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Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury
Open accessAbstract
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.
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“Macrophage activation via TLR4, a type of PRR, is also involved in gastric acid-induced ARDS and mouse ARDS models induced by SARS-CoV-1 or influenza virus H5N1 (355).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [355]
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“endogenous products such as oxidized phospholipids and matrix breakdown products also drive inflammation through TLR4 and probably other TLRs, providing a mechanism for perpetuating inflammation when microbial products are being cleared from the lungs (68,72).”
From Into the Eye of the Cytokine Storm (2012) · cites this paper as [68]
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Self-citationRETRACTED: Regulated programmed cell death in acute lung injury: from pathogenesis to therapy
Liu, S., Chen, Y., Liu, Y. F., Zhou, W., & Liu, X. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1630015 · Cited by 8
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Metadata
- Authors
- Imai, Y., Kuba, K., Neely, G. G., Yaghubian-Malhami, R., Perkmann, T., van Loo, G., Ermolaeva, M., Veldhuizen, R., Leung, Y. H. C., Wang, H., Liu, H., Sun, Y., Pasparakis, M., Kopf, M., Mech, C., Bavari, S., Peiris, J. S. M., Slutsky, A. S., Akira, S., Hultqvist, M., Holmdahl, R., Nicholls, J., Jiang, C., Binder, C. J., & Penninger, J. M.
- Affiliations
- Institute of Molecular Biotechnology (AT)
- Austrian Academy of Sciences (AT)
- University of Cologne (DE)
- Western University (CA)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- United States Army Medical Research Institute of Infectious Diseases (US)
- St. Michael's Hospital (CA)
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- Karolinska Institutet (SE)
- University of Hong Kong (HK)
- Corresponding author
- Imai, Yumiko
- Penninger, Josef M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2008-04
- Volume
- 133
- Issue
- 2
- Pages
- 235-249
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7112336
- OpenAlex
- W2156613610
- Cited by
- 1,356
- References
- 60
- Citations by year
- 2026: 34 · 2025: 53 · 2024: 56 · 2023: 76 · 2022: 105 · 2021: 143 · 2020: 152 · 2019: 47 · 2018: 69 · 2017: 64 · 2016: 80 · 2015: 65 · 2014: 82 · 2013: 68 · 2012: 53
- FWCI
- 29.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1933 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- University of Pittsburgh
- European Commission
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (100233)
- Defense Threat Reduction Agency
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- acute lung injury, TLR4, TRIF, TRAF6, oxidized phospholipids, OxPAPC, oxidative stress, reactive oxygen species, NCF1, lung macrophages, H5N1 avian influenza, SARS, anthrax, innate immunity, respiratory distress syndrome
- MeSH terms
- Animals, Humans, Influenza, Human, Lung, Mice, Inbred C57BL, Orthomyxoviridae Infections, Phospholipids, Respiratory Distress Syndrome, Signal Transduction, Interleukin-6, NF-kappa B, Oxidative Stress, NADPH Oxidases, Adaptor Proteins, Vesicular Transport, Severe Acute Respiratory Syndrome, Toll-Like Receptor 4, Mice
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