Dear Dr. XXX,
editor at largeThank you for arranging a timely review for our manuscript. We are pleased to know that our study is of general interest for the readers of NUTRITION. We have carefully evaluated the reviewers’ critical comments and thoughtful suggestions, responded to these suggestions point-by-point, and revised the manuscript accordingly. All changes made to the text are in red so that they may be easily identified. With regard to the reviewers’ comments and suggestions, we wish to reply as follows:
Enclosures:
(1)Correspondences to your reviewers;
(2)One copy of the revised manuscript;
(3)A floppy disk containing the revised manuscript.
(4)Copyright assignment
To reviewer　#1
1.The author should add a few review articles on ghrelin for readers in the Introduction.
We added two reviews in our revised manuscript.
2.The increase in ghrelin levels do not necessary indicate that weight loss in disease is well compensated (Introduction and Discussion). This may be interpreted to be insufficient to recover to the previous body weight.
There is possibility that the increase in ghrelin levels may result from the insufficient to recover to the previous body weight, but it is more likely that the increase in ghrelin level indicate that weight loss in disease is well compensated. Shimizu et al1 reported that baseline plasma ghrelin level was significantly higher in cachectic patients with lung cancer than in noncachectic patients and control subjects. As weight loss is a chronic process and ghrelin levels may change more rapid than weight loss, the increase in ghrelin in those chronic diseases is unlikely result from the insufficient to recover to the previous body weig
ht. Moreover, this author also reported that follow-up plasma ghrelin level increased in the presence of anorexia after chemotherapy, which further suggests that the increase ghrelin level may represent a compensatory mechanism under catabolic–anabolic imbalance in cachectic patients with lung cancer1.
3.The authors should refer to the original report that IL-1b decrease plasma ghrelin levels(Gastroentelorogy 120:337-345,2001)
        We referred this article as the reviewer suggested. In fact, this is a mistake of us. Many thanks for the reviewer’s suggestion.
4.Ref. 13 dose not include data on ghrelin.
We are so sorry to make this mistake for citing the Ref.13. We replaced the reference in the paper.
5.There is no report that desacyl ghrelin stimulates food intake. It is the consensus at present acyl ghrelin is involved in feeding response to starvation. Therefore, the authors sh
ould be careful about their interpretation described in the last paragraph in page 10.
      We made it clear in the paper that ghrelin has two isoforms (“active” and “inactive”). Only the “active” isoform is involved in feeding response to starvation. But the “inactive” isoform has other activities like anti-proliferative activity on tumor cell lines as described in the manuscript.
To reviewer　#2
Major comments
1.Earlier studies have shown that circulating ghrelin level is increased in underweight patients with CHF, lung cancer, and liver cirrhosis. In the present study, however, plasma ghrelin level was decreased despite a significant weight loss in COPD. In addition, earlier studies have reported that circulating ghrelin correlated positively with BMI in patients with CHF and lung cancer. However, the present study demonstrated that plasma ghrelin level correlated positively with BMI in COPD patients. Thus, there are considerable discrepancie
s between the present study and earlier studies. These discrepancies should be discussed in detail. The author also stated the regulation of ghrelin secretion was disturbed in COPD patients. However, they did not clarify this mechanism.
We stated that the role of ghrelin in patients with COPD may be different from its role in CHF, cancer and liver cirrhosis and discussed this difference in the last paragraph of page 9.
Following the reviewer’s suggestion, we added that “plasma ghrelin correlated positively with percent predicted residual volume and residual volume/total lung capacity ratio” as the evidence for further supporting that respiratory abnormalities may take part in the regulation of plasma ghrelin levels.
2.The authors demonstrated that plasma ghrelin level correlated negatively with plasma TND-a and CRP in COPD patients. However, Nagaya et al. have shown that plasma ghrelin level correlates positively with plasma TNF-a level in patients with CHF. This discrepancy should be discussed.
      According to the reviewer indicated, we discussed this discrepancy in the second paragraph of page 9.