Researchers have believed that although histamine and amine compounds released by the cells during an allergic reaction contribute to allergic discomfort, other mediators and neural pathways are also involved. Ideally, identifying the various levels of irritant- and allergen-induced reactions in the nasal passages would provide new insights. To do so, a suitable testing model is necessary to delineate novel target sites and to test potential efficacy and toxicity of new chemical entities before starting evaluations in humans.
Unfortunately, finding the animal model has been a lot more difficult than one would think. Several animal models of rhinitis have been used in previous research but the results were based on euthanizing the animals following the techniques tested, an action unsuitable for application to humans.
A New Study
Now, however, a team of researchers has found that the erstwhile companion of millions -- the friendly beagle dog -- closely resembles the pathophysiology for human allergic rhinitis. This discovery enables the use of experimental techniques similar to those used for the assessment of human nasal passages and permits other, related experiments.
The authors of "Canine Model of Nasal Congestion and Allergic Rhinitis" are Ruslan L. Tiniakov, Olga P. Tiniakova, and Donovan B. Yeates, from the University of Illinois at Chicago, and Veterans Affairs Chicago Health Care System, Chicago, IL; and Robbie L. McLeod and John A. Hey, at the Schering-Plough Research Institute, Kenilworth, NJ. Their findings appear in the May 2003 edition of the Journal of Applied Physiology.
Methodology
Beagles, sensitized to ragweed allergen at birth, were subjected to inhalation of the ragweed extract into the lower respiratory tract inducing a systemic anaphylactic response that manifested in bronchoconstriction, alteration of a breathing pattern, increase in bronchial mucociliary clearance, and temporary cardiovascular depression. The researchers believed that, in these dogs, exclusive exposure of the upper respiratory tract to the same ragweed allergen would precipitate the development of allergic rhinitis that was responsive to treatment with a-adrenergic agonists.
To test this hypothesis, they evaluated the degree of nasal congestion induced by ragweed and histamine in cohorts of ragweed-sensitized, sham-sensitized, and nonsensitized dogs. Nasal congestion was assessed by the measurement of the resistance to conducting air, i.e., nasal airway resistance (RNA) and the relative cross-sectional areas and the volume of nasal passages.
Three series of experiments were conducted on subgroups selected from 14 adult beagle dogs of both sexes, weighing 9.5–14.5 kg. Five dogs were neonatally sensitized to ragweed, three were their sham-sensitized littermates, and six dogs were nonsensitized. Newborn dogs were sensitized with intraperitoneal injections containing ragweed extract in a saline mix and aluminum hydroxide within 24 hours of birth. Injections were repeated weekly for six weeks and biweekly until 16 weeks of age. In the sham-sensitized animals, only the aluminum hydroxide in saline was injected. Five-milliliter samples of venous blood were drawn from each dog beginning at four months of age and thereafter four times per year to measure serum ragweed-specific IgE levels.
These sensitization and sham sensitization procedures were conducted in November 1992 (two dogs), July 1993 (three dogs), and December 1993 to January 1994 (three dogs). The ragweed-sensitized dogs previously exhibited an anaphylactic reaction on inhalation of ragweed extract, whereas their sham-sensitized littermates did not. (Editor's note: The research started in the early 1990s, but because it is a longitudinal study, these are the first significant results.)
The first series of experiments was designed to show, using a new method of anterior constant-flow nasal rhinomanometry, that a mediator of allergen-induced rhinitis, histamine, induced nasal congestion that was alleviated by the local administration of an á-adrenergic agonist. The second series of experiments was designed to determine, by using the researchers' method for RNA measurement in combination with acoustic rhinometry, whether any ragweed-induced nasal congestion in ragweed-sensitized, sham-sensitized, and nonsensitized dogs was immunologically induced and whether these responses were reversible by topically administered D-pseudoephedrine. The third series of experiments was designed to demonstrate the utility of this model in estimation of decongestive activity of orally administered á-adrenoceptor agonist, D-pseudoephedrine. The volume of nasal airways was assessed by acoustic rhinometry and resistance to airflow (RNA) by anterior rhinomanometry.
Results
In the first series of experiments, histamine delivered to the nasal passages of five dogs caused rapid increase in RNA from 0.75 + 0.26 to a maximum of 3.56 + 0.50 cmH2O·l-1·minutes within the first five minutes. The RNA in these dogs remained above the baseline for the next 40 minutes. The histamine-induced increase in RNA was almost completely reversed by the administration of aerosolized 0.1 percent phenylephrine to the nasal passages. The responses to histamine and phenylephrine in both the left and right nasal passages were similar. In the second series of experiments, administration of the ragweed extract into the nasal passages of five ragweed-sensitized dogs caused RNA to increase over a period of 20 minutes from 0.25 + 0.01 to a maximum of 1.98 + 0.84 cmH2O·l-1·minutes. Administration of aerosolized saline to these dogs caused a further increase in RNA. In the third series of experiments, 30–40 minutes after the intranasal delivery of aerosolized ragweed extract, signs of severe nasal congestion were observed in four of five sensitized dogs that received placebo 30 minutes before the ragweed challenge.
The nasal passages of ragweed-sensitized dogs demonstrated clear signs of hyperreactivity to the ragweed allergen, resulting in the development of severe nasal congestion. This nasal congestion was evidenced by the characteristic changes in RNA and nasal luminal geometry. In sensitized dogs, nasal congestion appeared to be immunologically precipitated because it was never observed in nonsensitized dogs challenged with the same ragweed allergen. Local vasodilatation and consequent mucosal edema play key roles in development of the observed nasal congestion given that both the histamine-induced congestion in nonsensitized dogs and the ragweed-induced changes in sensitized dogs were susceptible to the treatment with á-adrenomimetics.
Conclusions
The measurement of RNA using a modification of anterior constant-flow rhinomanometry appears to be a simple, practical, and sensitive method for assessment of nasal airway patency. The method is relatively noninvasive and allows multiple experiments in the same cohort of dogs and provides more detailed information about the present condition of nasal passages. The model here of allergic rhinitis described is relevant to human disease and can be successfully used in the identification of novel therapeutic target sites and the pharmacological screening of newly developed topically or systemically administered antiallergic drugs.
Source: May 2003 edition of the Journal of Applied Physiology
The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.
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Journal
Journal of Applied Physiology