Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury

By Y. Imai, K. Kuba, G. Neely, Rubina Yaghubian-Malhami, T. Perkmann, G. van Loo, M. Ermolaeva, R. Veldhuizen, Y. C. Leung, Hongliang Wang and 15 more. Cell, 2008

1,330 citations recorded by the source corpus.

Multiple lung pathogens such as chemical agents, H5N1 avian flu, or SARS cause high lethality due to acute respiratory distress syndrome. Here we report that Toll-like receptor 4 (TLR4) mutant mice display natural resistance to acid-induced acute lung injury (ALI). We show that TLR4-TRIF-TRAF6 signaling is a key disease pathway that controls the severity of ALI. The oxidized phospholipid (OxPL) OxPAPC was identified to induce lung injury and cytokine production by lung macrophages via TLR4-TRIF. We observed OxPL production in the lungs of humans and animals infected with SARS, Anthrax, or H5N1. Pulmonary challenge with an inactivated H5N1 avian influenza virus rapidly induces ALI and OxPL formation in mice. Loss of TLR4 or TRIF expression protects mice from H5N1-induced ALI. Moreover, deletion of ncf1, which controls ROS production, improves the severity of H5N1-mediated ALI. Our data identify oxidative stress and innate immunity as key lung injury pathways that control the severity of ALI.

Subfields: Epidemiology, Immunology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/c35f8f4b1e1fdd53795947bdb49abbf82c9e8323

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In Immunology

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In Pulmonary and Respiratory Medicine

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Citations in the corpus

• Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology (2017, background): “Since pathogenic human coronaviruses cause acute lung injury and promote OxPL production in the lungs [125], strategies to suppress OxPL either by using Eritoran or other similar compounds could be of value in dampening hCoVinduced inflammation.”
• Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses (2009, background): “These danger signals originate from host molecules with aberrant locations, structures, or interactions induced by, e.g., necrosis or oxidative damage of cells or tissues, as exemplified by uric acid, ATP, potassium, hyaluronan fragments, and HSPs (146, 236, 247, 362, 365).”
• IL-6 in inflammation, immunity, and disease. (2014, background): “The third group comprises such autoinflammatory diseases as TNF-receptor-associated periodic syndrome and chronic inflammatory neurological cutaneous articular syndrome, whereas other diseases include atherosclerosis, type 2 diabetes mellitus, atopic dermatitis, sciatica, and cancer-associated cache”
• Ferroptosis in infection, inflammation, and immunity (2021, background): “Moreover, lipid oxidation products (e.g., 4-HNE and oxPLs) trigger inflammation in vitro or in vivo partly through activating TLR4 signaling (Imai et al., 2008; Wang et al., 2019b).”
• The role of oxidative stress during inflammatory processes (2013, background): “Of particular relevance, these same conditions are also typically associated with significant alterations of redox balance, related to the upregulated production of multiple oxygen- and nitrogen-centered reactive chemical species, promoting the development of oxidative stress.”
• Toll-like receptors in antiviral innate immunity (2013, background): “024 Although recognition of viral pathogens by TLRs can initiate many intrinsic antiviral defense mechanisms to protect the host and eliminate the invader, stimulation of TLRs can enhance the severity of disease in certain viral infections, as exemplified by TLR3-mediated and TLR4-mediated detriment”
• Inflammatory dendritic cells—not basophils—are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen (2010, background): “The pathway of oxidized phospholipid triggering of TLR4 was found to be TRIF dependent, but not MyD88 dependent yet (Imai et al., 2008; Tang et al., 2010).”
• Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. (2019, background): “IL-6 favors macrophage accumulation at the site of injury and is important for the development of persistent inflammation and ALI (31, 32).”
• Pattern recognition receptors and inflammation. (2010, background): “In addition, TLR4 modulates the pathogenesis of H5N1 avian influenza virus infection by recognizing a DAMP rather than the virus itself (Imai et al., 2008).”