Behavioral Inhibition Is Associated With Airway Hyperresponsiveness but not Atopy in a Monkey Model of Asthma

Abstract

Objective To determine whether indicators of behavioral inhibition and cortisol responses to stressful situations, obtained in infancy, were associated with asthma-related measures (atopy and airway hyper-responsiveness) approximately two years later. Methods Measures reflecting inhibited temperament and cortisol response following a 25-hr separation from mother and relocation to a novel room were obtained for 21 rhesus monkeys (mean age 109 days, range 91–122). Inhibited temperament was measured by reduced emotionality and increased vigilance Atopy and airway hyperresponsiveness were assessed after two years (age range 19–35 months) using skin tests to common aeroallergens and inhaled methacholine challenge, respectively. Results No associations were found between atopy and either behavioral inhibition or cortisol levels (p > 0.56). Low emotionality was associated with airway hyper-responsiveness (r = 0.47, p = 0.03) and a trend was found for blunted cortisol responsiveness and airway hyper-responsiveness (r = 0.42, p = 0.06). Conclusions Inhibited temperament and blunted cortisol responsiveness may be related to the development of airway hyperresponsiveness that is common to both non-atopic and atopic asthma phenotypes, and may indicate risk for non-atopic asthma specifically.

Behavioral Inhibition in Rhesus Monkeys (Macaca mulatta) Is Related to the Airways Response, but Not Immune Measures, Commonly Associated with Asthma

“…Decades of research have likewise demonstrated close similarity between humans and rhesus monkeys in behavioral and physiological measures of behavioral inhibition [16], [17]. In fact, in a recent retrospective study in our laboratory, we found that behavioral inhibition in infancy was associated with AHR in adolescent and young adult rhesus monkeys, but was not associated with atopy [18]. Airway responsiveness, commonly assessed by recording the dosage of a bronchoconstrictor needed to increase airways resistance by a fixed amount, presents a much better measure of asthma than self- or parent-reports and is commonly used to confirm a diagnosis of asthma [19].…”

“…At the end of this period, animals were returned to their mothers and their field corrals. We defined BI using criteria identical to that in our retrospective analysis of BI and airways response [18]: behaviorally inhibited animals were identified by low emotionality (based on focal animal observations), high vigilance (based on temperament ratings conducted at the end of the 25-hr period), and blunted cortisol response (determined seven hours after separation/relocation). Other laboratories have shown continuity of BI in both rhesus monkeys [26], [27] and humans [28]–[30] using similar measures.…”

“…Airway responsiveness to doubling concentrations of inhaled methacholine aerosols was quantified using previously published procedures [14], [18]. Each animal was anesthetized with ketamine (10 mg/kg) and anesthesia was maintained with propofol (0.1 mg/kg/min).…”

“…Furthermore, our previous study did not assess potential mechanisms of how BI might relate to AHR; while BI was not related to an immediate hypersensitivity response [18], it might still be associated with the immune responses characteristic of asthma. In the present study we focused on (1) the T-helper type 2 (T H 2) cytokine IL-4, which could promote an asthmatic phenotype through recruitment of inflammatory cells (e.g., eosinophils) to the airway [20]; T-helper type 1 (T H 1) cytokines (IL-12, IFN-γ), which are considered protective [21]; and IL-10 associated with regulatory T-cells (T Regs ) [22]; (2) T Regs in peripheral blood, which suppress T H 2-type responses and have been found to be higher in healthy subjects [23]; (3) concentrations of the anti-inflammatory glucocorticoid, cortisol, in peripheral blood; and (4) cell differentials in peripheral blood and lavage fluid.…”

“…Although our previous study showed that behavioral inhibition was associated with AHR [18], retrospective analyses run the risk of generating spurious results because of chance associations in the data; consequently, it is important to confirm these results using prospective methodology. Furthermore, our previous study did not assess potential mechanisms of how BI might relate to AHR; while BI was not related to an immediate hypersensitivity response [18], it might still be associated with the immune responses characteristic of asthma.…”