Acute Psychosocial Stress Increases Circulating Inflammatory Mediators in the Humanized Sickle Cell Mouse Model

Vaso-occlusive crisis often occurs in sickle cell disease (SCD). Since psychosocial stress leads to impaired vascular function and inflammation, we hypothesized that acute psychosocial stress elicits an exaggerated blood pressure response and/or increased circulating inflammatory mediators in a mouse model of SCD. We utilized adult male (16-20 wks) humanized Townes sickle cell (HbSS) and control (HbAA) mice with telemetry (n=8) to monitor changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), spectral analysis (low frequency/high frequency, LF/HF ratio) of blood pressure variability, heart rate (HR), and locomotor activity (LA) in response to cage switch stress (CSS). CSS-induced increases in DBP were significantly attenuated in HbSS versus HbAA (HbSS: 23.3±1.8mmHg, HbAA: 31.6±1.7mmHg, p=0.004), while the increase in SBP was similar in HbSS and HbAA. CSS increased LF/HF in both strains, although HbSS was significantly less than HbAA (CSS HbAA : 3.21±0.2; CSS HbSS : 1.68±0.2, p<0.05). Increases in HR and LA were similar in HbSS and HbAA. Separate groups (n=6-7) were used to assess circulating inflammatory mediators (39-plex Luminex, ng/mL) at baseline (BL) and 30-min post-CSS. Interestingly, eotaxin (HbAA: 1.4±0.1, HbSS: 0.6±0.07, p<0.0001), plasminogen activator inhibitor-1 (PAI-1) (HbAA: 0.07±0.004, HbSS: 0.5±0.1, p=0.001), P-selectin (HbAA: 29±2.7, HbSS: 36±1.5, p=0.05), and soluble intercellular adhesion molecule-1 (sICAM-1) (HbAA: 2.4±0.05, HbSS: 2.9±0.2, p=0.04) were significantly higher in HbSS at BL. CSS significantly reduced eotaxin in HbAA mice (BL: 1.4±0.1, CSS: 1.1±0.08, p=0.02), whereas there was no change in HbSS mice. IL-6, CXCL1, sICAM-1, and PAI-1 were not changed in HbAA mice following CSS, but were significantly elevated following CSS in HbSS mice (IL-6: BL: 0.037±0.008, CSS: 0.065±0.005, p=0.01; CXCL1: BL: 0.11±0.02, CSS: 0.25±0.05, p=0.01; sICAM-1: BL: 2.9±0.2, CSS: 3.7±0.3, p=0.05; PAI-1: BL: 0.54±0.12, CSS: 1.17±0.24, p=0.007). The reduced response in DBP to CSS in HbSS mice is consistent with impaired vascular function. Further, exaggerated changes in select inflammatory mediators in response to CSS provide a potential link for psychosocial stress to vaso-occlusion and organ damage in SCD.