{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T01:22:47Z","timestamp":1784769767511,"version":"3.55.0"},"reference-count":30,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2018,9,9]],"date-time":"2018-09-09T00:00:00Z","timestamp":1536451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fu Jen Catholic University Research Foundation","award":["410031034022 and A0103017"],"award-info":[{"award-number":["410031034022 and A0103017"]}]},{"name":"Ministry of Science and Technology","award":["106-2221-E-151-051-"],"award-info":[{"award-number":["106-2221-E-151-051-"]}]},{"name":"En Chu Kong Hospital","award":["ECKH10505"],"award-info":[{"award-number":["ECKH10505"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Molecular mechanisms and pathological features of p-Cresyl sulfate (PCS)-induced uremic lung injury (ULI) in chronic kidney disease (CKD) remain unclear. We analyzed pleural effusions (PE) from CKD and non-CKD patients for uremic toxins, reactive oxygen species (ROS), and chemotactic cytokines. Correlations between PE biomarkers and serum creatinine were also studied. Cell viability and inflammatory signaling pathways were investigated in PCS-treated human alveolar cell model. To mimic human diseases, CKD-ULI mouse model was developed with quantitative comparison of immunostaining and morphometric approach. PE from CKD patients enhance expressions of uremic toxins, hydroxyl radicals, and IL-5\/IL-6\/IL-8\/IL-10\/IL-13\/ENA-78\/GRO \u03b1\/MDC\/thrombopoietin\/VEGF. PE concentrations of ENA-78\/VEGF\/IL-8\/MDC\/PCS\/indoxyl sulphate correlate with serum creatinine concentrations. In vitro, PCS promotes alveolar cell death, cPLA2\/COX-2\/aquaporin-4 expression, and NADPH oxidase\/mitochondria activation-related ROS. Intracellular ROS is abrogated by non-specific ROS scavenger N-acetyl cysteine (NAC), inhibitors of NADPH oxidase and mitochondria-targeted superoxide scavenger. However, only NAC protects against PCS-induced cell death. In vivo, expressions of cPLA2\/COX2\/8-OHdG, resident alveolar macrophages, recruited leukocytes, alveolar space, interstitial edema and capillary leakage increase in lung tissues of CKD-ULI mice, and NAC pretreatment ameliorates alveolar\u2013capillary injury. PCS causes alveolar\u2013capillary injury through triggering intracellular ROS, downstream prostaglandin pathways, cell death, and activating leukocytes to release multiplex chemoattractants and extracellular ROS. Thus PCS and nonspecific ROS serve as potential therapeutic targets.<\/jats:p>","DOI":"10.3390\/jcm7090266","type":"journal-article","created":{"date-parts":[[2018,9,10]],"date-time":"2018-09-10T10:28:57Z","timestamp":1536575337000},"page":"266","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Translational Medicine in Pulmonary-Renal Crosstalk: Therapeutic Targeting of p-Cresyl Sulfate Triggered Nonspecific ROS and Chemoattractants in Dyspneic Patients with Uremic Lung Injury"],"prefix":"10.3390","volume":"7","author":[{"given":"Jia-Feng","family":"Chang","sequence":"first","affiliation":[{"name":"Program in Nutrition and Food Sciences, College of Human Ecology, Fu Jen Catholic University, New Taipei City 242, Taiwan"},{"name":"Graduate Institution of Biomedical and Pharmaceutical Science, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan"},{"name":"Division of Nephrology, Department of Internal Medicine, En-Chu-Kong Hospital, New Taipei City 237, Taiwan"},{"name":"Renal Care Joint Foundation, New Taipei City 220, Taiwan"},{"name":"Division of Nephrology, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan"},{"name":"Department of Nursing, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Shin","family":"Liang","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung 804, Taiwan"},{"name":"Department of Biotechnology, College of Life Science; Center for Research, Resources and Development, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6437-7366","authenticated-orcid":false,"given":"Pounraj","family":"Thanasekaran","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0068-2366","authenticated-orcid":false,"given":"Hsueh-Wei","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Li","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology, Yuanpei University, Hsinchu 300, Taiwan"},{"name":"Department of Clinical Laboratory, En Chu Kong Hospital, New Taipei City 237, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Hua","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chest Medicine, En Chu Kong Hospital, New Taipei City 237, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Chiun","family":"Liou","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jih-Chen","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Dentistry, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Hao","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Pathology, En-Chu-Kong Hospital, New Taipei City 237, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huei-Min","family":"Dai","sequence":"additional","affiliation":[{"name":"Graduate Institution of Biomedical and Pharmaceutical Science, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Ning","family":"Lin","sequence":"additional","affiliation":[{"name":"Graduate Institution of Biomedical and Pharmaceutical Science, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.kint.2015.11.019","article-title":"Impact of acute kidney injury on distant organ function: Recent findings and potential therapeutic targets","volume":"89","author":"Doi","year":"2016","journal-title":"Kidney Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/nrcardio.2012.191","article-title":"Causes and treatment of oedema in patients with heart failure","volume":"10","author":"Clark","year":"2013","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/nrneph.2015.158","article-title":"Mechanisms and mediators of lung injury after acute kidney injury","volume":"12","author":"Faubel","year":"2016","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1681\/ASN.2013101062","article-title":"The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: A systematic review","volume":"25","author":"Vanholder","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1038\/ki.2008.314","article-title":"Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy","volume":"74","author":"Klein","year":"2008","journal-title":"Kidney Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2362","DOI":"10.1046\/j.1523-1755.1999.00460.x","article-title":"Renal ischemia\/reperfusion leads to macrophage-mediated increase in pulmonary vascular permeability","volume":"55","author":"Kramer","year":"1999","journal-title":"Kidney Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1046\/j.1523-1755.2003.00753.x","article-title":"Acute renal failure leads to dysregulation of lung salt and water channels","volume":"63","author":"Rabb","year":"2003","journal-title":"Kidney Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/ki.2008.648","article-title":"Compartmentalization of neutrophils in the kidney and lung following acute ischemic kidney injury","volume":"75","author":"Awad","year":"2009","journal-title":"Kidney Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.2353\/ajpath.2010.090793","article-title":"Neutrophil elastase contributes to acute lung injury induced by bilateral nephrectomy","volume":"177","author":"Ishii","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"L255","DOI":"10.1152\/ajplung.00218.2015","article-title":"Adipor-increased intracellular ROS promotes cpla2 and cox-2 expressions via activation of PKC and p300 in adiponectin-stimulated human alveolar type II cells","volume":"311","author":"Chen","year":"2016","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/j.bbamem.2009.03.009","article-title":"Aquaporins are multifunctional water and solute transporters highly divergent in living organisms","volume":"1788","author":"Gomes","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S12","DOI":"10.1038\/ki.2009.402","article-title":"Uremic toxins originating from colonic microbial metabolism","volume":"114","author":"Evenepoel","year":"2009","journal-title":"Kidney Int. Suppl."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e001852","DOI":"10.1161\/JAHA.115.001852","article-title":"P-cresyl sulfate aggravates cardiac dysfunction associated with chronic kidney disease by enhancing apoptosis of cardiomyocytes","volume":"4","author":"Han","year":"2015","journal-title":"J. Am. Heart Assoc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1038\/ki.2012.448","article-title":"P-cresyl sulfate causes renal tubular cell damage by inducing oxidative stress by activation of NADPH oxidase","volume":"83","author":"Watanabe","year":"2013","journal-title":"Kidney Int."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Chang, M.C., Chang, H.H., Chan, C.P., Yeung, S.Y., Hsien, H.C., Lin, B.R., Yeh, C.Y., Tseng, W.Y., Tseng, S.K., and Jeng, J.H. (2014). P-cresol affects reactive oxygen species generation, cell cycle arrest, cytotoxicity and inflammation\/atherosclerosis-related modulators production in endothelial cells and mononuclear cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0114446"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1093\/ndt\/gfl584","article-title":"P-cresylsulphate, the main in vivo metabolite of p-cresol, activates leucocyte free radical production","volume":"22","author":"Schepers","year":"2007","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1093\/ndt\/gfr453","article-title":"Serum free p-cresyl sulfate levels predict cardiovascular and all-cause mortality in elderly hemodialysis patients\u2014A prospective cohort study","volume":"27","author":"Wu","year":"2012","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1038\/ki.2008.31","article-title":"Free p-cresol is associated with cardiovascular disease in hemodialysis patients","volume":"73","author":"Meijers","year":"2008","journal-title":"Kidney Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1002\/jcsm.12202","article-title":"Potential therapeutic interventions for chronic kidney disease-associated sarcopenia via indoxyl sulfate-induced mitochondrial dysfunction","volume":"8","author":"Enoki","year":"2017","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.bbadis.2012.09.006","article-title":"Uremic toxins inhibit renal metabolic capacity through interference with glucuronidation and mitochondrial respiration","volume":"1832","author":"Mutsaers","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15799","DOI":"10.1073\/pnas.0406853101","article-title":"Role of proneuregulin 1 cleavage and human epidermal growth factor receptor activation in hypertonic aquaporin induction","volume":"101","author":"Herrlich","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1096\/fj.10-177279","article-title":"Proinflammatory role of aquaporin-4 in autoimmune neuroinflammation","volume":"25","author":"Li","year":"2011","journal-title":"FASEB J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1165\/rcmb.2016-0121TR","article-title":"Immune mechanisms in pulmonary fibrosis","volume":"55","author":"Kolahian","year":"2016","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1164\/rccm.201402-0245UP","article-title":"Update in chronic obstructive pulmonary disease 2013","volume":"189","author":"Barreiro","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1159\/000346180","article-title":"Development of a chronic kidney disease model in c57bl\/6 mice with relevance to human pathology","volume":"3","author":"Huang","year":"2013","journal-title":"Nephron Extra"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"791231","DOI":"10.1155\/2013\/791231","article-title":"Inflammatory signalings involved in airway and pulmonary diseases","volume":"2013","author":"Lee","year":"2013","journal-title":"Mediators Inflamm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.tcb.2011.06.008","article-title":"Taking a \"good\" look at free radicals in the aging process","volume":"21","author":"Hekimi","year":"2011","journal-title":"Trends Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1172\/JCI64181","article-title":"Transepithelial migration of neutrophils into the lung requires trem-1","volume":"123","author":"Keck","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.1172\/JCI60331","article-title":"The acute respiratory distress syndrome","volume":"122","author":"Matthay","year":"2012","journal-title":"J. Clin. Invest."},{"key":"ref_30","first-page":"887","article-title":"Blockade of nox2 and stim1 signaling limits lipopolysaccharide-induced vascular inflammation","volume":"123","author":"Gandhirajan","year":"2013","journal-title":"J. Clin. Investig."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/7\/9\/266\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:19:37Z","timestamp":1760195977000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/7\/9\/266"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,9]]},"references-count":30,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2018,9]]}},"alternative-id":["jcm7090266"],"URL":"https:\/\/doi.org\/10.3390\/jcm7090266","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,9]]}}}