RESUMEN
BACKGROUND: Several small molecule corrector and potentiator drugs have recently been licensed for Cystic Fibrosis (CF) therapy. However, other aspects of the disease, especially inflammation, are less effectively treated by these drugs. We hypothesized that small molecule drugs could function either alone or as an adjuvant to licensed therapies to treat these aspects of the disease, perhaps emulating the effects of gene therapy in CF cells. The cardiac glycoside digitoxin, which has been shown to inhibit TNFα/NFκB signaling in CF lung epithelial cells, may serve as such a therapy. METHODS: IB3-1 CF lung epithelial cells were treated with different Vertex (VX) drugs, digitoxin, and various drug mixtures, and ELISA assays were used to assess suppression of baseline and TNFα-activated secretion of cytokines and chemokines. Transcriptional responses to these drugs were assessed by RNA-seq and compared with gene expression in AAV-[wildtype]CFTR-treated IB3-1 (S9) cells. We also compared in vitro gene expression signatures with in vivo data from biopsied nasal epithelial cells from digitoxin-treated CF patients. RESULTS: CF cells exposed to digitoxin exhibited significant suppression of both TNFα/NFκB signaling and downstream secretion of IL-8, IL-6 and GM-CSF, with or without co-treatment with VX drugs. No evidence of drug-drug interference was observed. RNA-seq analysis showed that gene therapy-treated CF lung cells induced changes in 3134 genes. Among these, 32.6% were altered by digitoxin treatment in the same direction. Shared functional gene ontology themes for genes suppressed by both digitoxin and gene therapy included inflammation (84 gene signature), and cell-cell interactions and fibrosis (49 gene signature), while genes elevated by both were enriched for epithelial differentiation (82 gene signature). A new analysis of mRNA data from digitoxin-treated CF patients showed consistent trends in expression for genes in these signatures. CONCLUSIONS: Adjuvant gene therapy-emulating activities of digitoxin may contribute to enhancing the efficacy of currently licensed correctors and potentiators in CF patients.
Asunto(s)
Fibrosis Quística/metabolismo , Digitoxina/farmacología , Terapia Genética/métodos , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/metabolismo , Mucosa Respiratoria/metabolismo , Animales , Cardiotónicos/farmacología , Células Cultivadas , Fibrosis Quística/patología , Fibrosis Quística/terapia , Relación Dosis-Respuesta a Droga , Humanos , Ratas , Ratas Endogámicas F344 , Mucosa Respiratoria/efectos de los fármacos , Resultado del TratamientoRESUMEN
BACKGROUND: Non-communicable diseases (NCDs) and psychological hazards are increasingly observed in industries, necessitating the need to strengthen industrial health systems to control the same. District level data on level of functioning of industrial health systems and services with special focus on systems available for mental health care is lacking in India. This information is vital to plan need-based interventions for system strengthening. OBJECTIVE: To assess the status of functioning of industrial health systems and services in Kolar district, India, with special focus on systems and services available for mental health care. METHODS: This cross-sectional study was undertaken between October and December 2014 on a stratified random sample of 69 industries located in Kolar, which were stratified proportionately by their hazardous nature. Interview and observation checklist were used to assess and classify functioning of industrial health systems and services including those available for mental health care. RESULTS: Occupational safety and health (OSH) policy was present in 56% and health insurance in 39% of the 69 industries assessed. Pre-placement and periodical medical examination were conducted in 23% of industries. Health systems and services in hazardous industries were functioning at less than 50% level of functioning. Health systems and services for mental health care were non-existent. CONCLUSION: There is a need in Kolar district, India, to integrate the mental health components within existing industrial health systems, as per policy directives to implement setting based approaches in mental health programs.