{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T05:16:46Z","timestamp":1761628606750,"version":"build-2065373602"},"reference-count":42,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T00:00:00Z","timestamp":1761350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003329","name":"Ministerio de Econom\u00eda y Competitividad","doi-asserted-by":"crossref","award":["PI13\/00700","PI13\/0002"],"award-info":[{"award-number":["PI13\/00700","PI13\/0002"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100008061","name":"Fundaci\u00f3n Mutua Madrile\u00f1a","doi-asserted-by":"publisher","award":["FMM 14\/08"],"award-info":[{"award-number":["FMM 14\/08"]}],"id":[{"id":"10.13039\/100008061","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100030969","name":"NEUMOMADRID","doi-asserted-by":"crossref","award":["Neu 2010"],"award-info":[{"award-number":["Neu 2010"]}],"id":[{"id":"10.13039\/100030969","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ischemia\/reperfusion (I\/R) injury is a major complication in lung transplantation. Recent evidence suggests that mitogen-activated protein kinases (MAPKs) such as p-38 mitogen-activated protein kinase (p-38 MAPK) and extracellular signal-regulated kinase (ERK), along with functionally related kinases like phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT), contribute to I\/R pathophysiology by mediating inflammatory and stress-response signaling. MicroRNAs (miRNAs) also play a regulatory role in these processes. Lidocaine has demonstrated anti-inflammatory activity in several tissues; however, its ability to modulate miRNA expression and kinase activation in the lung is not yet fully understood. This study investigated the involvement of these signaling molecules in lung I\/R injury and evaluated the modulatory effect of intravenous lidocaine in a porcine lung auto-transplantation model. Eighteen large white pigs were assigned to sham-operated (n = 6), control (lung auto-transplantation, n = 6), or lidocaine-treated (n = 6) groups. Lidocaine was administered as a 1.5 mg\/kg bolus followed by a continuous infusion (1.5 mg\u00b7kg\u22121\u00b7h\u22121). Lung biopsies were collected before ischemia, before reperfusion, and at 30- and 60-min post-reperfusion to assess total and phosphorylated levels of p-38 MAPK, ERK, PI3K, and AKT (Thr308, Ser473), along with miR-126, miR-142-5p, miR-152, and miR-155 expression. I\/R increased p-38 MAPK and AKT, and enhanced phosphorylation of all four kinases. miRNA levels were also upregulated. Lidocaine partially or completely attenuated these changes. These findings support a role for these molecular pathways in lung I\/R injury and suggest that lidocaine may offer protective effects through their modulation.<\/jats:p>","DOI":"10.3390\/ijms262110385","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:51:42Z","timestamp":1761526302000},"page":"10385","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lidocaine Attenuates miRNA Dysregulation and Kinase Signaling Activation in a Porcine Model of Lung Ischemia\/Reperfusion Injury"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5580-030X","authenticated-orcid":false,"given":"Alberto","family":"Alonso","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery, 12 de Octubre University General Hospital, Avda. de C\u00f3rdoba, s\/n, 28041 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4646-4199","authenticated-orcid":false,"given":"Sergio D.","family":"Paredes","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Complutense University of Madrid, Avda. Complutense, s\/n, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agust\u00edn","family":"Turrero","sequence":"additional","affiliation":[{"name":"Departmental Unit of Biostatistics\u2014Department of Statistics and Operations Research, School of Medicine, Complutense University of Madrid, Avda. Complutense, s\/n, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1556-192X","authenticated-orcid":false,"given":"Lisa","family":"Rancan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, Complutense University of Madrid, Avda. Complutense, s\/n, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ignacio","family":"Garutti","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Gregorio Mara\u00f1\u00f3n University General Hospital, C\/Doctor Esquerdo, 46, 28007 Madrid, Spain"},{"name":"Department of Pharmacology and Toxicology, School of Medicine, Complutense University of Madrid, Avda. Complutense, s\/n, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Sim\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Gregorio Mara\u00f1\u00f3n University General Hospital, C\/Doctor Esquerdo, 46, 28007 Madrid, Spain"},{"name":"Department of Surgery, School of Medicine, Complutense University of Madrid, Avda. Complutense, s\/n, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5361-5215","authenticated-orcid":false,"given":"Elena","family":"Vara","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, Complutense University of Madrid, Avda. Complutense, s\/n, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1164\/rccm.200207-670SO","article-title":"Ischemia-reperfusion-induced lung injury","volume":"167","author":"Liu","year":"2003","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_2","first-page":"695","article-title":"Emerging role of microRNAs in drug response","volume":"12","author":"Zhang","year":"2010","journal-title":"Curr. Opin. Mol. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.trsl.2011.01.010","article-title":"Integrating microRNAs into a system biology approach to acute lung injury","volume":"157","author":"Zhou","year":"2011","journal-title":"Transl. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/nature07756","article-title":"Small RNAs in transcriptional gene silencing and genome defence","volume":"457","author":"Moazed","year":"2009","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1261\/rna.2248605","article-title":"MicroRNA function: Multiple mechanisms for a tiny RNA?","volume":"11","author":"Pillai","year":"2005","journal-title":"RNA"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Liang, G., Guo, C., Tang, H., and Zhang, M. (2024). miR-30a-5p attenuates hypoxia\/reoxygenation-induced cardiomyocyte apoptosis by regulating PTEN expression and activating PI3K\/Akt signaling pathway. BMC Cardiovasc. Disord., 24.","DOI":"10.1186\/s12872-024-03900-4"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/leu.2011.356","article-title":"MicroRNAs in inflammation and immune responses","volume":"26","author":"Contreras","year":"2012","journal-title":"Leukemia"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wang, Y., Tian, Y., Ding, Y., Wang, J., Yan, S., Zhou, L., Xie, H., Chen, H., Li, H., and Zhang, J. (2014). miR-152 may silence translation of CaMK II and induce spontaneous immune tolerance in mouse liver transplantation. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0105096"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4005","DOI":"10.4049\/jimmunol.1202911","article-title":"PU.1-dependent transcriptional regulation of miR-142 contributes to its hematopoietic cell-specific expression and modulation of IL-6","volume":"190","author":"Sun","year":"2013","journal-title":"J. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.devcel.2008.07.002","article-title":"The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis","volume":"15","author":"Wang","year":"2008","journal-title":"Dev. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1126\/science.7914033","article-title":"A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells","volume":"265","author":"Han","year":"1994","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e00189","DOI":"10.1177\/1759091415602463","article-title":"Crosstalk between MAPK\/ERK and PI3K\/AKT signal pathways during brain ischemia\/reperfusion","volume":"7","author":"Zhou","year":"2015","journal-title":"ASN Neuro"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1097\/00000542-200107000-00021","article-title":"Local anesthetic effects on priming and activation of human neutrophils","volume":"95","author":"Hollmann","year":"2001","journal-title":"Anesthesiology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.2165\/10898560-000000000-00000","article-title":"Impact of intravenous lidocaine infusion on postoperative analgesia and recovery from surgery: A systematic review of randomized controlled trials","volume":"70","author":"McCarthy","year":"2010","journal-title":"Drugs"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1038\/ni.1640","article-title":"The kinase p38 alpha serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression","volume":"9","author":"Kim","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Morrison, D.K. (2012). MAP kinase pathways. Cold Spring Harb. Perspect. Biol., 4.","DOI":"10.1101\/cshperspect.a011254"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/j.1600-6143.2012.04313.x","article-title":"MicroRNAs as biomarkers in solid organ transplantation","volume":"13","author":"Mas","year":"2013","journal-title":"Am. J. Transplant."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"S593","DOI":"10.1177\/09603271211043480","article-title":"Erythropoietin alleviates acute lung injury induced by ischemia-reperfusion through blocking p38 MAPK signaling","volume":"40","author":"Jia","year":"2021","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3908641","DOI":"10.1155\/2020\/3908641","article-title":"Heat Shock Protein 70 protects the heart from ischemia\/reperfusion injury through inhibition of p38 MAPK signaling","volume":"2020","author":"Song","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1124\/jpet.121.000956","article-title":"Empagliflozin protects against pulmonary ischemia\/reperfusion injury via an ERK1\/2-dependent mechanism","volume":"380","author":"Huang","year":"2022","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_21","first-page":"370","article-title":"Dexmedetomidine alleviates lung ischemia-reperfusion injury in rats by activating PI3K\/Akt pathway","volume":"23","author":"Liang","year":"2019","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.jtcvs.2009.09.027","article-title":"Prevention of lung ischemia-reperfusion injury by short hairpin RNA-mediated caspase-3 gene silencing","volume":"139","author":"Zhang","year":"2010","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_23","first-page":"206","article-title":"Clinical importance of anaesthetic preconditioning","volume":"42","author":"Lango","year":"2010","journal-title":"Anestezjol. Intensywna Ter."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1213\/ANE.0000000000000360","article-title":"Intravenous lidocaine decreases tumor necrosis factor alpha expression both locally and systemically in pigs undergoing lung resection surgery","volume":"119","author":"Garutti","year":"2014","journal-title":"Anesth. Analg."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.cell.2017.04.001","article-title":"AKT\/PKB signaling: Navigating the network","volume":"169","author":"Manning","year":"2017","journal-title":"Cell"},{"key":"ref_26","first-page":"1311","article-title":"Cross-talk between mitogenic Ras\/MAPK and survival PI3K\/Akt pathways: A fine balance","volume":"39","author":"Aksamitiene","year":"2011","journal-title":"Biochem. Soc. Trans."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1213\/ANE.0000000000001633","article-title":"Lidocaine administration controls microRNAs alterations observed after lung ischemia-reperfusion injury","volume":"123","author":"Rancan","year":"2016","journal-title":"Anesth. Analg."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8523","DOI":"10.1038\/ncomms9523","article-title":"miR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program","volume":"6","author":"Su","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7113","DOI":"10.1073\/pnas.0902636106","article-title":"Inositol phosphatase SHIP1 is a primary target of miR-155","volume":"106","author":"Chaudhuri","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.cytogfr.2008.04.011","article-title":"microRNAs and death receptors","volume":"19","author":"Park","year":"2008","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"119499","DOI":"10.1016\/j.lfs.2021.119499","article-title":"Interplay between MAPK\/ERK signaling pathway and microRNAs: A crucial mechanism regulating cancer cell metabolism and tumor progression","volume":"278","author":"Asl","year":"2021","journal-title":"Life Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.devcel.2008.07.008","article-title":"miR-126 regulates angiogenic signaling and vascular integrity","volume":"15","author":"Fish","year":"2008","journal-title":"Dev. Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1073\/pnas.0707493105","article-title":"MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1","volume":"105","author":"Harris","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1213\/ANE.0b013e3182288e01","article-title":"The effects of anesthetic preconditioning with sevoflurane in an experimental lung autotransplant model in pigs","volume":"113","author":"Casanova","year":"2011","journal-title":"Anesth. Analg."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Romera, A., Cebollero, M., Romero-G\u00f3mez, B., Carricondo, F., Zapatero, S., Garc\u00eda-Aldao, U., Mart\u00edn-Albo, L., Ortega, J., Vara, E., and Garutti, I. (2021). Effect of Intravenous Lidocaine on Inflammatory and Apoptotic Response of Ischemia-Reperfusion Injury in Pigs Undergoing Lung Resection Surgery. Biomed Res. Int., 2021.","DOI":"10.1155\/2021\/6630232"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/j.1365-2885.1993.tb00283.x","article-title":"Lidocaine decay and hepatic extraction in the pig","volume":"16","author":"Mets","year":"1993","journal-title":"J. Vet. Pharmacol. Ther."},{"key":"ref_37","first-page":"306","article-title":"Lidocaine pharmacokinetics and toxicity in newborn pigs","volume":"85","author":"Satas","year":"1997","journal-title":"Anesth. Analg."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13741-019-0112-4","article-title":"Intravenous lidocaine infusion as a component of multimodal analgesia for colorectal surgery-measurement of plasma levels","volume":"8","author":"Greenwood","year":"2019","journal-title":"Perioper. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s00408-017-0001-x","article-title":"Chemokine involvement in lung injury secondary to ischaemia\/reperfusion","volume":"195","author":"Rancan","year":"2017","journal-title":"Lung"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1097\/TP.0000000000000408","article-title":"Sevoflurane prevents liver inflammatory response induced by lung ischemia-reperfusion","volume":"98","author":"Rancan","year":"2014","journal-title":"Transplantation"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1111\/j.1740-0929.2011.00908.x","article-title":"Identification of suitable endogenous control microRNA genes in normal pig tissues","volume":"82","author":"Gu","year":"2011","journal-title":"Anim. Sci. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(\u2212\u0394\u0394C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10385\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T05:13:04Z","timestamp":1761628384000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10385"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,25]]},"references-count":42,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262110385"],"URL":"https:\/\/doi.org\/10.3390\/ijms262110385","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,10,25]]}}}