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J Thorac Cardiovasc Surg 2008;135:1226-1227
© 2008 The American Association for Thoracic Surgery
Invited Commentary |
In this study the authors evaluated the role of sPLA2 in a mouse model of surgically induced gastroduodenoesophageal reflux. By using an inbred mouse strain deficient in the gene for phospholipase A2, they were able to ascertain the role of this enzyme in early esophageal mucosal changes associated with reflux. Compared with normal mice, the knockout mice showed significantly less increase in epithelial thickness and in Ki67 activity, with levels in the knockout mice equivalent to those in control animals. They conclude that phospholipase A2 is involved in the early squamous mucosal changes associated with gastroduodenoesophageal reflux.
The authors are to be congratulated for several things. First, they successfully developed this mouse model of surgically induced reflux, which has been a hurdle for many investigators in the past. Second, they demonstrate that the phospholipase A2 protein can be found in esophageal tissue in the mouse. Third, they designed an elegant first experiment by using a mouse knockout model for this gene to demonstrate the role of phospholipase A2 in early squamous esophageal mucosal injury associated with reflux. I have 3 questions for you.
First, changes in esophageal mucosal thickness or the old (Ishmael Bagay) criteria for reflux are known to be quite nonspecific. Recent work by Ray Orlando and colleagues using transmission electron microscopy to look at dilated intracellular channels suggests that this might represent a very sensitive and specific way to assess early mucosal changes associated with reflux. Have you considered using transmission electron microscopy to evaluate in the mouse the presence or absence of these dilated intracellular channels?
Dr Weyant. I am aware of the technique, but at our institution, it is difficult to achieve the use of that specific technique, although it is something that we are certainly interested in looking at in the future.
Dr Demeester. Second, the really significant (ie, premalignant) changes that occur with reflux involve the transformation of the squamous esophageal mucosa to columnar cardiac mucosa and then subsequently to intestinal metaplasia. Do you anticipate that with a longer duration of reflux in this mouse model that these histologic changes will occur? In other words, can you replicate in the mouse model what has been shown to occur in the rat model of gastroduodenoesophageal reflux?
Dr Weyant. I believe we can. I am certainly very optimistic that we can. Even after 4 weeks in some of these mice, we are actually able to see changes that appear to be the early morphologic changes consistent with Barrett's esophagus. I did not have the time to show the slides here, but our next phase of these studies is going to be to take these mice and reflux them for several weeks, up to 40 weeks, and harvest the mice at several different time periods so that we have the whole spectrum of carcinogenesis of gastroesophageal junction adenocarcinoma; that will then allow us to study all of these molecular markers at these different time points in this model, as well as using the similar model in other genetic backgrounds, such as a P53 knockout mouse and others that are available, where we can apply this model now that we are proficient in it.
Dr Demeester. Lastly, although there is no doubt that a link between inflammation and cancer exists, the nature of that relationship is very complex. Rebecca Fitzgerald, in addition to work from our own laboratory, has shown that there is an inflammatory gradient within Barrett's esophagus with maximal expression of inflammatory genes proximally in a Barrett's esophagus segment, yet many of the cancers occur distally in areas with much lower levels of inflammatory gene expression. In light of this, can you give us your thoughts on the role of phospholipase A2 and what its role might be in carcinogenesis within Barrett's esophagus? Do you think it is an early mediator of progression in Barrett's esophagus or merely a marker for injury?
Congratulations again and thank you for the opportunity to discuss this paper.
Dr Weyant. Thank you very much for your comments, Dr DeMeester.
Part of our next phase of these studies also goes along with what our next main hypothesis is regarding the function of sPLA2 in that our initial observations showed of these quick and dirty findings of hyperplasia and thickening of the mucosa, but what that really points to for me is that sPLA2 is somehow a growth regulator in esophageal mucosa. Some of the articles I have listed on one of the previous slides are some of the less well-known literature regarding sPLA2, and not one of them has sort of hit on the main point that it interacts with EGF receptor and its ligand, which we know is already a growth factor in esophageal mucosa, as well as other growth factors. Again, these are reported in other tissues using different models, but I think our next step is to apply those hypotheses to this model to see really how sPLA2 acts as a growth factor in esophageal mucosa, and I think we will.
Doctor. I have a quick follow-up question for you, which speaks to my inherent suspicion of knockout mice. Can you comment more on these collateral secretory phenotypic changes associated with the black-6 mouse? In other words, I appreciate that your inhibitor studies validate that phospholipase A2 is at least a necessary cofactor in this preparation, but are there any other changes that result from this particular genetic variation as relates to acid or bile salt excretion?
Dr Weyant. As far as other experience goes, no. That is a continual concern of ours, and data that I did not present here that we have also recently accumulated in the laboratory—there is actually a mouse available with a black-6 background that has the sPLA2 gene reintroduced into it. When we do this same model here comparing a black-6 wild-type mouse and a black-6 mouse that has the sPLA2 gene reintroduced, we get the same findings of the hyperplasia and thickening of mucosa. Between the inhibitor studies and what we call the "knock-in" studies, that is as confident as I can be that we are actually seeing a real change here. The reason we went to these lengths of using the inhibitor study and the knock-in mouse was because of those concerns that we shared also.
Doctor. I agree. Excellent job. Elegant work, and everybody on the project should be commended on technically pulling this off. That is a real feat of technical expertise. Congratulations.
Related Article
J. Thorac. Cardiovasc. Surg. 2008 135: 1220-1227.
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