An Expandable Mechanopharmaceutical Device (2): Drug Induced Granulomas Maximize the Cargo Sequestering Capacity of Macrophages in the Liver
| Autor: | Rahul K. Keswani, Gi Sang Yoon, Mikhail D. Murashov, Ingrid L. Bergin, Phillip Rzeczycki, Gus R. Rosania, Kathleen A. Stringer, Jason Baik, Sudha Sud |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Cell Population Pharmaceutical Science 02 engineering and technology 030226 pharmacology & pharmacy Clofazimine Article 03 medical and health sciences Mice 0302 clinical medicine Immune system Drug Delivery Systems medicine Organoid Cytotoxic T cell Animals Pharmacology (medical) education Pharmacology education.field_of_study Granuloma Chemistry Macrophages Organic Chemistry 021001 nanoscience & nanotechnology medicine.disease medicine.anatomical_structure Liver Toxicity Cancer research Molecular Medicine TFEB Chemical and Drug Induced Liver Injury 0210 nano-technology Biotechnology |
| Zdroj: | Pharmaceutical research. 36(1) |
| ISSN: | 1573-904X |
| Popis: | PURPOSE: Drug-induced liver injuries (DILI) comprise a significant proportion of adverse drug reactions leading to hospitalizations and death. One frequent DILI is granulomatous inflammation from exposure to harmful metabolites that activate inflammatory pathways of immune cells of the liver, which may act as a barrier to isolate the irritating stimulus and limit tissue damage. METHODS: Paralleling the accumulation of CFZ precipitates in the liver, granulomatous inflammation was studied to gain insight into its effect on liver structure and function. A structural analog that does not precipitate within macrophages was also studied using micro-analytical approaches. Depleting macrophages was used to inhibit granuloma formation and assess its effect on drug bioaccumulation and toxicity. RESULTS: Granuloma-associated macrophages showed a distinct phenotype, differentiating them from non-granuloma macrophages. Granulomas were induced by insoluble CFZ cargo, but not by the more soluble analog, pointing to precipitation being a factor driving granulomatous inflammation. Granuloma-associated macrophages showed increased activation of lysosomal master-regulator transcription factor EB (TFEB). Inhibiting granuloma formation increased hepatic necrosis and systemic toxicity in CFZ-treated animals. CONCLUSIONS: Granuloma-associated macrophages are a specialized cell population equipped to actively sequester and stabilize cytotoxic chemotherapeutic agents. Thus, drug-induced granulomas may function as drug sequestering “organoids” –an induced, specialized sub-compartment– to limit tissue damage. |
| Databáze: | OpenAIRE |
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