Functional disturbance of the stress-adaptation system in patients with scleroderma.

There have been several reports indicating the association between recent stress experiences and the onset or the exacerbation of rheumatic diseases, although few such reports exist in patients with scleroderma (SSc). The present study was performed to elucidate whether there were any functional disturbances in the neuro-endocrine-immune system as a homeostatic system upon stress in SSc patients. Various serum levels of stress-related hormones and cytokines were examined before and after a mental calculation stress test, and a basal questionnaire study of sense of coherence (SOC, which is related to the ability to cope with stress), recent stress experiences, and quality of life (QOL) was performed in 17 SSc patients and in 38 healthy volunteers. Physical QOL state was impaired in patients, but there were no differences in recent stress experiences and SOC scores between patients and controls. Basal serum cortisol levels were similar in patients and controls, but increased levels of proinflammatory cytokine and noradrenalin were seen in SSc patients. Characteristically, contrary to the control group, whose cortisol levels increased significantly following the mental calculation stress test, no significant increase was observed in the patients when post-test cortisol levels were compared to pre-test levels, suggesting a defect in the normal cortisol response upon stress in SSc patients. The present results suggest that there may be impaired function of the neuro-endocrine-immune system upon stress in SSc patients.

Imbalance in the stress-adaptation system in patients with inflammatory bowel disease.

AIM: Though inflammatory bowel disease (IBD) is known as a stress-related disorder, basic evidence for this claim is lacking. The current study was performed to investigate the function of the neuroendocrine-immune system as a main pathway in stress response and stress-coping ability and the associations among stress response, stress-coping ability, and disease activity in IBD patients. METHOD: A questionnaire was administered to obtain information concerning stress state and stress-coping ability (self-efficacy and sense of coherence [SOC]) in 78 IBD patients and 21 healthy volunteers. Blood samples were taken for determining the serum levels of various stress-related hormones and cytokines before and after a calculation stress test. RESULTS: Self-efficacy was significantly decreased in patients, though the degree of perceived stress and SOC did not differ between patients and controls. Basal levels of cortisol did not differ, but levels of adrenocorticotropic hormone, ß-endorphin and interleukin (IL)-6 were significantly higher in patients than in controls. In addition, the control group, but not the patient group, demonstrated significant differences in the basal cortisol levels between low and high SOC subgroups and between low and high perceived stress subgroups. Furthermore, IL-6 levels were significantly increased following the calculation stress test in patients only. CONCLUSION: Results indicate that IBD patients may have skewed neuroendocrine-immune systems and that emotional stress may aggravate the disease. Stress-management interventions might be useful, not only for patients' quality of life (QOL) but also for disease control.

Antifibrotic effects of hepatocyte growth factor on scleroderma fibroblasts and analysis of its mechanism.

We investigated the effect of hepatocyte growth factor (HGF) on collagen metabolism in cultured fibroblasts from scleroderma (SSc) patients and discussed the possible mechanism of its effect. Synthesis of matrix metalloproteinase-1 (MMP-1) and collagen and mRNA levels of various cytokines were examined by enzyme-linked immunosorbent assay and real-time polymerase chain reaction, respectively. Hepatocyte growth factor enhanced MMP-1 production and mRNA levels of MMP-1 and Ets-1 (a transcriptional factor of MMPs). In addition, HGF suppressed collagen synthesis and mRNA levels of procollagenalpha1(I) and connective tissue growth factor (CTGF) in SSc fibroblasts. Expression of transforming growth factor (TGF)-beta1 was not inhibited significantly in SSc or control fibroblasts. Hepatocyte growth factor also increased interferon (IFN)-gamma mRNA significantly in SSc and control fibroblasts. Addition of anti-HGF antibody neutralized these effects of HGF on MMP-1 and collagen synthesis. The results suggest that HGF can suppress collagen accumulation in SSc fibroblasts by increasing MMP-1 levels possibly via activation of Ets-1 and also by decreasing collagen synthesis, which may be partly related to inhibition of CTGF, and increasing IFN-gamma levels rather than the effect on TGF-beta1. The present study indicates that HGF may be a promising therapeutic agent for this intractable disease.