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Dichotomous Role of Plasmin in Regulation of Macrophage Function after Acetaminophen Overdose.
- Source :
-
The American journal of pathology [Am J Pathol] 2019 Oct; Vol. 189 (10), pp. 1986-2001. Date of Electronic Publication: 2019 Aug 02. - Publication Year :
- 2019
-
Abstract
- Kupffer cells and monocyte-derived macrophages are critical for liver repair after acetaminophen (APAP) overdose. These cells produce promitogenic cytokines and growth factors, and they phagocytose dead cell debris, a process that is critical for resolution of inflammation. The factors that regulate these dynamic functions of macrophages after APAP overdose, however, are not fully understood. We tested the hypothesis that the fibrinolytic enzyme, plasmin, is a key regulator of macrophage function after APAP-induced liver injury. In these studies, inhibition of plasmin in mice with tranexamic acid delayed up-regulation of proinflammatory cytokines after APAP overdose. In culture, plasmin directly, and in synergy with high-mobility group B1, stimulated Kupffer cells and bone marrow-derived macrophages to produce cytokines by a mechanism that required NF-κB. Inhibition of plasmin in vivo also prevented trafficking of monocyte-derived macrophages into necrotic lesions after APAP overdose. This prevented phagocytic removal of dead cells, prevented maturation of monocyte-derived macrophages into F4/80-expressing macrophages, and prevented termination of proinflammatory cytokine production. Our studies reveal further that phagocytosis is an important stimulus for cessation of proinflammatory cytokine production as treatment of proinflammatory, monocyte-derived macrophages, isolated from APAP-treated mice, with necrotic hepatocytes decreased expression of proinflammatory cytokines. Collectively, these studies demonstrate that plasmin is an important regulator of macrophage function after APAP overdose.<br /> (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Chemical and Drug Induced Liver Injury etiology
Chemical and Drug Induced Liver Injury metabolism
Drug Overdose
Inflammation Mediators metabolism
Kupffer Cells drug effects
Kupffer Cells metabolism
Macrophages drug effects
Macrophages metabolism
Male
Mice
Mice, Inbred C57BL
Necrosis
Acetaminophen toxicity
Analgesics, Non-Narcotic toxicity
Chemical and Drug Induced Liver Injury pathology
Fibrinolysin metabolism
Kupffer Cells pathology
Macrophages pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1525-2191
- Volume :
- 189
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The American journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 31381887
- Full Text :
- https://doi.org/10.1016/j.ajpath.2019.07.003