Gulf war illness-related chemicals increase CD11b/c+ monocyte infiltration into the liver and aggravate hepatic cholestasis in a rodent model

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.

Corticosterone and pyridostigmine/DEET exposure attenuate peripheral cytokine expression: Supporting a dominant role for neuroinflammation in a mouse model of Gulf War Illness

“…Many of the studies investigating the consequences of Gulf War Illness-relevant exposures in animal models combine PB and DEET with pesticide exposures, but have not evaluated the individual contribution of PB, DEET, or pesticide to their observed responses (Parihar et al, 2013; Zakirova et al, 2017; Shetty et al, 2017; Kodali et al, 2018; Petrescu et al, 2018; Seth et al, 2018). Thus, it is impossible to separate the responses to the individual agents as we have shown for the liver, serum, and brain (Figs.…”

Acetylcholinesterase inhibitor exposures as an initiating factor in the development of Gulf War Illness, a chronic neuroimmune disorder in deployed veterans

“…In addition, a significant number of exposure models have been developed that combine PB with other, non-AChEI, GW-relevant chemicals including: permethrin (PER) with or without stress ( Abdullah et al, 2011 ; Zakirova et al, 2015 ; Alhasson et al, 2017 ; Nizamutdinov et al, 2018 ; Seth et al, 2018 ; Joshi et al, 2019 ); PER and DEET with or without stress ( Abou-Donia et al, 1996 ; Abdel-Rahman et al, 2002 ; Abdullah et al, 2012 ; Parihar et al, 2013 ; Hattiangady et al, 2014 ; Megahed et al, 2015 ; Pierce et al, 2016 ; Shetty et al, 2017 ; Carerras et al, 2018 ; Petrescu et al, 2018 ; Madhu et al, 2019 ); PER and CPF with or without DEET ( Ojo et al, 2014 ; Nutter et al, 2015 ; Cooper et al, 2016 , 2018 ; Flunker et al, 2017 ). The prominence of these mixtures in GWI models, which largely revolve around combined exposures with PER and DEET, stem from a recommendation in the report from the Institute of Medicine (US) Committee to Review the Health Consequences of Service During the Persian Gulf War (1995 ) and an initial study of these chemicals in a hen model ( Abou-Donia et al, 1996 ).…”

Moesin, an Ezrin/Radixin/Moesin Family Member, Regulates Hepatic Fibrosis

“…Serum alanine aminotransferase (ALT) and total bilirubin levels were measured in wild‐type (WT) and moesin KO animals (control, CCI 4 ‐trated, sham, BDL) by using a Catalyst One Chemistry analyzer from IDEXX Laboratories (Westbrook, Maine). Intrahepatic bile duct mass was evaluated by semiquantitative immunohistochemistry to detect cytokeratin‐19 (CK‐19) as described . Hydroxyproline assay was performed according to the method described …”

“…Intrahepatic bile duct mass was evaluated by semiquantitative immunohistochemistry to detect cytokeratin-19 (CK-19) as described. (20,22) Hydroxyproline assay was performed according to the method described. (23) Real-tIMe pCR RNA from HSCs was isolated using TRIzol (Invitrogen), and 1 to 2 μg of total RNA was used for first-strand complementary DNA (cDNA) synthesis with SuperScript III (Invitrogen).…”