These processes define the stage of sterile inflammatory responses to irradiation ( 3). These events transition into a cascade of aberrant metabolic and immune responses, including recruitment/activation of innate immune cells, which create a prooxidant environment that facilitates the initiation of several types of nonapoptotic regulated cell death programs. Unearthing complex PAO1 pathogenic/virulence mechanisms, including effects on the host anti/proinflammatory responses, lipid metabolism, and ferroptotic cell death, points toward potentially new therapeutic and radiomitigative targets.Įxposure to ionizing radiation initiates generation of a multitude of reactive intermediates leading to DNA damage, and this triggers predominantly apoptotic death of sensitive cell populations - gut epithelium and bone marrow hematopoietic cells ( 1, 2). Opportunistic PAO1 mechanisms included stimulation of the antiinflammatory lipoxin A 4, production and suppression of the proinflammatory hepoxilin A 3, and leukotriene B 4. A lipoxygenase inhibitor, baicalein, significantly attenuated animal lethality, PAO1 colonization, intestinal epithelial cell death, and generation of ferroptotic PEox signals. Global redox phospholipidomics of the ileum revealed that lysophospholipids and oxidized phospholipids, particularly oxidized phosphatidylethanolamine (PEox), represented the major factors that contributed to the pathogenic changes induced by total body irradiation and infection by PAO1. The PAO1-driven pathogenic mechanism includes theft-ferroptosis realized via (a) curbing of the host antiferroptotic system, GSH/GPx4, and (b) employing bacterial 15-lipoxygenase to generate proferroptotic signal - 15-hydroperoxy-arachidonoyl-PE (15-HpETE-PE) - in the intestines of irradiated and PAO1-infected mice. We found enhanced Pseudomonas aeruginosa (PAO1) colonization of the gut leading to host cell death and strikingly decreased survival of irradiated mice. Total body irradiation (TBI) targets sensitive bone marrow hematopoietic cells and gut epithelial cells, causing their death and inducing a state of immunodeficiency combined with intestinal dysbiosis and nonproductive immune responses.
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