{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:11Z","timestamp":1787028551227,"version":"build-2736575974"},"reference-count":55,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T00:00:00Z","timestamp":1729468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Alcohol Abuse and Alcoholism of the National Institutes of Health","award":["P50AA024337"],"award-info":[{"award-number":["P50AA024337"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sepsis remains an important healthcare challenge. The lungs are often affected in sepsis, resulting in acute lung injury characterized by inflammation. Mechanisms involving lipopolysaccharide (LPS) stimulation of toll-like receptor (TLR) signaling with induction of proinflammatory pathways have been implicated in this process. To date, however, studies targeting these pathways have failed to improve outcomes. We have found that LPS may also promote lung injury through the activation of \u03b14 nicotinic acetylcholine receptors (\u03b14 nAChRs) in immune cells. We observed increased expression of \u03b14 nAChRs in human THP-1 monocytic cells exposed to LPS (100 ng\/mL, 24 h). We also observed that LPS stimulated the expression of other relevant genes, including tumor necrosis factor-\u03b1, interleukin-1\u03b2, plasminogen activator inhibitor-1, the solute carrier family 7 member 11, extracellular superoxide dismutase, and transforming growth factor-\u03b21. Of interest, dihydro-\u03b2-erythroidine hydrobromide (DH\u03b2E), a specific chemical inhibitor of \u03b14 nAChRs, inhibited the LPS-induced expression of these genes. We generated mice with a global knockout mutation of the \u03b14 nAChR subunit in the C57BL\/6 background using CRISPR\/Cas9 technology. The lungs of these LPS-treated animals demonstrated a reduction in the expression of the above-mentioned genes when compared with the lungs of wild-type animals. In support of the role of oxidative stress, we observed that LPS induced expression of the cystine transporter Slc7a11 in both THP-1 cells and in wild-type mouse lungs. The effects of LPS on THP-1 cells were blocked by the thiol antioxidant N-acetylcysteine and mimicked by redox stress. Importantly, the induction of IL-1\u03b2 by redox stress was inhibited by the \u03b14 nAChR inhibitor DH\u03b2E. Finally, we showed that LPS stimulated calcium influx in THP-1 cells, which was blocked by the \u03b14 nAChR inhibitor. Our observations suggest that LPS promotes lung injury by stimulating redox stress, which activates \u03b14 nAChR signaling and drives proinflammatory cytokine expression.<\/jats:p>","DOI":"10.3390\/ijms252011305","type":"journal-article","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T06:35:00Z","timestamp":1729492500000},"page":"11305","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["\u03b14 Nicotinic Acetylcholine Receptors in Lipopolysaccharide-Related Lung Inflammation"],"prefix":"10.3390","volume":"25","author":[{"given":"Jeffrey D.","family":"Ritzenthaler","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine and the Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter H.","family":"Watson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville, Louisville, KY 40292, USA"},{"name":"Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40292, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse","family":"Roman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine and the Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.4161\/viru.27372","article-title":"Epidemiology of severe sepsis","volume":"5","author":"Mayr","year":"2014","journal-title":"Virulence"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1056\/NEJMp1707170","article-title":"Recognizing sepsis as a global health priority\u2014A WHO Resolution","volume":"377","author":"Reinhart","year":"2017","journal-title":"N. 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