© 2002 American Thoracic Society
Rebuttal from Dr. PerssonDepartment of C linical Pharmacology Lund University Hospital Lund, Sweden Dr. Gelfand provides an impressive but incomplete list of agents that are effective in mouse models but are not effective in asthma. The immediate conclusion then is that mice, although of use in studies of immune regulation etc., are not a good model of human airway disease. It is noteworthy that Gelfand acknowledges finally that he has been erring with regard to mouse eosinophil degranulation (1). May the future hold more concessions of this nature. One cannot be fooled by the gallant turns in Gelfand's fandango-like performance as he attempts to defend the fantasy that asthma occurs in mice. A mischievous person (pun intended) is clearly hidden there. Gelfand now proposes that heterogeneity in mouse systems "is equal to heterogeneity of human disease." This kind of proposal may exemplify that if you use selected information at the molecular level you can claim almost anything. The term "heterogeneity" can also refer to diverging observations. But heterogeneity, just the same as hyperresponsiveness, is merely a label likely reflecting very different things in mouse models and in human asthma. I appreciate Gelfand's attempts to distinguish between the pharmacology of primary and secondary allergen challenges (2), and I agree that research on drug efficacy must focus on complex "downstream" conditions. Unfortunately, there is a severe imbalance between studies of "prophylactic" effects of drugs (administration before an allergen challenge) and studies of "curative" effects of drugs (administration when inflammation is already established). The latter is clinically relevant, but it is rarely studied in vivo—even in mice. Considering the broad "prophylactic" and narrow "curative" pharmacology of many drugs and drug candidates (2, 3), a shift in focus toward reversal of established airway inflammation would reduce the cornucopia of inflated promises of novel antiasthma drugs. This too, however, is an area where mouse models, lacking significant asthma-like pathology and pathophysiology, are insufficient. Hopefully, the era of wishful thinking—everything is fine with current mouse models—is gone. Instead, let continuous criticism be a stimulus to the development of meaningful disease-like animal models using combined animal–human approaches. "Disease-like" primarily involves the major pathophysiologic processes, and then molecular medicine comes into the picture. Without getting the pathophysiology right, molecular "links" between model and disease may be of little value. REFERENCES
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