Reviewer's report
Title:Liver fibrosis secondary to bile duct injury: correlation of Smad7 with TGF-b
(beta)and fibrotic proteins
Version: 2Date:5 May 2009
Reviewer: Ian Hines
Reviewer's report:
The manuscript entitled “Liver fibrosis secondary to bile duct injury: correlation of
Smad7 with TGF-b (beta) and fibrotic proteins” by Alatorre-Carranza et al
demonstrates the expression of key fibrotic and potentially anti-fibrotic proteins
within the livers of humans suffering from cholestatic liver disease and fibrosis.
The data essentially confirm experimental findings in animals showing
expression of TGFb, Platelet activating inhibitor-1, etc. within the fibrotic liver.
The studies also suggest a positive correlation of the expression of these factors
with the induction of Smad7 expression. Again these findings are similar to those
shown in animal models but does extend findings to the human condition which
is important. Several concerns were noted during review which should be
addressed.
Major Compulsory Revisions
1. While this paper provides some translational data to suggest that findings in
animal models are consistent with processes activated in humans, it falls short of
providing important information about the cellular source of certain factors,
specifically Smad7. The source of expression of TGF# and PAI-1 is less
important as these are soluble proteins however Smad7 is an intracellular
inhibitor of Smad signaling. In hepatocytes, Smad7 induction serves to inhibit
Smad2-3-4 signaling and likely inhibits apoptosis whereas its expression in
stellate cells limits collagen gene expression. It is likely that this protein is
expressed in both cell types however these data need to be shown.
Immunohistochemical localization of Smad7 would greatly strengthen the
findings and significance of this work.
Minor essential revisions
2. The patient population examined appears to be somewhat heterogeneous with
respect to the duration of the diagnosed disease. While it is recognized that
heterogeneity is inevidable when examining human samples, does this
heterogeneity potentially weaken the findings. Alternatively, are there two
populations within this study (short term disease vs. long-term disease) which
may show differences in the relative correlations among expression of the factors
examined. Please comment.
3. The image provided for Trichrome staining is not clear. While there is no doubt
fibrosis exists, other stains such as Picrosirius red should be considered as the
typical blue staining denoting collagen in Trichrome is not visible and such data
would be most helpful to readers not familiar with fibrosis-associated
histopathological changes. Also, given the heterogeneity of the patients, it should
be noted which patient sample was used for this image.
4. The manuscript suffers from substantial grammatical errors which must be
corrected prior to publication.
Quality of written English: Not suitable for publication unless extensively edited
Reviewer's report
Title:Liver fibrosis secondary to bile duct injury: correlation of Smad7 with TGF-b
(beta)and fibrotic proteins
Version: 2Date:5 May 2009
Reviewer: Ian Hines
Reviewer's report:
The manuscript entitled “Liver fibrosis secondary to bile duct injury: correlation of
Smad7 with TGF-b (beta) and fibrotic proteins” by Alatorre-Carranza et al
demonstrates the expression of key fibrotic and potentially anti-fibrotic proteins
within the livers of humans suffering from cholestatic liver disease and fibrosis.
The data essentially confirm experimental findings in animals showing
expression of TGFb, Platelet activating inhibitor-1, etc. within the fibrotic liver.
The studies also suggest a positive correlation of the expression of these factors
with the induction of Smad7 expression. Again these findings are similar to those
shown in animal models but does extend findings to the human condition which
is important. Several concerns were noted during review which should be
addressed.
Major Compulsory Revisions
1. While this paper provides some translational data to suggest that findings in
animal models are consistent with processes activated in humans, it falls short of
providing important information about the cellular source of certain factors,
specifically Smad7. The source of expression of TGF# and PAI-1 is less
important as these are soluble proteins however Smad7 is an intracellular
inhibitor of Smad signaling. In hepatocytes, Smad7 induction serves to inhibit
Smad2-3-4 signaling and likely inhibits apoptosis whereas its expression in
stellate cells limits collagen gene expression. It is likely that this protein is
expressed in both cell types however these data need to be shown.
Immunohistochemical localization of Smad7 would greatly strengthen the
findings and significance of this work.
Minor essential revisions
2. The patient population examined appears to be somewhat heterogeneous with
respect to the duration of the diagnosed disease. While it is recognized that
heterogeneity is inevidable when examining human samples, does this
heterogeneity potentially weaken the findings. Alternatively, are there two
populations within this study (short term disease vs. long-term disease) which
may show differences in the relative correlations among expression of the factors
examined. Please comment.
3. The image provided for Trichrome staining is not clear. While there is no doubt
fibrosis exists, other stains such as Picrosirius red should be considered as the
typical blue staining denoting collagen in Trichrome is not visible and such data
would be most helpful to readers not familiar with fibrosis-associated
histopathological changes. Also, given the heterogeneity of the patients, it should
be noted which patient sample was used for this image.
4. The manuscript suffers from substantial grammatical errors which must be
corrected prior to publication.
Quality of written English: Not suitable for publication unless extensively edited
Please review this paper.
user
Reviewer's report
Title:Liver fibrosis secondary to bile duct injury: correlation of Smad7 with TGF-b
(beta)and fibrotic proteins
Version: 2Date:5 May 2009
Reviewer: Ian Hines
Reviewer's report:
The manuscript entitled “Liver fibrosis secondary to bile duct injury: correlation of
Smad7 with TGF-b (beta) and fibrotic proteins” by Alatorre-Carranza et al
demonstrates the expression of key fibrotic and potentially anti-fibrotic proteins
within the livers of humans suffering from cholestatic liver disease and fibrosis.
The data essentially confirm experimental findings in animals showing
expression of TGFb, Platelet activating inhibitor-1, etc. within the fibrotic liver.
The studies also suggest a positive correlation of the expression of these factors
with the induction of Smad7 expression. Again these findings are similar to those
shown in animal models but does extend findings to the human condition which
is important. Several concerns were noted during review which should be
addressed.
Major Compulsory Revisions
1. While this paper provides some translational data to suggest that findings in
animal models are consistent with processes activated in humans, it falls short of
providing important information about the cellular source of certain factors,
specifically Smad7. The source of expression of TGF# and PAI-1 is less
important as these are soluble proteins however Smad7 is an intracellular
inhibitor of Smad signaling. In hepatocytes, Smad7 induction serves to inhibit
Smad2-3-4 signaling and likely inhibits apoptosis whereas its expression in
stellate cells limits collagen gene expression. It is likely that this protein is
expressed in both cell types however these data need to be shown.
Immunohistochemical localization of Smad7 would greatly strengthen the
findings and significance of this work.
Minor essential revisions
2. The patient population examined appears to be somewhat heterogeneous with
respect to the duration of the diagnosed disease. While it is recognized that
heterogeneity is inevidable when examining human samples, does this
heterogeneity potentially weaken the findings. Alternatively, are there two
populations within this study (short term disease vs. long-term disease) which
may show differences in the relative correlations among expression of the factors
examined. Please comment.
3. The image provided for Trichrome staining is not clear. While there is no doubt
fibrosis exists, other stains such as Picrosirius red should be considered as the
typical blue staining denoting collagen in Trichrome is not visible and such data
would be most helpful to readers not familiar with fibrosis-associated
histopathological changes. Also, given the heterogeneity of the patients, it should
be noted which patient sample was used for this image.
4. The manuscript suffers from substantial grammatical errors which must be
corrected prior to publication.
Quality of written English: Not suitable for publication unless extensively edited
assistant