title: Functional repair of human donor lungs by IL-10 gene therapy.
abstract: More than 80% of potential donor lungs are injured during brain death of the donor and from complications experienced in the intensive care unit, and therefore cannot be used for transplantation. These lungs show inflammation and disruption of the alveolar-capillary barrier, leading to poor gas exchange. Although the number of patients in need of lung transplantation is increasing, the number of donors is static. We investigated the potential to use gene therapy with an adenoviral vector encoding human interleukin-10 (AdhIL-10) to repair injured donor lungs ex vivo before transplantation. IL-10 is an anti-inflammatory cytokine that mainly exerts its suppressive functions by the inactivation of antigen-presenting cells with consequent inhibition of proinflammatory cytokine secretion. In pigs, AdhIL-10-treated lungs exhibited attenuated inflammation and improved function after transplantation. Lungs from 10 human multiorgan donors that had suffered brain death were determined to be clinically unsuitable for transplantation. They were then maintained for 12 hours at body temperature in an ex vivo lung perfusion system with or without intra-airway delivery of AdhIL-10 gene therapy. AdhIL-10-treated lungs showed significant improvement in function (arterial oxygen pressure and pulmonary vascular resistance) when compared to controls, a favorable shift from proinflammatory to anti-inflammatory cytokine expression, and recovery of alveolar-blood barrier integrity. Thus, treatment of injured human donor lungs with the cytokine IL-10 can improve lung function, potentially rendering injured lungs suitable for transplantation into patients.
authors.affiliation: Latner Thoracic Surgery Research Laboratories, McEwen Centre for Regenerative Medicine, Toronto General Research Institute, University Health Network, 101 College Street, Toronto, Ontario, Canada.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Cypel
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Matt
authors.initials: M
authors.lastname: Rubacha
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Yeung
authors.forename: Shin
authors.initials: S
authors.lastname: Hirayama
authors.forename: Masaki
authors.initials: M
authors.lastname: Anraku
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sato
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Medin
authors.forename: Beverly L
authors.initials: BL
authors.lastname: Davidson
authors.forename: Marc
authors.initials: M
authors.lastname: de Perrot
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Waddell
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Slutsky
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
mesh_terms: D000818:Animals; D015316:Genetic Therapy; D006801:Humans; D007249:Inflammation; D016753:Interleukin-10 / Q000235:genetics*; D008168:Lung / Q000503:physiopathology*; D016040:Lung Transplantation; D023421:Models, Animal; D013552:Swine; D019108:Tight Junctions; D009927:Tissue and Organ Procurement
chemical_list: D016753:Interleukin-10