Reviewer's report
Title:The effect of sulindac, a non-steroidal anti-inflammatory drug, attenuates
inflammation and fibrosis in a mouse model of chronic pancreatitis
Version: 4Date:8 May 2012
Reviewer: Matthias Sendler
Reviewer's report:
The authors use an established mouse model of chronic pancreatitis to evaluate
sulindac as a therapeutic drug to reduce severity of chronic pancreatitis. The
investigation of sulindac as a possible reagent for the treatment of chronic
pancreatitis shows clearly the relationship of acinar cell damage, fibrosis and
infiltration of immune cells and the reaction of immune system. A diminished
immune reaction results in reduced pancreatic damage and acinar cell loss with
a reduced fibrosis. Sulindac treated animals show a significant reduced severity
of chronic pancreatitis.
general comments
The authors use a chronic model of pancreatitis to investigate the effect of
sulindac on disease severity. They investigate pancreatic damage and immune
reaction in sulindac treated animals and in untreated controls. Sulindac is well
known as COX-inhibitor in tumour therapy [Liedtke AJ et. al., J Med Chem. 2012
Mar 8;55(5):2287-300.], the authors also discuss sulindac very intensiv for
cancer prevention but not in relationship to chronic pancreatitis. On the one hand
they investigate chronic pancreatitis, but on the other hand they discuss the
results in the background of cancer progression. This need to be changed in the
discussion, the manuscript must be discussed more in the context of chronic
pancreatitis.
special comments
1.
The authors can show a strong anti-inflammatory activity of sulindac in chronic
pancreatitis and they identify MAPK signaling pathway as one target of sulindac
treatment. The phosphorylation of MEK and ERK is effected by sulindac. MEK
and ERK are involved in different pathways, also in the NFkappaB pathway and
so in the regulation of inflammation during pancreatitis [Rakonczay Z Jr et. al.,
Gut. 2008 Feb;57(2):259-67.]. The authors need to show the effect of sulindac on
the activation of NFkappaB to clarify the origin of the diminished inflammatory
reaction more in detail.
2.
Activated stellate cells are the source of extracellular matrix proteins and
fibrinogenisis [Masamune A et. al. Clin Gastroenterol Hepatol. 2009 Nov;7(11
Suppl):S48-54.]. The experiments show a reduced fibrosis by trichrome staining
of pancreatic tissue. Is the recruitment of stellate cells and the activation of
stellate cells in pancreatic tissue modified direct by sulindac treatment or is this
an secondary effect of the diminished immune reaction? This needs to be
proofed.
3.
Sulindac treated animals show a significant reduced fibrotic reaction compared to
untreated controls. In contrast to this result they can not measure significant
elevated expression of TGF-# and PDGF-# in pancreatic tissue. TGF-# and
PDGF-# are known as major cytokines, which are involved in fibrogenesis
[Talukdar R. et. al., J Gastroenterol Hepatol. 2008 Jan;23(1):34-41.].
Macrophages, especially alternative activated M2 macrophages, are a major
source of TGF-#. The authors show a significant reduction of infiltrating
macrophages, this does not result in a significant reduced TGF-# expression.
Does the treatment with sulindac leads to a shift in macrophage differentiation?
This needs to be discussed more in detail.
Declaration of competing interests:
I declare that I have no competing interests
Reviewer's report
Title:The effect of sulindac, a non-steroidal anti-inflammatory drug, attenuates
inflammation and fibrosis in a mouse model of chronic pancreatitis
Version: 4Date:8 May 2012
Reviewer: Matthias Sendler
Reviewer's report:
The authors use an established mouse model of chronic pancreatitis to evaluate
sulindac as a therapeutic drug to reduce severity of chronic pancreatitis. The
investigation of sulindac as a possible reagent for the treatment of chronic
pancreatitis shows clearly the relationship of acinar cell damage, fibrosis and
infiltration of immune cells and the reaction of immune system. A diminished
immune reaction results in reduced pancreatic damage and acinar cell loss with
a reduced fibrosis. Sulindac treated animals show a significant reduced severity
of chronic pancreatitis.
general comments
The authors use a chronic model of pancreatitis to investigate the effect of
sulindac on disease severity. They investigate pancreatic damage and immune
reaction in sulindac treated animals and in untreated controls. Sulindac is well
known as COX-inhibitor in tumour therapy [Liedtke AJ et. al., J Med Chem. 2012
Mar 8;55(5):2287-300.], the authors also discuss sulindac very intensiv for
cancer prevention but not in relationship to chronic pancreatitis. On the one hand
they investigate chronic pancreatitis, but on the other hand they discuss the
results in the background of cancer progression. This need to be changed in the
discussion, the manuscript must be discussed more in the context of chronic
pancreatitis.
special comments
1.
The authors can show a strong anti-inflammatory activity of sulindac in chronic
pancreatitis and they identify MAPK signaling pathway as one target of sulindac
treatment. The phosphorylation of MEK and ERK is effected by sulindac. MEK
and ERK are involved in different pathways, also in the NFkappaB pathway and
so in the regulation of inflammation during pancreatitis [Rakonczay Z Jr et. al.,
Gut. 2008 Feb;57(2):259-67.]. The authors need to show the effect of sulindac on
the activation of NFkappaB to clarify the origin of the diminished inflammatory
reaction more in detail.
2.
Activated stellate cells are the source of extracellular matrix proteins and
fibrinogenisis [Masamune A et. al. Clin Gastroenterol Hepatol. 2009 Nov;7(11
Suppl):S48-54.]. The experiments show a reduced fibrosis by trichrome staining
of pancreatic tissue. Is the recruitment of stellate cells and the activation of
stellate cells in pancreatic tissue modified direct by sulindac treatment or is this
an secondary effect of the diminished immune reaction? This needs to be
proofed.
3.
Sulindac treated animals show a significant reduced fibrotic reaction compared to
untreated controls. In contrast to this result they can not measure significant
elevated expression of TGF-# and PDGF-# in pancreatic tissue. TGF-# and
PDGF-# are known as major cytokines, which are involved in fibrogenesis
[Talukdar R. et. al., J Gastroenterol Hepatol. 2008 Jan;23(1):34-41.].
Macrophages, especially alternative activated M2 macrophages, are a major
source of TGF-#. The authors show a significant reduction of infiltrating
macrophages, this does not result in a significant reduced TGF-# expression.
Does the treatment with sulindac leads to a shift in macrophage differentiation?
This needs to be discussed more in detail.
Declaration of competing interests:
I declare that I have no competing interests
Please review this paper.
user
Reviewer's report
Title:The effect of sulindac, a non-steroidal anti-inflammatory drug, attenuates
inflammation and fibrosis in a mouse model of chronic pancreatitis
Version: 4Date:8 May 2012
Reviewer: Matthias Sendler
Reviewer's report:
The authors use an established mouse model of chronic pancreatitis to evaluate
sulindac as a therapeutic drug to reduce severity of chronic pancreatitis. The
investigation of sulindac as a possible reagent for the treatment of chronic
pancreatitis shows clearly the relationship of acinar cell damage, fibrosis and
infiltration of immune cells and the reaction of immune system. A diminished
immune reaction results in reduced pancreatic damage and acinar cell loss with
a reduced fibrosis. Sulindac treated animals show a significant reduced severity
of chronic pancreatitis.
general comments
The authors use a chronic model of pancreatitis to investigate the effect of
sulindac on disease severity. They investigate pancreatic damage and immune
reaction in sulindac treated animals and in untreated controls. Sulindac is well
known as COX-inhibitor in tumour therapy [Liedtke AJ et. al., J Med Chem. 2012
Mar 8;55(5):2287-300.], the authors also discuss sulindac very intensiv for
cancer prevention but not in relationship to chronic pancreatitis. On the one hand
they investigate chronic pancreatitis, but on the other hand they discuss the
results in the background of cancer progression. This need to be changed in the
discussion, the manuscript must be discussed more in the context of chronic
pancreatitis.
special comments
1.
The authors can show a strong anti-inflammatory activity of sulindac in chronic
pancreatitis and they identify MAPK signaling pathway as one target of sulindac
treatment. The phosphorylation of MEK and ERK is effected by sulindac. MEK
and ERK are involved in different pathways, also in the NFkappaB pathway and
so in the regulation of inflammation during pancreatitis [Rakonczay Z Jr et. al.,
Gut. 2008 Feb;57(2):259-67.]. The authors need to show the effect of sulindac on
the activation of NFkappaB to clarify the origin of the diminished inflammatory
reaction more in detail.
2.
Activated stellate cells are the source of extracellular matrix proteins and
fibrinogenisis [Masamune A et. al. Clin Gastroenterol Hepatol. 2009 Nov;7(11
Suppl):S48-54.]. The experiments show a reduced fibrosis by trichrome staining
of pancreatic tissue. Is the recruitment of stellate cells and the activation of
stellate cells in pancreatic tissue modified direct by sulindac treatment or is this
an secondary effect of the diminished immune reaction? This needs to be
proofed.
3.
Sulindac treated animals show a significant reduced fibrotic reaction compared to
untreated controls. In contrast to this result they can not measure significant
elevated expression of TGF-# and PDGF-# in pancreatic tissue. TGF-# and
PDGF-# are known as major cytokines, which are involved in fibrogenesis
[Talukdar R. et. al., J Gastroenterol Hepatol. 2008 Jan;23(1):34-41.].
Macrophages, especially alternative activated M2 macrophages, are a major
source of TGF-#. The authors show a significant reduction of infiltrating
macrophages, this does not result in a significant reduced TGF-# expression.
Does the treatment with sulindac leads to a shift in macrophage differentiation?
This needs to be discussed more in detail.
Declaration of competing interests:
I declare that I have no competing interests
assistant