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]

Spacing and crowding among African and Caucasian children.

Contains fulltext : 71005.pdf (publisher's version ) (Closed access)OBJECTIVE: To determine spacing and crowding according to ethnic group, gender and dental emergence stage among Tanzanian African and Caucasian children. DESIGN: Cross-sectional epidemiological clinical study. SETTING: A total of 869 African (428 boys, 441 girls) and 706 Caucasian (319 boys, 387 girls) school children, aged 3(1/2)-16 years. MAIN OUTCOME MEASURES: Comparison of spacing and crowding between African and Caucasian children according to gender and dental emergence stage. RESULTS: Spacing was more often found in the maxilla, while crowding was more common in the mandible. Only during the transition of the maxillary permanent front teeth was there significantly more spacing in Caucasians. No gender differences were found. In both samples spacing decreased during later emergence stages. Crowding was more often found in Caucasian children than in African children. In Caucasian children the frequency of crowding increased with advanced emergence stages, while for Africans the trend was not consistent. CONCLUSION: When planning resources for orthodontic treatment for different populations as well as planning treatment for individuals, ethnic background and emergence stage of the dentition need to be considered