In vivo molecular imaging: a useful tool in respiratory drug discovery to visualize key components of lung inflammation

Abstract

Chronic respiratory diseases are major causes of morbidity and mortality, comprising 7% of deaths and 4% of disability adjusted life years (DALYs) worldwide (1-2). Asthma and chronic obstructive pulmonary disease (COPD) affect approximately 300 and 210 million people, respectively, with most of the deaths associated with both disorders occurring in low- and middle-income countries. In recent years, drug discovery efforts have largely centered around two different approaches – the improvements on existing therapies like bronchodilators and glucocorticoids, and novel therapeutic approaches aimed at specific molecular targets. Where, the latter approaches are becoming particularly important. For such approach, biological models of disease are vital for the development of all therapies, for instance, it has become commonplace to validate the “central role” of a particular molecular target in the pathogenesis of either asthma or COPD by characterizing the responses of particular target gene, either knocked-out or overexpressed, in the most relevant system before in vitro and after in vivo models. Therefore, the development of a new drug is the direct consequence of the model system quality employed. As with most human diseases, studies in laboratory animals have produced much of what we currently think we know about the mechanisms responsible for asthma. Obviously, the relevance and validity of these studies are tied to how well we can produce accurate animal equivalents of human asthma. The development of such “animal models” is still very much a work in progress; although many of the various features of asthma have been convincingly recapitulated in animals, invariably every animal model misses some important aspect of the human syndrome . On the other hand, given that we still do not fully understand what asthma in humans actually is, it remains difficult to know whether an animal really has it or not. Accordingly, much of the challenge in studying animal models of asthma lies in phenotyping them properly, particularly as asthma is defined in humans in terms of phenotype rather than underlying pathology. In this thesis, we therefore focus on the issue of how to assess the relevant function, structure molecular events in the mice lungs, fusing together: histological, FACS analysis and non-invasive in vivo molecular imaging technologies.