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J. Clin. Med. 2018, 7(9), 266; https://doi.org/10.3390/jcm7090266

Translational Medicine in Pulmonary-Renal Crosstalk: Therapeutic Targeting of p-Cresyl Sulfate Triggered Nonspecific ROS and Chemoattractants in Dyspneic Patients with Uremic Lung Injury

1
Program in Nutrition and Food Sciences, College of Human Ecology, Fu Jen Catholic University, New Taipei City 242, Taiwan
2
Graduate Institution of Biomedical and Pharmaceutical Science, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
3
Division of Nephrology, Department of Internal Medicine, En-Chu-Kong Hospital, New Taipei City 237, Taiwan
4
Renal Care Joint Foundation, New Taipei City 220, Taiwan
5
Division of Nephrology, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan
6
Department of Nursing, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan
7
Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
8
Department of Biotechnology, College of Life Science; Center for Research, Resources and Development, Kaohsiung Medical University, Kaohsiung 807, Taiwan
9
Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan
10
Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
11
Department of Medical Laboratory Science and Biotechnology, Yuanpei University, Hsinchu 300, Taiwan
12
Department of Clinical Laboratory, En Chu Kong Hospital, New Taipei City 237, Taiwan
13
Department of Chest Medicine, En Chu Kong Hospital, New Taipei City 237, Taiwan
14
School of Biomedical Engineering, Taipei Medical University, Taipei 110, Taiwan
15
Department of Dentistry, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan
16
Division of Pathology, En-Chu-Kong Hospital, New Taipei City 237, Taiwan
*
Author to whom correspondence should be addressed.
Received: 15 August 2018 / Revised: 31 August 2018 / Accepted: 7 September 2018 / Published: 9 September 2018
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Abstract

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 α/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–capillary injury. PCS causes alveolar–capillary 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. View Full-Text
Keywords: p-cresyl sulfate; alveolar cell death; reactive oxygen species; cytokines; uremic lung injury; chronic kidney disease p-cresyl sulfate; alveolar cell death; reactive oxygen species; cytokines; uremic lung injury; chronic kidney disease
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Chang, J.-F.; Liang, S.-S.; Thanasekaran, P.; Chang, H.-W.; Wen, L.-L.; Chen, C.-H.; Liou, J.-C.; Yeh, J.-C.; Liu, S.-H.; Dai, H.-M.; Lin, W.-N. Translational Medicine in Pulmonary-Renal Crosstalk: Therapeutic Targeting of p-Cresyl Sulfate Triggered Nonspecific ROS and Chemoattractants in Dyspneic Patients with Uremic Lung Injury. J. Clin. Med. 2018, 7, 266.

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