Modeling of asthma, COPD and cystic fibrosis in sheep
Introduction
The sheep has been used extensively to study the pathophysiology of asthma and more recently allergic rhinitis, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. A primary strength of the model is the ability to repeatedly and accurately assess changes in measures of pulmonary function, including mucociliary function, and/or nasal function after provocation with antigen and other irritant stimuli. These functional changes have been characterized extensively and are very similar to the respective pathophysiological changes seen in human subjects in clinical studies. The similarities in airway functional responses and overall pathophysiology have been a major factor in the model's use for the development of drugs for asthma and allergic rhinitis [1]. The overall characteristics of the model are summarized in Table 1.
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General characteristics—asthma model
As indicated in Table 1, sheep that are used for the study of asthma and allergic rhinitis in our laboratory have a natural sensitivity to the provoking antigen, i.e. Ascaris suum. Thus, allergen-induced responses are not dependent on laboratory immunization procedures and/or pharmacological manipulation, which can influence the pathophysiology [2]. Allergic animals have different characteristics than non-allergic (normal) animals, and the allergic group can be further differentiated into those
Differences between allergic and non-allergic (normal) sheep
One of the defining features of asthma is the inherent AHR to airway challenge with non-specific stimuli between asthmatic patients and normal individuals. This basal AHR is to be distinguished from the AHR that follows allergen challenge. Allergic sheep demonstrate basal AHR when compared to their normal counterparts. Specifically, allergic sheep show increased responsiveness to carbachol, histamine, leukotriene D4, sulfur dioxide, cold air, metabisulfite and bradykinin, when compared to
Airway responses to antigen challenge
In both acute and dual responders, the immediate response to inhaled antigen is characterized by bronchoconstriction, a fall in dynamic compliance, an increase in thoracic gas volume (hyperinflation), and hypoxemia [3], [26]. In dual responders, the late response is characterized by bronchoconstriction and hyperinflation, but the changes in dynamic compliance and the hypoxemia are less severe than those seen in the immediate response [3], [26]. Late responses occur in 30–50% of the sheep tested
Airway inflammation
The recognition that recruitment, activation and retention of inflammatory cells are an important component in asthma pathophysiology has fostered a great interest in the events that initiate and amplify antigen-induced inflammation. Because antigen-induced late airway responses are associated with a prolonged period of AHR following a single allergen exposure, the late response and the subsequent AHR are thought to be the physiological indicators of a heightened and continued inflammatory
Airway responses to chronic allergen challenge
The acute allergen provocation model is useful for rapid assessment of pharmacological targets and mechanisms, however, the changes in airway function and inflammatory responses are transient and reverse with time between challenges. To better assess the irreversible decline in lung function that occurs with chronic severe asthma, we chronically challenged sheep with A. suum antigen [45]. The challenge protocol resulted in a non-reversible increase in pulmonary airflow resistance which was
Mediators and pharmacology
The mediators released following allergen challenge in sheep and pharmacological antagonists and inhibitors used in this model have been summarized previously [1]. In general, the mediators identified are consistent with findings in humans. In dual responders, BALF obtained immediately (5–10 min) after aerosol challenge with A. suum antigen show increased levels of histamine, tryptase, prostaglandin (PG) D2, PGE2, TAME-esterase and immunoreactive (i)-kinins [4], [47], [48], [49]. Instillation of
Antigen-induced impairment of mucociliary clearance
The impairment of normal mucociliary function in the airways is an important consequence of asthma exacerbation. Clinically, there is evidence which suggests a relationship between mucociliary dysfunction and asthma severity [17], [18]. Thus, although there is a tendency to focus on airflow obstruction in asthma, excessive secretion and clearing of airway luminal mucus is another important pathophysiologic feature of the disease that contributes to its morbidity and, in the case of status
Allergic rhinitis
As the sheep show overall systemic hypersensitivity to A. suum, it is not surprising that nasal challenge with this antigen elicits an acute increase in nasal resistance [74] and a late cellular response [75]. In the allergic rhinitis model, nasal airway resistance (NAR) is measured by rhinomanometry, similar to what is done clinically in humans. The response to allergen is shown in Fig. 7. As in humans, the response to allergen can be blocked by pretreatment with the antihistamine azelastin,
Modeling COPD and cystic fibrosis
In addition to its use in as a model of allergic airway disease, sheep provide a useful model to evaluate agents that may be used in the treatment of COPD and/or cystic fibrosis. In general, changes in MCC seen in this model under normal and impaired conditions in the presence and absence of therapeutic intervention mimic responses observed in healthy individuals and subjects with airway disease [14], [15], [16], [19], [20], [77]. Thus, the model can be used for comparative purposes to address
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