A murine model of pulmonary inflammation

Abstract

Asthma is the commonest treatable chronic pulmonary disease affecting all ages and affecting up to 2-3 million each year in the UK. Yet despite improvements in the potency and selectivity and anti-asthmatic medication and a greater understanding of the pathophysiology of the disease there is clear evidence to indicate that the incidence and severity of asthma is now reaching epidemic proportions.

Over the last twenty years it has become apparent that asthma is a chronic inflammatory disease driven by a Th-2 subpopulation of lymphocytes. Consequently a number of Th-2 driven models of allergic inflammation have been developed in animals. The two most commonly employed strategies to provoke a Th-2 response, particularly in rodents, are infection with gastrointestinal nematode Nippostrongylus brasiliensis (N.b.) or nebulisation of ovalbumin (OA) to the airways of OA-sensitised animals. However many OA models do not mimic the chronic inflammation of the airways so typical of asthma in humans and until only recently they did not induce airway obstruction at all.

In this thesis we examined systemic and pulmonary response to N.b. in wild-type and genetically manipulated mice to determine how closely this mimicked allergic inflammation seen in humans. Our results suggest that there are a number of similarities in the cellular response in the lungs and elsewhere between N.b. infection and the allergic inflammation seen in asthmatic airways. Specifically, N.b. infection provoked an early and late inflammatory response, which culminated in the selective recruitment from the microvasculature of eosinophils and T cells expressing a restricted range of cell adhesion molecules. These eosinophils were shown to be small, mature, functionally active and recruited in much greater numbers than seen in OA-induced models. Furthermore, N.b. was shown to override genetically manipulated obstructions to the development of a Th-2 response. The similarity in the histopathology, bronchoalveolar lavage and effector cell function, between this model and allergic inflammation of the airways suggests that infection with N.b. may confer a number of specific advantages over OA-induced models of asthma and therefore represent a useful investigative tool in the fight against this common disease.

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