Details

Autor(en) / Beteiligte

• Cruz Hernandez, Angela Alexandra

Titel

Contribution of Mast Cells to Lung and Brain Toxicity Following Nitrogen Mustard Exposure

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2022

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• Sulfur mustard (SM) has been widely used as a chemical warfare agent throughout war history, including most recently in Syria. Veterans that have served in the Gulf War (GW) and been diagnosed with Gulf War Illness (GWI) have experienced respiratory complications that closely mirror SM toxicity. Mice exposed to SM exhibit an increase in pro-inflammatory cytokines followed by immune cell infiltration in the lung; however, the mechanisms leading to these inflammatory responses are not well understood. Additionally, veterans and civilians exposed to SM have also reported cognitive dysfunction. Aside from affecting the lungs, SM exposure has also been implicated in the degradation of the blood-brain barrier (BBB), abnormalities in the cerebellum and hypothalamus, neuronal inflammation, and neuronal necrosis. We believe that long-term inflammation contributes to disease pathology seen in both organs. Mast cells are one of the first responding innate immune cells found at the mucosal surfaces of the lung and various locations in the brain. Studies have shown that SM can activate mast cells in the skin days post-exposure. Therefore, we hypothesized that nitrogen mustard (NM: a surrogate for SM) exposure promotes activation of mast cells, causing chronic respiratory and neurological inflammation. To assess the role of mast cells in NM-mediated pulmonary toxicity, we compared the effects of NM exposure between C57BL/6 and B6.Cg-KitW-sh/HNihrJaeBsmJ (KitW-sh; mast cell-deficient) mice. Lung injury was observed in C57BL/6J mice following NM exposure (0.125 mg/kg) at 72 h, significantly abrogated in KitW-sh mice. Although both strains exhibited damage from NM, C57BL/6J mice had higher inflammatory cell infiltration and more elevated prostaglandin D2 (PGD2) present in bronchoalveolar lavage fluid compared with KitW-sh mice. In the brain of C57BL/6J mice, there was an increasing trend in mRNA gene expression of various pro-inflammatory cytokines. This new information will shed light on the role of mast cells in two critical organ systems, the lungs, and brain, in response to a persistent chemical warfare agent. We will be able to characterize mast cells role in the lung and brain and determine how damage is initiated. Understanding these mechanisms will help us stop toxicity by helping us detect damage and developing novel therapeutic targets or prophylaxis for soldiers, veterans, and civilians.