0
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      An Expandable Mechanopharmaceutical Device (2): Drug Induced Granulomas Maximize the Cargo Sequestering Capacity of Macrophages in the Liver

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          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.

          Related collections

          Author and article information

          Journal
          8406521
          6573
          Pharm Res
          Pharm. Res.
          Pharmaceutical research
          0724-8741
          1573-904X
          4 April 2019
          07 November 2018
          07 November 2018
          07 November 2019
          : 36
          : 1
          : 3
          Affiliations
          [1. ]Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI, 48104
          [2. ]Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI, 48104
          [3. ]Unit for Laboratory Animal Medicine, Medical School Office of Research, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI, 48109
          Author notes
          [* ]Corresponding author: Gus R. Rosania, PhD, Professor of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, MI 48109, Phone: 734-763-1032; Fax: 734-615-6162, grosania@ 123456umich.edu

          Author Contributions: P.R., G.S.Y, J.B., K.A.S. and G.R.R designed the research. P.R., G.S.Y., J.B., E.B., and M.E. conducted the experiments. G.R.R. and K.A.S. contributed new reagents and analytical tools. P.R., G.S.Y and I. B. analyzed the data. P.R., G.S.Y., I.B., K.A.S. and G.R.R. wrote or contributed to the writing of the manuscript.

          Article
          PMC6506721 PMC6506721 6506721 nihpa1021802
          10.1007/s11095-018-2541-z
          6506721
          30406478
          c5cec37f-76ac-4d1b-8fe1-f64d637ce9be
          History
          Categories
          Article

          macrophage,TFEB,Granuloma,biocrystal,clofazimine
          macrophage, TFEB, Granuloma, biocrystal, clofazimine

          Comments

          Comment on this article