Job strain results from a combination of high workload and few decision-making opportunities in the workplace. There is inconsistent evidence regarding the association between job strain and hypertension, and methodological shortcomings preclude firm conclusions. Thus, a meta-analysis of observational studies on hypertension among occupational groups was conducted to determine whether job strain was associated with hypertension. In January 2012, we carried out a comprehensive, topic-specific electronic literature search of the Ovid MEDLINE, EMBASE and PsychoINFO databases complemented by individual help from non-communicable disease experts. Experimental/interventional studies and studies on personality disorders were excluded. Nine of 894 identified studies met the eligibility criteria and were included in the meta-analysis. The pooled OR of the nine studies was 1.29 (95% CI 1.14 to 1.47; p<0.001), of case–control studies 2.88 (95% CI 1.63 to 5.09; p<0.001) and of cohort studies 1.24 (95% CI1.09 to 1.41; p<0.001), all of which indicated statistically significant positive associations between job strain and hypertension [corrected]. In a subgroup analysis, cohort studies of good methodological quality showed significant associations between job strain and hypertension, while those of poor methodological quality showed no association or subgroup differences. We conclude that despite methodological differences, case-control and cohort studies of good methodological quality showed positive associations between hypertension and job strain.

Background

Psychological stress and heightened mast cell (MC) activation are linked with important immunologic disorders, including allergy, anaphylaxis, asthma, and functional bowel diseases, but the mechanisms remain poorly defined. We have previously demonstrated that activation of the corticotropin-releasing factor (CRF) system potentiates MC degranulation responses during IgE-mediated anaphylaxis and psychological stress through corticotropin-releasing factor receptor subtype 1 (CRF₁) expressed on MCs.

Objective

In this study we investigated the role of corticotropin-releasing factor receptor subtype 2 (CRF₂) as a modulator of stress-induced MC degranulation and associated disease pathophysiology.

Methods

In vitro MC degranulation assays were performed with bone marrow-derived mast cells (BMMCs) derived from wild-type (WT) and CRF₂-deficient (CRF₂^-/-) mice and RBL-2H3 MCs transfected with CRF₂-overexpressing plasmid or CRF₂ small interfering RNA. In vivo MC responses and associated pathophysiology in IgE-mediated passive systemic anaphylaxis and acute psychological restraint stress were measured in WT, CRF₂^-/-, and MC-deficient Kit^W-sh/W-sh knock-in mice.

Results

Compared with WT mice, CRF₂^-/- mice exhibited greater serum histamine levels and exacerbated IgE-mediated anaphylaxis and colonic permeability. In addition, CRF₂^-/- mice exhibited increased serum histamine levels and colonic permeability after acute restraint stress. Experiments with BMMCs and RBL-2H3 MCs demonstrated that CRF₂ expressed on MCs suppresses store-operated Ca²⁺ entry signaling and MC degranulation induced by diverse MC stimuli. Experiments with MC-deficient Kit^W-sh/W-sh mice systemically engrafted with WT and CRF₂^-/- BMMCs demonstrated the functional importance of MC CRF₂ in modulating stress-induced pathophysiology.

Conclusions

MC CRF₂ is a negative global modulator of stimuli-induced MC degranulation and limits the severity of IgE-mediated anaphylaxis and stress-related disease pathogenesis.