Phillip Rzeczycki1, Gi Sang Yoon1, Rahul K Keswani1, Sudha Sud1, Jason Baik1, Mikhail D Murashov1, Ingrid L Bergin2, Kathleen A Stringer3, Gus R Rosania4,5. 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan, 48109, USA. 2. Unit for Laboratory Animal Medicine, Medical School Office of Research, University of Michigan, 2800 Plymouth Road, Ann Arbor, Michigan, 48109, USA. 3. Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan, 48104, USA. 4. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan, 48109, USA. grosania@umich.edu. 5. University of Michigan College of Pharmacy, Ann Arbor, Michigan, 48109, USA. grosania@umich.edu.
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.
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.
Authors: Mikhail D Murashov; Vernon LaLone; Phillip M Rzeczycki; Rahul K Keswani; Gi S Yoon; Sudha Sud; Walajapet Rajeswaran; Scott Larsen; Kathleen A Stringer; Gus R Rosania Journal: J Invest Dermatol Date: 2017-10-16 Impact factor: 8.551
Authors: Swan Lin; Jennifer Racz; Melissa F Tai; Kristina M Brooks; Phillip Rzeczycki; Lauren J Heath; Michael W Newstead; Theodore J Standiford; Gus R Rosania; Kathleen A Stringer Journal: Pharm Res Date: 2015-08-01 Impact factor: 4.200
Authors: Steven Dunne; Andrew R Willmer; Rosemary Swanson; Deepak Almeida; Nicole C Ammerman; Kathleen A Stringer; Edmund V Capparelli; Gus R Rosania Journal: Pharmaceutics Date: 2021-12-22 Impact factor: 6.321