Inhaled corticosteroids as treatment for adolescent asthma: effects on adult anxiety-related outcomes in a murine model

Abstract

Rationale: Allergic asthma, typically controlled with inhaled corticosteroids (ICS), is the leading chronic health condition for youth under 18 years of age. During this peri-adolescent period, significant brain maturation occurs. Prior studies indicate that both chronic inflammation and corticosteroid medications increase risk for developing an internalizing disorder like anxiety.

Objectives: To determine if chronic ICS treatments exacerbate or alleviate anxiety symptoms associated with developmental allergic asthma, we used a mouse model to isolate the influence of ICS (fluticasone propionate, FLU) vs. airway inflammation (induced with house dust mite extract, HDM).

Methods: During development, male and female BALB/cJ mice were repeatedly exposed to HDM or saline plus one of four FLU doses (none/vehicle, low, moderate, or high). In adulthood, we assessed lung inflammation, circulating and excreted corticosteroids, anxiety-like behavior, and gene expression in stress and emotion regulation brain regions.

Results: FLU treatment decreased body weight and anxiety-like behavior and increased fecal corticosterone metabolite concentrations and Crhr2 gene expression in ventral hippocampus. FLU effects were only observed in saline/non-HDM-exposed mice, and the FLU doses used did not significantly decrease HDM-induced airway inflammation. Females had greater serum and fecal corticosterone concentrations, less anxiety-like behavior, and lower Crhr1 gene expression in ventral hippocampus and prefrontal cortex than males.

Conclusions: These findings suggest that steroid medications for youth with allergic asthma may not exacerbate anxiety-related symptoms, and that they should be avoided in children/adolescents without a health condition. The results are informative to future work on the use of corticosteroid medications during childhood or adolescent development.

Keywords: Adolescence; Anxiety; Asthma; Comorbidity; Development; HPA axis; Inhaled corticosteroids.

Figure 1. Timeline for experimental study.

Time of house dust mite extract (HDM)/saline and fluticasone (FLU)/vehicle exposure and all other samples/tests. HDM/saline exposure and FLU/vehicle exposure occurred three times/week on the same days. Abbreviations: P=postnatal day, USVs=ultrasonic vocalizations recorded, CORT=corticosteroids, EPM=elevated plus maze, VHIP=ventral hippocampus, PFC=prefrontal cortex.

Figure 2. Lung inflammation.

(a, b) HDM-exposed females had more and larger lung inflammation patches than HDM-exposed males. (c) Females had greater lung IL-5 gene expression than males. Main effects of sex F>M: ⁺⁺p<0.01, ⁺⁺⁺p<0.001.

Figure 3. Body weight gain.

(a) Cumulative increase in body weight relative to P24 during FLU treatments for males and females in each condition. (b) In saline control females, mice treated with the moderate FLU dose (0.5μg/μL) grew less than those exposed to vehicle or low FLU dose (0, and 0.25μg/μL). During adolescence, females grew less than males. (c) During the two weeks after HDM and FLU exposure ended, there were no group differences in body weight gain. Main effects of sex F<M: ⁺⁺⁺p<0.001; FLU dose significantly different from vehicle and low dose: ^‡p<0.05. Significant effects in repeated measures analyses are not shown on the figure but are provided in text.

Figure 4. Fecal and serum corticosteroids.

(a) In saline control females, all FLU doses (0.25, 0.5, and 1.0μg/μL) led to increased CORT excretion in feces compared to vehicle (0μg/μL). In HDM-exposed females, only mice treated with a moderate FLU dose (0.5μg/μL) produced more CORT than vehicle and low FLU dose groups (0μg/μL, 0.25μg/μL). Females excreted more corticosteroid (CORT) metabolites than males. (b) Females had higher circulating CORT concentrations than males. Main effects of sex F>M: ⁺⁺⁺p<0.001; FLU dose significantly different from vehicle: ^‡p<0.05, ^‡‡p<0.01.

Figure 5. Elevated plus maze behavior.

(a) In saline control mice, those treated with the highest FLU dose (1.0μg/μL) entered open arms of the EPM more than all other groups (0, 0.25, and 0.5μg/μL). (b) No group differences were observed in percent open arm time. (c) HDM-exposed males entered closed arms of EPM more than females. Main effects of sex: F>M ^#p<0.10, F<M ⁺p<0.05; FLU doses significantly different from high dose: ^#p<0.10, ^‡p<0.05, ^‡‡p<0.01.

Figure 6. Gene expression in ventral hippocampus.

(a) No significant group differences were observed in CRH gene expression. (b, c, d) In saline control mice, males had greater ventral hippocampus Crhr1, Crhr2, and GR gene expression than females. (c) In saline control males, mice treated with moderate FLU dose (0.5μg/μL) had greater Crhr2 expression than vehicle and low dose males (0 and 0.25 μg/μL). Main effect of sex F<M: ^#p<0.10, ⁺⁺p<0.01; FLU dose significantly different from vehicle and low dose: ^‡‡p<0.01.