Abstract
Gulf War Illness (GWI) is a chronic multisymptom disorder affecting veterans of the 1990–91 Gulf war. GWI was linked with exposure to chemicals including the nerve gas prophylactic drug pyridostigmine-bromide (PB) and pesticides (DEET, permethrin). Veterans with GWI exhibit prolonged, low-level systemic inflammation, though whether this impacts the liver is unknown. While no evidence exists that GWI-related chemicals are hepatotoxic, the prolonged inflammation may alter the liver’s response to insults such as cholestatic injury. We assessed the effects of GWI-related chemicals on macrophage infiltration and its subsequent influence on hepatic cholestasis. Sprague Dawley rats were treated daily with PB, DEET and permethrin followed by 15 minutes of restraint stress for 28 days. Ten weeks afterward, GWI rats or naïve age-matched controls underwent bile duct ligation (BDL) or sham surgeries. Exposure to GWI-related chemicals alone increased IL-6, and CD11b+F4/80− macrophages in the liver, with no effect on biliary mass or hepatic fibrosis. However, pre-exposure to GWI-related chemicals enhanced biliary hyperplasia and fibrogenesis caused by BDL, compared to naïve rats undergoing the same surgery. These data suggest that GWI patients could be predisposed to developing worse liver pathology due to sustained low-level inflammation of the liver when compared to patients without GWI.
Highlights
Gulf War Illness (GWI) is a medical condition affecting the veterans of the 1990–1991 Persian Gulf war, and includes a cluster of chronic symptoms such as headaches, joint pain, muscle pain, indigestion, fatigue, insomnia, dizziness, respiratory disorders, cognitive and memory problems[1]
When histological changes were assessed by Hematoxylin and eosin (H&E) staining of the livers, it was confirmed that rats exposed to GWI-related chemicals and stress exhibited a greater degree of biliary injury than the naïve rats after BDLinduced cholestasis (Fig. 1C)
When hepatic cholestasis was induced by bile duct ligation (BDL) surgery, the rats subjected to GWI-related exposure manifested worse damage of the liver than the naïve, unexposed animals
Summary
Gulf War Illness (GWI) is a medical condition affecting the veterans of the 1990–1991 Persian Gulf war, and includes a cluster of chronic symptoms such as headaches, joint pain, muscle pain, indigestion, fatigue, insomnia, dizziness, respiratory disorders, cognitive and memory problems[1]. Removal of the injurious agents results in the clearance of activated HSCs by the cytotoxic actions of natural killer cells and regression of fibrosis Those activated HSCs that escape removal by natural killer cells may revert to a quiescent-like phenotype and downregulate the expression of extracellular matrix proteins[20,21]. In this study we aimed to determine if the exposure to GWI-related chemicals and stress is conducive to changes in cholangiocyte proliferation, proinflammatory immune response, HSC activation and liver fibrosis in an animal model of cholestasis, i.e. bile duct ligation (BDL), when compared to GWI unexposed counterparts. We considered the “two-hit” hypothesis to explore the possibility that exposure to Gulf War chemicals and stress environment could sensitize the liver and prime it for a stronger than normal immune response and hepatic fibrosis in case of a chronic disease such as biliary cholestasis. Subtle but significant changes in the liver, such as lipid accumulation in the case of NAFLD due to high fat diet and sedentary lifestyle for example, act as a first insult of the liver with no evident symptoms of disease; in the event of a second liver insult such as an acute or chronic hepatic disease, the inflammation and fibrosis of the liver are enhanced in the sensitized liver due to molecular and cellular events from the first insult[22,23]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
