title: Mast cells in a murine lung ischemia-reperfusion model of primary graft dysfunction.
abstract: Primary graft dysfunction (PGD), as characterized by pulmonary infiltrates and high oxygen requirements shortly after reperfusion, is the major cause of early morbidity and mortality after lung transplantation. Donor, recipient and allograft-handling factors are thought to contribute, although new insights regarding pathogenesis are needed to guide approaches to prevention and therapy. Mast cells have been implicated in ischemic tissue injury in other model systems and in allograft rejection, leading to the hypothesis that mast cell degranulation contributes to lung injury following reperfusion injury.We tested this hypothesis in a mouse model of PGD involving reversible disruption of blood flow to one lung. Metrics of injury included albumin permeability, plasma extravasation, lung histopathology, and mast cell degranulation. Responses were assessed in wild-type (Kit+/+) and mast cell-deficient (KitW-sh/W-sh) mice. Because mouse lungs have few mast cells compared with human lungs, we also tested responses in mice with lung mastocytosis generated by injecting bone marrow-derived cultured mast cells (BMCMC).We found that ischemic lung responses of mast cell-deficient KitW-sh/W-sh mice did not differ from those of Kit+/+ mice, even after priming for injury using LPS. Degranulated mast cells were more abundant in ischemic than in non-ischemic BMCMC-injected KitW-sh/W-sh lungs. However, lung injury in BMCMC-injected KitW-sh/W-sh and Kit+/+ mice did not differ in globally mast cell-deficient, uninjected KitW-sh/W-sh mice or in wild-type Kit+/+ mice relatively deficient in lung mast cells.These findings predict that mast cells, although activated in lungs injured by ischemia and reperfusion, are not necessary for the development of PGD.
authors.affiliation: Medical Service, VA Medical Center, San Francisco, CA, USA. john.greenland@ucsf.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Greenland
authors.forename: Xiang
authors.initials: X
authors.lastname: Xu
authors.forename: David M
authors.initials: DM
authors.lastname: Sayah
authors.forename: Feng Chun
authors.initials: FC
authors.lastname: Liu
authors.forename: Kirk D
authors.initials: KD
authors.lastname: Jones
authors.forename: Mark R
authors.initials: MR
authors.lastname: Looney
authors.forename: George H
authors.initials: GH
authors.lastname: Caughey
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology / Q000473:pathology*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D008407:Mast Cells / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055031:Primary Graft Dysfunction / Q000276:immunology / Q000473:pathology*; D015427:Reperfusion Injury / Q000276:immunology / Q000473:pathology