Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis

Background: The beneficial outcome associated with the use of proton pump inhibitors (PPIs) in idiopathic pulmonary fibrosis (IPF) has been reported in retrospective studies. To date, no prospective study has been conducted to confirm these outcomes. In addition, the potential mechanism by which PPIs improve measures of lung function and/or transplant-free survival in IPF has not been elucidated. Methods: Here, we used biochemical, cell biological and preclinical studies to evaluate regulation of markers associated with inflammation and fibrosis. In our in vitro studies, we exposed primary lung fibroblasts, epithelial and endothelial cells to ionizing radiation or bleomycin; stimuli typically used to induce inflammation and fibrosis. In addition, we cultured lung fibroblasts from IPF patients and studied the effect of esomeprazole on collagen release. Our preclinical study tested efficacy of esomeprazole in a rat model of bleomycin-induced lung injury. Furthermore, we performed retrospective analysis of interstitial lung disease (ILD) databases to examine the effect of PPIs on transplant-free survival. Results: The cell culture studies revealed that esomeprazole controls inflammation by suppressing the expression of pro-inflammatory molecules including vascular cell adhesion molecule-1, inducible nitric oxide synthase, tumor necrosis factor-alpha (TNF-alpha) and interleukins (IL-1 beta and IL-6). The antioxidant effect is associated with strong induction of the stress-inducible cytoprotective protein heme oxygenase-1 (HO1) and the antifibrotic effect is associated with potent inhibition of fibroblast proliferation as well as downregulation of profibrotic proteins including receptors for transforming growth factor beta (TGF beta), fibronectin and matrix metalloproteinases (MMPs). Furthermore, esomeprazole showed robust effect in mitigating the inflammatory and fibrotic responses in a murine model of acute lung injury. Finally, retrospective analysis of two ILD databases was performed to assess the effect of PPIs on transplant-free survival in IPF patients. Intriguingly, this data demonstrated that IPF patients on PPIs had prolonged survival over controls (median survival of 3.4 vs 2 years). Conclusions: Overall, these data indicate the possibility that PPIs may have protective function in IPF by directly modulating the disease process and suggest that they may have other clinical utility in the treatment of extra-intestinal diseases characterized by inflammatory and/or fibrotic phases.Stanford School of Medicine [1049528-149- KAVFB]; Tobacco-Related Disease Research Program of the University of California [20FT-0090]; National Institutes of Health National Heart, Lung, and Blood Institute [5K01HL118683, P01HL114470]; Houston Methodist Research Institute [25150001]; Stanford SPARK Translational Research ProgramSCI(E)[email protected]

Determinants of denervation-independent depletion of putamen dopamine in Parkinson's disease and multiple system atrophy

Severe putamen dopamine depletion characterizes Parkinson's disease (PD) and multiple system atrophy (MSA). The extent of the depletion is greater than can be accounted for by loss of nigrostriatal dopaminergic terminals alone. We used putamen tissue levels and ratios of cysteinyl and parent catechols to explore possible denervation-independent abnormalities of dopamine synthesis and fate in PD and MSA. 5-S-Cysteinyldopa (Cys-DOPA) is produced from spontaneous oxidation of DOPA and 5-S-cysteinyldopamine (Cys-DA) from spontaneous oxidation of DA. Post-mortem putamen tissue samples from 17 PD and 25 MSA patients and 30 controls were assayed for endogenous catechols including DA, its cytoplasmic metabolites (Cys-DA, 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxyphenylethanol, and 3,4-dihydroxyphenylacetaldehyde), and tyrosine hydroxylation products proximal to DA (DOPA and Cys-DOPA). The PD and MSA groups did not differ in mean values of parent or cysteinyl catechols, and the data for the two groups were lumped. In the patients an index of vesicular storage of DA (the ratio of DA to the sum of its cytoplasmic metabolites) averaged 54% of control (p = 0.001), and an index of L-aromatic-amino-acid decarboxylase (LAAAD) activity (the ratio of DA and the sum of its cytoplasmic metabolites to the sum of DOPA + Cys-DOPA) averaged 21% of control (p < 0.0001). An index of innervation (the sum of DOPA + Cys-DOPA) averaged 63% of control (p = 0.01). Based on patterns of parent and cysteinyl catechols in putamen, PD and MSA involve decreased vesicular uptake and decreased LAAAD activity in the residual dopaminergic terminals. The combination seems to contribute importantly to dopamine depletion in these diseases. [Display omitted] •Putamen dopamine depletion typifies Parkinson's disease and multiple system atrophy.•The depletion is greater than explained by nigrostriatal denervation alone.•We measured putamen cysteinyl and parent catechols in both diseases.•Evidence was obtained for decreased dopamine synthesis and vesicular uptake.•The results indicate denervation-independent abnormalities of dopamine metabolism

Depression and health-related quality of life in ethnic minorities seeking care in general medical settings

Background: To examine ethnic groups differences in (a) prevalence of depressive disorders and (b) health related quality of life in fee-for-service and managed care patients (n=21 504) seeking care in general medical settings. Methods: Data are from the Medical Outcomes Study, a multi-site observational study of outpatient practices. The study screened patients of clinicians (family practice, internal medicine, cardiology, diabetology and endocrinology) for four chronic medical conditions; depression, coronary heart disease, hypertension and diabetes. A brief eight-item depression screener followed by the Diagnostic Interview Schedule-Depression Section (DIS) for screener positives identified depressed patients (n=2195). The Short Form Health Survey (SF-36) assessed health-related quality of life. Patient self-report determined ethnicity. Results: Before adjusting for demographic factors, African-Americans and Hispanics had highest rates of depressive symptoms. Asian-Americans had the lowest. adjusting for demographics (particularly gender and income), we found few statistically significant differences in prevalence or severity of depression. However, among the depressed, Whites were the most, and African-Americans the least likely to report suicidal ideation (p<0.01), and Hispanics and Whites were more likely to have melancholia (p<0.01). African-Americans reported the poorest quality of life. Limitations: DSM III criteria (though few changes in DSM IV), and relatively small sample size of Asian-Americans compared to other groups. Conclusions: Gender and socioeconomic status are more significant factors than ethnicity in determining risk for depressive disorder. However, ethnic differences in symptom presentation, and health-related quality of life could have clinical and social consequences, and merit further study.https://www.sciencedirect.com/science/article/pii/S016503279900069

Depression and health-related quality of life in ethnic minorities seeking care in general medical settings

Background: To examine ethnic groups differences in (a) prevalence of depressive disorders and (b) health related quality of life in fee-for-service and managed care patients (n=21 504) seeking care in general medical settings. Methods: Data are from the Medical Outcomes Study, a multi-site observational study of outpatient practices. The study screened patients of clinicians (family practice, internal medicine, cardiology, diabetology and endocrinology) for four chronic medical conditions; depression, coronary heart disease, hypertension and diabetes. A brief eight-item depression screener followed by the Diagnostic Interview Schedule-Depression Section (DIS) for screener positives identified depressed patients (n=2195). The Short Form Health Survey (SF-36) assessed health-related quality of life. Patient self-report determined ethnicity. Results: Before adjusting for demographic factors, African-Americans and Hispanics had highest rates of depressive symptoms. Asian-Americans had the lowest. adjusting for demographics (particularly gender and income), we found few statistically significant differences in prevalence or severity of depression. However, among the depressed, Whites were the most, and African-Americans the least likely to report suicidal ideation (p<0.01), and Hispanics and Whites were more likely to have melancholia (p<0.01). African-Americans reported the poorest quality of life. Limitations: DSM III criteria (though few changes in DSM IV), and relatively small sample size of Asian-Americans compared to other groups. Conclusions: Gender and socioeconomic status are more significant factors than ethnicity in determining risk for depressive disorder. However, ethnic differences in symptom presentation, and health-related quality of life could have clinical and social consequences, and merit further study