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Mice Are Not a Good Model of Human Airway Disease

Department of Clinical Pharmacology Lund University Hospital Lund, Sweden

Spurred by dramatic developments in reductive biology, mouse models of asthma are now in extensive use. Who wouldn't wish that a small, easily bred animal, in which you can do so much knocking in and out of genes and where so much immunology has already been put on the map (1), were a good model? However, as discussed in the following passages, reports of molecular and cellular mechanisms in allergic mice disregard or are unaware of the lack of asthma-like pathophysiology. Not surprisingly then, there is coincidence between the popularity of mouse models and the paucity of innovative airway drugs. Indeed, one may ask if we have learned anything important about human asthma by carrying out experiments in mice? Before blaming the mouse too much, it needs iterating that other popular test systems have shortcomings also. Cell phenotypes studied in vitro often exist exclusively in the test tube. Similarly, cell phenotypes and events examined in the accessible airway lumen, although of interest, may not mimic features of the diseased, blood-perfused airway tissue (2). Inferentially, we do need in vivo models of asthma. But studying allergic mice is not a good solution. The wishful thinking that mice are a good model of human airway disease is particularly problematic.

Plasma exudation is a cardinal sign of bronchial asthma and allergic rhinitis. Numerous plasma-derived, inflammatory-, repair-, leukocyte-, and growth factor-active proteins, irrespective of size, distribute throughout human inflamed airway tissues (3). By contrast, little plasma exudation occurs, especially in late phases, in mouse airways, however allergen-loaded (3, 4). Inflammatory cells also differ greatly between disease and model. In mice, lung accumulation of eosinophils is the prime outcome parameter. Yet the distribution of eosinophils, particularly in airway epithelium, differs between mouse and human asthma (4, 5). More significantly, the mouse eosinophils consistently do not degranulate (4–7). By comparison, it is now clear that piecemeal degranulation and degranulation through cytolysis are conspicuous, although variable, features of human airway disease (8, 9). Such novel human in vivo data may be helpful in patient selection for assessments of the actual roles of eosinophils (9). Meanwhile, it would be nice to see a mouse test system exhibiting degranulated eosinophils in decent contrast to the widely disseminated pretenses of degranulation (4, 10)! Because plasma exudation and eosinophil degranulation may correlate with disease severity, it appears logical that asthma-like symptoms more or less are lacking in allergic mice inhaling tons of allergen (4).

Human asthma further features epithelial injury and shedding. However, this does not necessarily mean that denuded airways and mucosal hyperpermeability are present (3, 11). Lack of denudation and unchanged absorption permeability at shedding may be explained in part by speedy epithelial restitution in vivo (12). Furthermore, as suggested by findings in guinea pigs in vivo and as widely discussed based on in vitro and purely molecular data, simple epithelial restitution processes potentially contribute to disease by evoking many inflammatory and remodeling sequelae (12, 13). It is unfortunate, therefore, that evidence for epithelial injury repair in allergic mice is meager to nonexistent (4). The epithelium of mouse tracheobronchial airways is further aberrant by a dominant presence of Clara cells; it appears that transformation of Clara cells may explain the goblet cell metaplasia occurring in mouse models (4, 5). This latter feature is of interest in its own right. However, goblet cell metaplasia may also be treacherously interpreted as evidence of epithelial injury repair processes in allergic mice (14).

Mouse is not man and hyperresponsiveness is not hyperresponsiveness. Without knowing the involved mechanisms and accepting that it is not pathognomonic, we consider airway hyperresponsiveness a hallmark of bronchial asthma. But airway hyperresponsiveness is also used to describe an unexplained, exaggerated response of mouse lungs. How likely is it that this black box phenomenon in mice has any important mechanistic resemblance to asthmatic hyperresponsiveness where the pathology is so different from what you may see in mice? Lacking other phenomena hyperresponsiveness, nevertheless, is accepted proof of asthma-like physiology in mouse models (1, 4, 10).

So where do mouse models fit in? Their lack of similarities with human airway disease does not preclude utility in studies of development of allergy and tolerance (15). However, also considering late pathogenic and curative mechanisms, mouse experiments no doubt will continue to flourish. What one then can wish for is that critical tests of emerging murine concepts will also flourish, or at least that experimental shortcomings are spelled out as in a recent discussion of airway remodeling in mice (16). The author also hopes that the present debate as well as previous warnings of "the mouse trap" (4) will stimulate research into possible improvements of mouse models (17). Unfortunately, the hard work of really critical research is seldom undertaken, simply because it is not rewarded by the kind of appraisals of scientific work and journals that have evolved (2, 18). It is so much easier, and "successful," to grab the novel technological and molecular advances that always emerge these days, and produce so-called cutting edge work instead of bothering about relevancy of your model or about what happened to the promises made only a year or so ago. In vitro and mouse models have been instrumental to this sad development.

No model can be properly validated unless we have sufficient undisputable knowledge about the human disease itself. Ann Woolcock ran a series of meetings aiming at brutal honesty regarding what we really know about "asthma: the important questions" (19); whether endothelium, epithelium, smooth muscle, eosinophils, or other cells, actual facts about roles and processes in asthma are rare. So we need to learn much more about the disease itself. Perhaps this cannot be accomplished unless the balance is shifted significantly toward patient-oriented research, where in vivo discoveries independent of mouse and in vitro paradigms are allowed, even encouraged (2, 20). Incidentally, the strategy of making such "surprise" discoveries in disease-relevant complex biosystems has produced the major asthma drug classes of today (2). The author concludes that progress in respiratory research has been slowed down by the false inference that a "furred, four-legged hypothesis generator" (16), the allergic mouse, provides a good model of human airway disease.

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