Animal models respiratory disease

Selgrade, M.K., Air pollution and respiratory disease extrapolating from animal models to human health effects, Immunopharmacology, 48, 319, 2000. 

A series of 7-diazabicycloalkyl quinolones has been prepared and found to exhibit excellent broad spectrum activity against important veterinary pathogenic bacteria [105], The structures of several of these interesting bicyclic analogues (76) as well as MIC data are summarized in Table 6.28. Compound (76e) (danofloxacin), which also exhibits excellent p.o. and s.c. activity in a mouse protection model for Pasteurella multocida [ 106], is undergoing development for use in veterinary medicine. It has been shown to exhibit excellent bioavailability properties in cattle, swine and poultry [107] and is efficacious in models for the treatment of respiratory diseases in food-producing animals [108],... 

The size of the fibrous particles that appear to induce disease in the animal models is compatible with the measured respiratory range in humans (Lipp-man, 1977). Most particulate deposition takes place not in the upper or conducting portion of the airways but in the alveolar region of the pulmonary tree (the respiratory unit). Some surface deposition may occur at bifurcations in the bronchial tree, but the actual amount at each location is influenced by anatomy, specific to the species—probably to an individual—as well as the variety of fiber. A large proportion of airborne particulates are rejected as part of the normal clearance mechanisms in animals, but in humans clearance mechanisms may be compromised by smoking, for example. We are unaware of any experiments on fiber toxicity using smoking rats ... 

In this chapter we review the defects of respiratory function and DNA mutations in the mitochondrial genome and nuclear DNA underlying mitochondrial diseases and discuss the roles that oxidative stress, oxidative damage, and apoptosis may play in the pathogenesis of this group of overt metabolic disorders. The cell cultures and animal models for studies of mitochondrial diseases and potential therapies are also discussed. 

A recent review [73] describes the various animal models used to mimic the different aspects of this disease. For KCAs, the in vivo models employed have generally been bronchoconstrictor in nature, where test compounds have been examined for their ability to prevent or reverse an induced bronchoconstriction. This can be achieved in several ways, the simplest being the respiratory embarrassment model, where a guinea-pig is exposed to a concentration of a bronchoconstrictor that causes dyspnoea. The KCAs may be tested by the oral route for their ability to attenuate the onset of dyspnoea. Even in the control animals, in which dyspnoea leads to rapid collapse, removal of the animals from the chamber and away from the bronchoconstrictor agent, allows a full recovery [74]. Various other ways of inducing bronchoconstriction in conscious animals are available, one of the... 

Alterations in the previous respiratory defenses would be expected to make the lung more vulnerable to infectious disease. Animal models have served to demonstrate the effects of airborne chemicals and to establish associations between these effects and actual increases in susceptibility to respiratory disease. These in vivo models combine the adverse effects of the toxicant with the added stress induced... 

The observation that T-cell immune responses may be involved in the pathogenesis of occupational respiratory diseases is supported by animal models (Dearman et al., 1992). Rodents can be easily sensitized to LMW chemicals such as acid anhydrides and diisocyanates. A murine model has been used to study the differential production of cytokines by helper T-cell subsets (Thl and Th2) after exposure to different reactive chemicals. It has been shown that under normal conditions Thl lymphocytes primarily secrete IL-2, interferon-/and tumour necrosis factor J3 (TNI -/ ) whereas Th2 lymphocytes secrete IL-4, IL-5, IL-10 and IL-13. A predominance of Th2 cells correlated with IgE-mediated immune responses, while a predominance of Thl cells was associated with cell-mediated immune responses (Dearman et al., 1992). These investigators demonstrated preferential activation of Th2 cells by phthalic anhydride (PA), trunellitic anhydride (TMA) and diphenyl-methylene diisocyanate, indicating that chemical structure may be important for determining the quality of immune response elicited (Dearman et al., 1992). 

A wide variety of species have been treated with both case-associated and reconstituted oils, with only a few reports that some of the classical symptoms have been observed in mice (eosinophilia and elevated IgE) and rats (lung oedema, respiratory difficulties, splenomegaly). Possible explanations for the generally negative results in animal models are that toxic oil syndrome may be a uniquely human disease, animals may have a lower sensitivity to toxic oils, the dose used may not have been adequate, and multiple agents, genetic factors, and biochemical alterations may be involved in disease development. 

Respiratory syncytial virus (RSV) and parainfluenza virus (PIV) are leading causes of respiratory disease in infants, young children, immuno-compromized patients, and the elderly. Bitko et al. [140] used viral-specific siRNAs for the treatment of these respiratory syndromes in an animal model. In this study, either, or both, viral infections could be specifically prevented and inhibited when corresponding siRNAs were infused intranasally in mice, with or without transfection reagents. These investigators noted an excellent correlation between the activities observed in their siRNAs in in vitro cell cultures and those observed in their animal model. This type of approach presents a fast screen for efficient siRNA sequences before more expensive and demanding applications are pursued in animals. In addition, nasal administration of siRNA compounds seems to provide a convenient... 

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