Reviewer's report 
 Urokinase-type plasminogen activator supports liver repair independent of binding to its cellular Title: 
receptor 
 1  1 August 2006 Version: Date: 
 Gavin E Arteel Reviewer: 
Reviewer's report: 
General 
The authors investigated the effect of knocking urokinase plasminogen activator (uPa), its receptor (uPaR) and tissue plasminogen activator (tPA) on the recovery of damaged liver in a model of bolus CCl4-induced liver injury in mice. Whereas knocking out tPA and uPaR (and combined) had no effect on clearance of 
centrilobular damage and fibrin, knocking out uPa (alone) had a dramatic effect on blunting recovery. The 
authors conclude that uPa alone (without binding to uPaR) is sufficient for adequate recovery of liver structure in this model. 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can be reached) 
While an interesting study, the authors make some rather strong mechanistic statements regarding 
molecular interactions based on holistic results in their knockout strains. It is understood that there is a 
certain â €˜black boxâ €™ intrinsic to in vivo research, but the authors also largely ignore the possibility of 
compensatory mechanisms in their knockouts that can explain their results. There are 2 experimental 
suggestions to help bolster their claims. First, the uPaR and tPa knockouts should be crossed with the uPa 
knockouts. If the authorsâ €™ hypotheses are correct, then these double knockouts should fair no worse in 
the model. To address the result with the uPaR knockouts (i.e., transient impairment of growth after injury), it is recommended that levels of active HGF be measured. However, the authors will still need to 
â€˜tone-downâ €™ in some sections the strength of their conclusions based on the level at which they 
studied the question, as detailed below. 
------------------------------------------------------------------------------- 
Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the author 
can be trusted to correct) 
Title 
The authors have no direct evidence of the role of binding of uPA to its receptor, but rather this conclusion 
is inferred from the results. The title should be modified accordingly. 
Results 
Page 7, para. 2. The subheading for this section implies direct studies of the receptor/free status of uPA. 
However, this is not the case, the subheading should refer to the experiments performed, not the conclusions derived. 
Discussion 
Page 10, para. 2. Again, the strength of the mechanistic information (free vs. bound) should be toned down. The results clearly imply such a conclusion, but do not definitively prove it. For example, â €œThese results 
support the hypothesisâ €¦â € 
 Unable to decide on acceptance or rejection until the authors have responded to the major What next?: 
compulsory revisions 
 An article whose findings are important to those with closely related research interests Level of interest: 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
I declare that I have no competing interests 
Reviewer's report 
 Urokinase-type plasminogen activator supports liver repair independent of binding to its cellular Title: 
receptor 
 1  1 August 2006 Version: Date: 
 Gavin E Arteel Reviewer: 
Reviewer's report: 
General 
The authors investigated the effect of knocking urokinase plasminogen activator (uPa), its receptor (uPaR) and tissue plasminogen activator (tPA) on the recovery of damaged liver in a model of bolus CCl4-induced liver injury in mice. Whereas knocking out tPA and uPaR (and combined) had no effect on clearance of 
centrilobular damage and fibrin, knocking out uPa (alone) had a dramatic effect on blunting recovery. The 
authors conclude that uPa alone (without binding to uPaR) is sufficient for adequate recovery of liver structure in this model. 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can be reached) 
While an interesting study, the authors make some rather strong mechanistic statements regarding 
molecular interactions based on holistic results in their knockout strains. It is understood that there is a 
certain â €˜black boxâ €™ intrinsic to in vivo research, but the authors also largely ignore the possibility of 
compensatory mechanisms in their knockouts that can explain their results. There are 2 experimental 
suggestions to help bolster their claims. First, the uPaR and tPa knockouts should be crossed with the uPa 
knockouts. If the authorsâ €™ hypotheses are correct, then these double knockouts should fair no worse in 
the model. To address the result with the uPaR knockouts (i.e., transient impairment of growth after injury), it is recommended that levels of active HGF be measured. However, the authors will still need to 
â€˜tone-downâ €™ in some sections the strength of their conclusions based on the level at which they 
studied the question, as detailed below. 
------------------------------------------------------------------------------- 
Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the author 
can be trusted to correct) 
Title 
The authors have no direct evidence of the role of binding of uPA to its receptor, but rather this conclusion 
is inferred from the results. The title should be modified accordingly. 
Results 
Page 7, para. 2. The subheading for this section implies direct studies of the receptor/free status of uPA. 
However, this is not the case, the subheading should refer to the experiments performed, not the conclusions derived. 
Discussion 
Page 10, para. 2. Again, the strength of the mechanistic information (free vs. bound) should be toned down. The results clearly imply such a conclusion, but do not definitively prove it. For example, â €œThese results 
support the hypothesisâ €¦â € 
 Unable to decide on acceptance or rejection until the authors have responded to the major What next?: 
compulsory revisions 
 An article whose findings are important to those with closely related research interests Level of interest: 
 Acceptable 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 
 Urokinase-type plasminogen activator supports liver repair independent of binding to its cellular Title: 
receptor 
 1  1 August 2006 Version: Date: 
 Gavin E Arteel Reviewer: 
Reviewer's report: 
General 
The authors investigated the effect of knocking urokinase plasminogen activator (uPa), its receptor (uPaR) and tissue plasminogen activator (tPA) on the recovery of damaged liver in a model of bolus CCl4-induced liver injury in mice. Whereas knocking out tPA and uPaR (and combined) had no effect on clearance of 
centrilobular damage and fibrin, knocking out uPa (alone) had a dramatic effect on blunting recovery. The 
authors conclude that uPa alone (without binding to uPaR) is sufficient for adequate recovery of liver structure in this model. 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can be reached) 
While an interesting study, the authors make some rather strong mechanistic statements regarding 
molecular interactions based on holistic results in their knockout strains. It is understood that there is a 
certain â €˜black boxâ €™ intrinsic to in vivo research, but the authors also largely ignore the possibility of 
compensatory mechanisms in their knockouts that can explain their results. There are 2 experimental 
suggestions to help bolster their claims. First, the uPaR and tPa knockouts should be crossed with the uPa 
knockouts. If the authorsâ €™ hypotheses are correct, then these double knockouts should fair no worse in 
the model. To address the result with the uPaR knockouts (i.e., transient impairment of growth after injury), it is recommended that levels of active HGF be measured. However, the authors will still need to 
â€˜tone-downâ €™ in some sections the strength of their conclusions based on the level at which they 
studied the question, as detailed below. 
------------------------------------------------------------------------------- 
Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the author 
can be trusted to correct) 
Title 
The authors have no direct evidence of the role of binding of uPA to its receptor, but rather this conclusion 
is inferred from the results. The title should be modified accordingly. 
Results 
Page 7, para. 2. The subheading for this section implies direct studies of the receptor/free status of uPA. 
However, this is not the case, the subheading should refer to the experiments performed, not the conclusions derived. 
Discussion 
Page 10, para. 2. Again, the strength of the mechanistic information (free vs. bound) should be toned down. The results clearly imply such a conclusion, but do not definitively prove it. For example, â €œThese results 
support the hypothesisâ €¦â € 
 Unable to decide on acceptance or rejection until the authors have responded to the major What next?: 
compulsory revisions 
 An article whose findings are important to those with closely related research interests Level of interest: 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
I declare that I have no competing interests 
assistant