic progression and cytokine responses in acute pancreatitis (AP) are altered in the absence of endotoxemia. Summary Background Data: Previous studies have demonstrated that AP is characterized by rapid production and release of inflammatory cytokines, which play a major role in the local pancreatic and systemic complications of this disease. Infection and endotoxemia have been implicated as a major source of morbidity and death in AP and as possible stimuli for the overwhelming cytokine response seen in this disease. Methods: AP was induced by a choline-deficient and ethionine-supplemented diet for 4 days in normal C57BL/6J mice (controls, n = 23) and in CD14 knockout mice (CD14KO, n = 23), which cannot produce circulating cytokines in response to endotoxin. Control and endotoxin-resistant mice were killed at time 0, then at 24, 48, 72, and 96 hours after the start of the diet. At each time point serum was collected for amylase, glucose, and cytokine measurements (tumor necrosis factor-alpha [TNFα] and interleukin-1β [IL 1β]), and the pancreas was removed for histologic examination. TNFα was measured with a bioassay using WEHI-2F cells and IL1β with a bioassay using D10.G4.1 cells. Results: CD14KO mice developed biochemical manifestations of AP with alterations in amylase levels, hypoglycemia, weight loss, and histologic changes of pancreatitis similar to the pattern seen in control mice. TNFα and IL1 β production had similar kinetics in both groups, with significant peak TNFα serum levels at 72 hours and a progressive rise of IL1β levels throughout the study period. Histologic changes appeared earlier and were more pronounced in the control versus the CD14KO mice. However, the mortality rate was identical (20{\%} at 96 hours) for both groups. Conclusions: These results demonstrate that the progression of AP, the cytokine response associated with the disease, and early death are independent of endotoxin action. These findings, which suggest that an uncharacterized stimulus is responsible for triggering the cytokine cascade in this disease, may have significant implications for the management of patients with AP.",
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AU - Sabek, Omaima

AU - Kotb, Malak

AU - Gaber, Lillian W.

AU - Henry, James

AU - Hijiya, Naoki

AU - Britt, Louis G.

AU - Gaber, A. Osama

AU - Goyert, Sanna M.

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