Reviewer's report 
 Antioxidant mechanisms of insulin-like growth factor-I (IGF-I) in rats with advanced liver Title: 
cirrhosis. 
 1  14 November 2004 Version: Date: 
 Rafael Bruck Reviewer: 
Reviewer's report: 
General 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can 
be reached) 
Garcia-Fernandez et al. demonstrated in previous studies that IGF-I is hepatoprotective and anti 
fibrogenic in rats exposed to the hepatotoxin CCl4. In the present study, they investigated the effects 
of IGF-I on pro and antioxidant mechanisms in rats using the same experimental model of CCl4. 
They demonstrated increased hepatic levels of iron, ferritin, transferrin, copper, MPO and iNOS in 
the cirrhotic rats which were all reduced by IGF treatment. They concluded that the beneficial effects 
of IGF-I in cirrhosis are associated with decreased hepatic contents of prooxidants and some 
proinflammatory factors. The studies are designed properly and the paper is well written. 
Major comments: 
1. The present study still does not clarify the mechanisms responsible for the beneficial effects of 
IGF in liver cirrhosis. Is there a direct anti fibrotic effect (I,e,, effect on hepatic stellate cell activation 
and collagen synthesis) or is this only an indirect (and therefore nonspecific) effect of one more antioxidant and/or anti inflammatory substance ? 2. The changes in iron, ferritin, transferring, and iNOS and the effect of IGF may be secondary to 
prevention of oxidative stress, inflammation and fibrogenesis and thus do not explain the primary 
mechanism of action of IGF. 3. The authors measured only MDA as a marker of oxidative stress. For example, transcription factors such as NF-kB that have a major role in oxidative stress and inflammation may give more 
information from the mechanistic point of view. 
4. As the IGF was administered only during the last 3 weeks (week 27 to 30) of treatment and the 
inflammatory, oxidative and fibrogenic processes occur from the beginning of CCl4 administration, it 
is amazing how the inflammation, oxidative parameters and fibrosis regress and improve after 3 
weeks of IGF treatment. What are the mechanisms of regression (collagen degradation, increased 
MMP’s activity, inhibition of TIMP’s etc.)? The mechanisms during regression may differ from those 
acting during prevention. 
------------------------------------------------------------------------------- 
Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the 
author can be trusted to correct) 
------------------------------------------------------------------------------- 
Discretionary Revisions (which the author can choose to ignore) 
 Unable to decide on acceptance or rejection until the authors have responded to the What next?: 
major compulsory revisions 
 An article whose findings are important to those with closely related research Level of interest: 
interests 
 Needs some language corrections before being published Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
I declare that I have no competing interests 
Reviewer's report 
 Antioxidant mechanisms of insulin-like growth factor-I (IGF-I) in rats with advanced liver Title: 
cirrhosis. 
 1  14 November 2004 Version: Date: 
 Rafael Bruck Reviewer: 
Reviewer's report: 
General 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can 
be reached) 
Garcia-Fernandez et al. demonstrated in previous studies that IGF-I is hepatoprotective and anti 
fibrogenic in rats exposed to the hepatotoxin CCl4. In the present study, they investigated the effects 
of IGF-I on pro and antioxidant mechanisms in rats using the same experimental model of CCl4. 
They demonstrated increased hepatic levels of iron, ferritin, transferrin, copper, MPO and iNOS in 
the cirrhotic rats which were all reduced by IGF treatment. They concluded that the beneficial effects 
of IGF-I in cirrhosis are associated with decreased hepatic contents of prooxidants and some 
proinflammatory factors. The studies are designed properly and the paper is well written. 
Major comments: 
1. The present study still does not clarify the mechanisms responsible for the beneficial effects of 
IGF in liver cirrhosis. Is there a direct anti fibrotic effect (I,e,, effect on hepatic stellate cell activation 
and collagen synthesis) or is this only an indirect (and therefore nonspecific) effect of one more antioxidant and/or anti inflammatory substance ? 2. The changes in iron, ferritin, transferring, and iNOS and the effect of IGF may be secondary to 
prevention of oxidative stress, inflammation and fibrogenesis and thus do not explain the primary 
mechanism of action of IGF. 3. The authors measured only MDA as a marker of oxidative stress. For example, transcription factors such as NF-kB that have a major role in oxidative stress and inflammation may give more 
information from the mechanistic point of view. 
4. As the IGF was administered only during the last 3 weeks (week 27 to 30) of treatment and the 
inflammatory, oxidative and fibrogenic processes occur from the beginning of CCl4 administration, it 
is amazing how the inflammation, oxidative parameters and fibrosis regress and improve after 3 
weeks of IGF treatment. What are the mechanisms of regression (collagen degradation, increased 
MMP’s activity, inhibition of TIMP’s etc.)? The mechanisms during regression may differ from those 
acting during prevention. 
------------------------------------------------------------------------------- 
Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the 
author can be trusted to correct) 
------------------------------------------------------------------------------- 
Discretionary Revisions (which the author can choose to ignore) 
 Unable to decide on acceptance or rejection until the authors have responded to the What next?: 
major compulsory revisions 
 An article whose findings are important to those with closely related research Level of interest: 
interests 
 Needs some language corrections before being published Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
I declare that I have no competing interests 
Please review this paper.
user
Reviewer's report 
 Antioxidant mechanisms of insulin-like growth factor-I (IGF-I) in rats with advanced liver Title: 
cirrhosis. 
 1  14 November 2004 Version: Date: 
 Rafael Bruck Reviewer: 
Reviewer's report: 
General 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can 
be reached) 
Garcia-Fernandez et al. demonstrated in previous studies that IGF-I is hepatoprotective and anti 
fibrogenic in rats exposed to the hepatotoxin CCl4. In the present study, they investigated the effects 
of IGF-I on pro and antioxidant mechanisms in rats using the same experimental model of CCl4. 
They demonstrated increased hepatic levels of iron, ferritin, transferrin, copper, MPO and iNOS in 
the cirrhotic rats which were all reduced by IGF treatment. They concluded that the beneficial effects 
of IGF-I in cirrhosis are associated with decreased hepatic contents of prooxidants and some 
proinflammatory factors. The studies are designed properly and the paper is well written. 
Major comments: 
1. The present study still does not clarify the mechanisms responsible for the beneficial effects of 
IGF in liver cirrhosis. Is there a direct anti fibrotic effect (I,e,, effect on hepatic stellate cell activation 
and collagen synthesis) or is this only an indirect (and therefore nonspecific) effect of one more antioxidant and/or anti inflammatory substance ? 2. The changes in iron, ferritin, transferring, and iNOS and the effect of IGF may be secondary to 
prevention of oxidative stress, inflammation and fibrogenesis and thus do not explain the primary 
mechanism of action of IGF. 3. The authors measured only MDA as a marker of oxidative stress. For example, transcription factors such as NF-kB that have a major role in oxidative stress and inflammation may give more 
information from the mechanistic point of view. 
4. As the IGF was administered only during the last 3 weeks (week 27 to 30) of treatment and the 
inflammatory, oxidative and fibrogenic processes occur from the beginning of CCl4 administration, it 
is amazing how the inflammation, oxidative parameters and fibrosis regress and improve after 3 
weeks of IGF treatment. What are the mechanisms of regression (collagen degradation, increased 
MMP’s activity, inhibition of TIMP’s etc.)? The mechanisms during regression may differ from those 
acting during prevention. 
------------------------------------------------------------------------------- 
Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the 
author can be trusted to correct) 
------------------------------------------------------------------------------- 
Discretionary Revisions (which the author can choose to ignore) 
 Unable to decide on acceptance or rejection until the authors have responded to the What next?: 
major compulsory revisions 
 An article whose findings are important to those with closely related research Level of interest: 
interests 
 Needs some language corrections before being published Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
I declare that I have no competing interests 
assistant