title: Necroptosis and parthanatos are involved in remote lung injury after receiving ischemic renal allografts in rats.
abstract: Early renal graft injury could result in remote pulmonary injury due to kidney-lung cross talk. Here we studied the possible role of regulated necrosis in remote lung injury in a rat allogeneic transplantation model. In vitro, human lung epithelial cell A549 was challenged with TNF-α and conditioned medium from human kidney proximal tubular cells (HK-2) after hypothermia-hypoxia insults. In vivo, the Brown-Norway rat renal grafts were extracted and stored in 4 °C Soltran preserving solution for up to 24 h and transplanted into Lewis rat recipients, and the lungs were harvested on day 1 and day 4 after grafting for further analysis. Ischemia-reperfusion injury in the renal allograft caused pulmonary injury following engraftment. PARP-1 (marker for parthanatos) and receptor interacting protein kinase 1 (Rip1) and Rip3 (markers for necroptosis) expression was significantly enhanced in the lung. TUNEL assays showed increased cell death of lung cells. This was significantly reduced after treatment with necrostatin-1 (nec-1) or/and 3-aminobenzamide (3-AB). Acute immune rejection exacerbated the remote lung injury and 3-AB or/and Nec-1 combined with cyclosporine A conferred optimal lung protection. Thus, renal graft injury triggered remote lung injury, likely through regulated necrosis. This study could provide the molecular basis for combination therapy targeting both pathways of regulated necrosis to treat such complications after renal transplantation.
authors.affiliation: Faculty of Medicine, Department of Surgery and Cancer, Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors.forename: Hailin
authors.initials: H
authors.lastname: Zhao
authors.affiliation: 1] Faculty of Medicine, Department of Surgery and Cancer, Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, London, UK [2] Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Jiaolin
authors.initials: J
authors.lastname: Ning
authors.affiliation: Faculty of Medicine, Department of Surgery and Cancer, Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Lemaire
authors.affiliation: Faculty of Medicine, Department of Surgery and Cancer, Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors.forename: Foteini-Stefania
authors.initials: FS
authors.lastname: Koumpa
authors.affiliation: Faculty of Medicine, Department of Surgery and Cancer, Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors.forename: James J
authors.initials: JJ
authors.lastname: Sun
authors.affiliation: Faculty of Medicine, Department of Surgery and Cancer, Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Fung
authors.affiliation: Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Jianteng
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yi
authors.affiliation: Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Kaizhi
authors.initials: K
authors.lastname: Lu
authors.affiliation: Faculty of Medicine, Department of Surgery and Cancer, Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, London, UK.
authors.forename: Daqing
authors.initials: D
authors.lastname: Ma
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016572:Cyclosporine / Q000627:therapeutic use; D053938:DNA Fragmentation / Q000187:drug effects; D006084:Graft Rejection / Q000150:complications; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology; D016030:Kidney Transplantation / Q000009:adverse effects*; D007687:Kidney Tubules, Proximal / Q000166:cytology; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009336:Necrosis / Q000473:pathology / Q000517:prevention & control; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications*; D014184:Transplantation, Homologous / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D001549:Benzamides; D017077:Culture Media, Conditioned; D007093:Imidazoles; D007166:Immunosuppressive Agents; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C507699:necrostatin-1; D016572:Cyclosporine; C025160:3-aminobenzamide; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; C586536:RIPK1 protein, rat; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C582791:Ripk3 protein, rat