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Regulation and Function of Macrophages During Acute Liver Injury and Acute Liver Failure
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Regulation and Function of Macrophages During Acute Liver Injury and Acute Liver Failure. |
| 개인저자 | Roth, Katherine Jane. |
| 단체저자명 | Michigan State University. Cell and Molecular Biology - Environmental Toxicology - Doctor of Philosophy. |
| 발행사항 | [S.l.]: Michigan State University., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 161 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-03B. Dissertation Abstract International |
| ISBN | 9781085742894 |
| 학위논문주기 | Thesis (Ph.D.)--Michigan State University, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-03, Section: B.
Advisor: Copple, Bryan L. |
| 이용제한사항 | This item must not be sold to any third party vendors.This item must not be sold to any third party vendors. |
| 요약 | Acetaminophen (APAP) is one of the most commonly used over-the-counter analgesic and antipyretic agents. When taken at high doses, APAP produces liver injury that can rapidly progress to acute liver failure (ALF). Pharmacological therapies for APAP overdose are limited to N-acetyl-cysteine (NAC), which is only highly efficacious when administered early after APAP overdose. Unfortunately, many patients do not seek medical attention until liver injury is extensive and NAC is no longer effective. Therefore, a more detailed understanding of the mechanisms controlling liver repair after injury could provide insight into better therapies and new ways to stimulate repair in ALF patientsHepatic macrophages, including Kupffer cells and monocyte-derived macrophages, are critical for liver repair following APAP overdose. These macrophages produce pro-mitogenic cytokines and growth factors and phagocytose dead cell debris, a process that is critical for resolution of inflammation. However, the factors that regulate these dynamic functions of macrophages after APAP overdose are not fully understood. The fibrinolytic enzyme, plasmin, is known to regulate various macrophage functions. Therefore, we hypothesized that plasmin is critical for macrophage functions after APAP overdose. To test this hypothesis, we inhibited plasmin with tranexamic acid in a mouse model of APAP overdose, which delayed upregulation of proinflammatory cytokines after APAP overdose. In culture, plasmin directly, and in synergy with high-mobility group B1 (HMGB1), stimulated macrophages to produce cytokines by a mechanism that required NF-觀B. Furthermore, inhibition of plasmin in vivo 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. These data demonstrate that plasmin is an important regulator of macrophage function after APAP overdose.Clinical studies demonstrate that ALF patients with the worst prognosis have the highest systemic levels of both pro- and anti-inflammatory cytokines. Although the cause remains unknown, it has been proposed that cytokine dysregulation in ALF results from impaired macrophage function. We hypothesized that macrophage function would be dysregulated in a mouse model of ALF and that the dysregulation would impact liver repair. To test this hypothesis, we treated mice with either 300 mg/kg APAP, a dose that produces moderate, fully repaired liver, or with 600 mg/kg acetaminophen, a dose that recapitulates many of the features of ALF in patients. In mice treated with 600 mg/kg APAP, proinflammatory monocyte-derived macrophages accumulated in the liver but failed to traffic into the necrotic lesions and failed to remove dead cell debris. Further, the proinflammatory macrophages did not switch phenotype to pro-repair macrophages, leading to the sustained production of several proinflammatory cytokines. Similar to ALF patients, systemic IL-10 concentrations were also higher in mice treated with 600 mg/kg APAP. Administration of an IL-10 neutralizing antibody fully restored macrophage trafficking into the necrotic lesions. Neutralization of IL-10 did not, however, stimulate macrophage-dependent clearance of dead cells from the liver or promote survival.Collectively, these studies demonstrate that plasmin is an important regulator of macrophage function after APAP overdose. Furthermore, macrophages become dysregulated in ALF, leading to impaired intrahepatic macrophage trafficking, impaired phagocytic clearance of dead cells, and failed macrophage phenotype switching, resulting in the sustained production of proinflammatory cytokines. Overall, these studies demonstrate the mechanisms and functions of macrophages during acute liver injury, as well as how these functions are dysregulated in ALF. |
| 일반주제명 | Molecular biology. Immunology. Toxicology. |
| 언어 | 영어 |
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