Inhibition of geranylgeranyltransferase attenuates neutrophil accumulation and tissue injury in severe acute pancreatitis.
Merza, Mohammed LU ; Wetterholm, Erik LU ; Zhang, Su LU ; Regnér, Sara LU
and Thorlacius, Henrik
LU
(2013)
In Journal of Leukocyte Biology
94(3).
p.493-502
- Abstract
- Leukocyte infiltration and acinar cell necrosis are hallmarks of severe AP, but the signaling pathways regulating inflammation and organ injury in the pancreas remain elusive. In the present study, we investigated the role of geranylgeranyltransferase in AP. Male C57BL/6 mice were treated with a geranylgeranyltransferase inhibitor GGTI-2133 (20 mg/kg) prior to induction of pancreatitis by infusion of taurocholate into the pancreatic duct. Pretreatment with GGTI-2133 reduced plasma amylase levels, pancreatic neutrophil recruitment, hemorrhage, and edema formation in taurocholate-evoked pancreatitis. Moreover, administration of GGTI-2133 decreased the taurocholate-induced increase of MPO activity in the pancreas and lung. Treatment with... (More)
- Leukocyte infiltration and acinar cell necrosis are hallmarks of severe AP, but the signaling pathways regulating inflammation and organ injury in the pancreas remain elusive. In the present study, we investigated the role of geranylgeranyltransferase in AP. Male C57BL/6 mice were treated with a geranylgeranyltransferase inhibitor GGTI-2133 (20 mg/kg) prior to induction of pancreatitis by infusion of taurocholate into the pancreatic duct. Pretreatment with GGTI-2133 reduced plasma amylase levels, pancreatic neutrophil recruitment, hemorrhage, and edema formation in taurocholate-evoked pancreatitis. Moreover, administration of GGTI-2133 decreased the taurocholate-induced increase of MPO activity in the pancreas and lung. Treatment with GGTI-2133 markedly reduced levels of CXCL2 in the pancreas and IL-6 in the plasma in response to taurocholate challenge. Notably, geranylgeranyltransferase inhibition abolished neutrophil expression of Mac-1 in mice with pancreatitis. Finally, inhibition of geranylgeranyltransferase had no direct effect on secretagogue-induced activation of trypsinogen in pancreatic acinar cells in vitro. A significant role of geranylgeranyltransferase was confirmed in an alternate model of AP induced by L-arginine challenge. Our findings show that geranylgeranyltransferase regulates neutrophil accumulation and tissue damage via expression of Mac-1 on neutrophils and CXCL2 formation in AP. Thus, these results reveal new signaling mechanisms in pancreatitis and indicate that targeting geranylgeranyltransferase might be an effective way to ameliorate severe AP. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3913624
- author
- Merza, Mohammed
LU
; Wetterholm, Erik
LU
; Zhang, Su
LU
; Regnér, Sara
LU
and Thorlacius, Henrik
LU
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Leukocyte Biology
- volume
- 94
- issue
- 3
- pages
- 493 - 502
- publisher
- John Wiley & Sons Inc.
- external identifiers
-
- wos:000328839400013
- pmid:23744643
- scopus:84883235825
- ISSN
- 1938-3673
- DOI
- 10.1189/jlb.1112546
- language
- English
- LU publication?
- yes
- id
- 03840f41-0d06-481b-9cd5-cb34cb2743c2 (old id 3913624)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/23744643?dopt=Abstract
- date added to LUP
- 2016-04-01 10:25:42
- date last changed
- 2022-03-19 20:37:40
@article{03840f41-0d06-481b-9cd5-cb34cb2743c2,
abstract = {{Leukocyte infiltration and acinar cell necrosis are hallmarks of severe AP, but the signaling pathways regulating inflammation and organ injury in the pancreas remain elusive. In the present study, we investigated the role of geranylgeranyltransferase in AP. Male C57BL/6 mice were treated with a geranylgeranyltransferase inhibitor GGTI-2133 (20 mg/kg) prior to induction of pancreatitis by infusion of taurocholate into the pancreatic duct. Pretreatment with GGTI-2133 reduced plasma amylase levels, pancreatic neutrophil recruitment, hemorrhage, and edema formation in taurocholate-evoked pancreatitis. Moreover, administration of GGTI-2133 decreased the taurocholate-induced increase of MPO activity in the pancreas and lung. Treatment with GGTI-2133 markedly reduced levels of CXCL2 in the pancreas and IL-6 in the plasma in response to taurocholate challenge. Notably, geranylgeranyltransferase inhibition abolished neutrophil expression of Mac-1 in mice with pancreatitis. Finally, inhibition of geranylgeranyltransferase had no direct effect on secretagogue-induced activation of trypsinogen in pancreatic acinar cells in vitro. A significant role of geranylgeranyltransferase was confirmed in an alternate model of AP induced by L-arginine challenge. Our findings show that geranylgeranyltransferase regulates neutrophil accumulation and tissue damage via expression of Mac-1 on neutrophils and CXCL2 formation in AP. Thus, these results reveal new signaling mechanisms in pancreatitis and indicate that targeting geranylgeranyltransferase might be an effective way to ameliorate severe AP.}},
author = {{Merza, Mohammed and Wetterholm, Erik and Zhang, Su and Regnér, Sara and Thorlacius, Henrik}},
issn = {{1938-3673}},
language = {{eng}},
number = {{3}},
pages = {{493--502}},
publisher = {{John Wiley & Sons Inc.}},
series = {{Journal of Leukocyte Biology}},
title = {{Inhibition of geranylgeranyltransferase attenuates neutrophil accumulation and tissue injury in severe acute pancreatitis.}},
url = {{http://dx.doi.org/10.1189/jlb.1112546}},
doi = {{10.1189/jlb.1112546}},
volume = {{94}},
year = {{2013}},
}