Methyldopa-lnduced Granulomatous Hepatitis

Miller, Alex C.

doi:10.1001/jama.1976.03260440053026

Cited by 23 publications

(1 citation statement)

References 7 publications

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“…Conversely, non-aggregated, resting state Kupffer cells are primarily surrounded by hepatocytes or endothelial cells, and are localized to the sinusoidal regions of the organ. Interestingly, there are over sixty currently marketed drugs that are associated with drug-induced granulomatous inflammation, such as methyldopa (55) and phenylbutazone (56). The classes of drugs that are associated with this phenomenon are broad, ranging from antibiotics to non-steroidal anti-inflammatory agents, pointing to a variety of mechanisms that may result in the induction of inflammation.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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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 subcompartment-to limit tissue damage.

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Section: Discussionmentioning

confidence: 99%