Eotaxin and Nitric Oxide Production as Markers of Inflammation in Allergic Cynomolgus Monkeys

Abstract

Background: Cynomolgus monkeys have a natural hypersensitivity to Ascaris suum antigen. Inhalation of antigen produces immediate and delayed allergic reactions and an influx of inflammatory cells into the lungs. This study investigated the production of nitric oxide (NO) and the chemokine eotaxin during this allergic response. The effect of bronchoscopy alone on lung inflammatory cells was also investigated along with the time course of the eosinophil influx into the lung. Methods: Allergic cynomolgus monkeys were challenged with antigen. Bronchoalveolar lavage (BAL) was performed before and after challenge, and end–tidal NO was measured before and 24 h after challenge. Eotaxin was measured in the BAL fluid 6, 24 and 72 h after challenge. One group of animals was treated with dexamethasone before challenge to block the influx of cells into the lung. Results: BLA alone induced an influx of neutrophils, but not eosinophils, into the lung 24 h later. A single antigen challenge produced a marked increase in BAL eosinophils that was apparent at 6 h but increased at 72 h after challenge. The increase at 6 h was largely blocked by dexamethasone. Three antigen challenges produced elevated BAL eosinophil levels that persisted for at least 8 weeks. Eotaxin levels rose dramatically 6 h after challenge and remained the same after 24 h. By 72 h, the eotaxin levels had returned to baseline. The increase in eotaxin at 6 h was nonsignificantly reduced by dexamethasone. Exhaled NO levels doubled 24 h after challenge and were not affected by dexamethasone. Conclusions: Eotaxin and NO production were increased after airway challenge in allergic monkeys. The rise in NO was not blocked by dexamethasone. The effects of bronchoscopy on the BAL can be avoided by using alternate lungs on consecutive occasions. Eosinophils persist in the BAL for many weeks after antigen challenge.

Functional Expression and Characterization of Macaque C-C Chemokine Receptor 3 (CCR3) and Generation of Potent Antagonistic Anti-macaque CCR3 Monoclonal Antibodies

“…In the model, animals are exposed to single or multiple challenges of A. suum antigen, resulting in a prominent BAL eosinophilia. Indeed, eotaxin has been observed in the BAL rapidly within 6 h of after allergen challenge and remained high for 24 h in this cynomolgus macaque asthma model (17). Moreover, these non-human primates exhibit an early and late phase bronchoconstriction as well as a prominent airway hyperresponsiveness (AHR).…”

“…CCR3-activating ␤-chemokines are elevated in human asthmatics (14 -16) and are markedly up-regulated upon allergen challenge in animal models (5,(17)(18)(19)(20)(21) and in humans (22)(23)(24)(25)(26).…”

A Novel, Orally Active CXCR1/2 Receptor Antagonist, Sch527123, Inhibits Neutrophil Recruitment, Mucus Production, and Goblet Cell Hyperplasia in Animal Models of Pulmonary Inflammation

“…A catheter was introduced into the cephalic vein, and anesthesia was induced by intravenous propofol (1-2 ml bolus; 2-4 mg/kg). Blood pressure, heart rate, and arterial oxygen saturation were monitored using techniques that have been described previously (Young et al, 1999). Before the introduction of the bronchoscope, a 2-to 3-ml bolus of propofol was given to suppress the cough reflex.…”

“…At this point, a BAL fluid sample was obtained. The BAL samples were analyzed for the total and differential cell enumeration as described previously (Young et al, 1999). Interleukin-8 levels were measured in the BAL fluid by ELISA following the manufacturer's protocol (R&D Systems, Inc., Minneapolis, MN).…”

Modelling asthma in macaques: longitudinal changes in cellular and molecular markers

“…Previous reports have described findings in monkeys sensitive to Ascarus suum [2,[7][8][9][10]. A small number of primate studies have used clinically meaningful aeroallergens, such as ragweed [11] or house dust mite (HDM) delivered in aerosol form [6,12,13].…”