Abstract
Objectives
Clodronate-liposome is used for depleting mononuclear phagocytes associated with ischemia-reperfusion
injury. We hypothesized that administration of clodronate-liposome into the perfusate
during ex vivo lung perfusion could reduce mononuclear phagocytes and attenuate ischemia-reperfusion
injury.
Methods
First, the number of mononuclear phagocytes in flushed grafts (minimum cold ischemic
time, 6-hour cold ischemic time, 15-hour cold ischemic time, and 18-hour cold ischemic
time; n = 6 each) was determined using flow cytometry. Second, grafts (15-hour cold
ischemic time) were allocated to control or clodronate (n = 5 each). In the clodronate
group, clodronate-liposome is administered into the perfusate. After 4 hours of ex vivo
lung perfusion, the number of mononuclear phagocytes in the perfusate and lung tissues
was measured. Third, grafts (15-hour cold ischemic time) were allocated to control
or clodronate (n = 6 each). After 4 hours of ex vivo lung perfusion, the left lungs
were transplanted and reperfused for 2 hours. Lung function was evaluated, and samples
were analyzed.
Results
First, mononuclear phagocytes remain in flushed grafts after prolonged cold ischemia.
Second, the number of mononuclear phagocytes in lung tissues after ex vivo lung perfusion
was significantly reduced in the clodronate group (P = .008). Third, lung compliance and vascular resistance during ex vivo lung perfusion
were significantly improved in the clodronate group (P < .001 for both). Blood oxygenation and pulmonary edema were significantly improved
in the clodronate group after 2 hours of reperfusion (P = .015 and P = .026, respectively). Histological findings showed reduced lung injury in the clodronate
group (P = .013).
Conclusions
Administration of clodronate-liposome into the perfusate during ex vivo lung perfusion
resulted in a significant reduction of mononuclear phagocytes in donor lungs, leading
to attenuation of ischemia-reperfusion injury.
Graphical abstract
Graphical Abstract
Key Words
Abbreviations and Acronyms:
CIT (cold ischemic time), EVLP (ex vivo lung perfusion), IL (interleukin), IRI (ischemia-reperfusion injury), LTx (lung transplantation), MP (mononuclear phagocyte), PGD (primary graft dysfunction)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The Journal of Thoracic and Cardiovascular SurgeryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult lung and heart-lung transplant report-2018; focus theme: multiorgan transplantation.J Heart Lung Transplant. 2018; 37: 1169-1183
- Immunopathogenesis of primary graft dysfunction after lung transplantation.Ann Thorac Surg. 2018; 105: 671-674
- Late primary graft dysfunction after lung transplantation and bronchiolitis obliterans syndrome.Am J Transplant. 2008; 8: 2454-2462
- Ischemia-reperfusion injury in lung transplantation.Cells. 2021; 10: 1333
- Intravascular donor monocytes play a central role in lung transplant ischaemia-reperfusion injury.Thorax. 2018; 73: 350-360
- Mechanical removal of dendritic cell-generating non-classical monocytes via ex vivo lung perfusion.J Heart Lung Transplant. 2014; 33: 864-869
- Crosstalk between nonclassical monocytes and alveolar macrophages mediates transplant ischemia-reperfusion injury through classical monocyte recruitment.JCI Insight. 2021; 6: e147282
- The depletion of donor macrophages reduces ischaemia-reperfusion injury after mouse lung transplantation.Eur J Cardiothorac Surg. 2014; 45: 703-709
- Alveolar macrophage activation is a key initiation signal for acute lung ischemia-reperfusion injury.Am J Physiol Lung Cell Mol Physiol. 2006; 291: L1018-L1026
- The mononuclear phagocyte system of the rat.J Immunol. 2021; 206: 2251-2263
- Macrophage/monocyte depletion by clodronate, but not diphtheria toxin, improves renal ischemia/reperfusion injury in mice.Kidney Int. 2012; 82: 928-933
- Bone marrow-derived Ly6C(-) macrophages promote ischemia-induced chronic kidney disease.Cell Death Dis. 2019; 10: 291
- Donor pulmonary intravascular nonclassical monocytes recruit recipient neutrophils and mediate primary lung allograft dysfunction.Sci Transl Med. 2017; 9: eaal4508
- Normothermic ex vivo lung perfusion in clinical lung transplantation.N Engl J Med. 2011; 364: 1431-1440
- Lung lavage and surfactant replacement during ex vivo lung perfusion for treatment of gastric acid aspiration-induced donor lung injury.J Heart Lung Transplant. 2017; 36: 577-585
- Functional repair of human donor lungs by IL-10 gene therapy.Sci Transl Med. 2009; 1: 4ra9
- Rat immunology from genes to proteins to cells.https://dokument.pub/dl/rat-immunology-from-genes-to-proteins-to-cells-flipbook-pdfDate accessed: March 10, 2022
- Sevoflurane attenuates ischemia-reperfusion injury in a rat lung transplantation model.Ann Thorac Surg. 2017; 103: 1578-1586
- A method for translational rat ex vivo lung perfusion experimentation.Am J Physiol Lung Cell Mol Physiol. 2020; 319: L61-L70
- Impact of triptolide during ex vivo lung perfusion on grafts after transplantation in a rat model.J Thorac Cardiovasc Surg. 2020; ([In press])
- Protective effects of a hydrogen-rich preservation solution in a canine lung transplantation model.Ann Thorac Surg. 2021; 111: 246-252
- Transmission of donor lymphocytes in clinical lung transplantation.Transpl Int. 1994; 7: 414-419
- Evaluation of role of G-CSF in the production, survival, and release of neutrophils from bone marrow into circulation.Blood. 2002; 100: 854-861
- Neutrophil maturation and activation determine anatomic site of clearance from circulation.Am J Physiol Lung Cell Mol Physiol. 2001; 281: L913-L921
- Lymphocyte survival in men treated with x-rays for ankylosing spondylitis.Nature. 1967; 214: 470-473
- Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis.Immunity. 2013; 38: 79-91
- Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans.J Exp Med. 2008; 205: 2139-2149
- A leukocyte filter does not provide further benefit during ex vivo lung perfusion.ASAIO J. 2017; 63: 672-678
- CD11c(+)/CD11b(+) cells are critical for organic dust-elicited murine lung inflammation.Am J Respir Cell Mol Biol. 2012; 47: 652-659
- Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone.Proc Natl Acad Sci U S A. 2014; 111: 1545-1550
- Synovial macrophage depletion with clodronate-containing liposomes in rheumatoid arthritis.Arthritis Rheum. 2000; 43: 1951-1959
- Monocytes are potent facilitators of alveolar neutrophil emigration during lung inflammation: role of the CCL2-CCR2 axis.J Immunol. 2003; 170: 3273-3278
- Spleen-derived classical monocytes mediate lung ischemia-reperfusion injury through IL-1β.J Clin Invest. 2018; 128: 2833-2847
- Emergency granulopoiesis promotes neutrophil-dendritic cell encounters that prevent mouse lung allograft acceptance.Blood. 2011; 118: 6172-6182
- Altered immunogenicity of donor lungs via removal of passenger leukocytes using ex vivo lung perfusion.Am J Transplant. 2016; 16: 33-43
E-References
- A method for translational rat ex vivo lung perfusion experimentation.Am J Physiol Lung Cell Mol Physiol. 2020; 319: L61-L70
- Functional repair of human donor lungs by IL-10 gene therapy.Sci Transl Med. 2009; 1: 4ra9
- Specialized proresolving lipid meditators agonistic to formyl peptide receptor type 2 attenuate ischemia-reperfusion injury in rat lung.Transplantation. 2022; 106: 1159-1169
Article info
Publication history
Published online: October 21, 2022
Accepted:
October 13,
2022
Received in revised form:
September 28,
2022
Received:
July 2,
2022
Footnotes
This work was supported by the Japan Society for the Promotion of Science KAKENHI (19K09302) and SPIRITS 2021 from Kyoto University.
The experimental protocol was approved by the Ethics Committee of the Graduate School of Medicine at Kyoto University (date: April 1, 2018, reference number: Med Kyo 20294).
Identification
Copyright
© 2022 by The American Association for Thoracic Surgery
