title: Ischemia-mediated aggregation of the actin cytoskeleton is one of the major initial events resulting in ischemia-reperfusion injury.
abstract: Ischemia-reperfusion (IR) injury represents a major clinical challenge, which contributes to morbidity and mortality during surgery. The critical role of natural immunoglobulin M (IgM) and complement in tissue injury has been demonstrated. However, cellular mechanisms that result in the deposition of natural IgM and the activation of complement are still unclear. In this report, using a murine intestinal IR injury model, we demonstrated that the beta-actin protein in the small intestine was cleaved and actin filaments in the columnar epithelial cells were aggregated after a transient disruption during 30 min of ischemia. Ischemia also led to deposition of natural IgM and complement 3 (C3). A low dose of cytochalasin D, a depolymerization reagent of the actin cytoskeleton, attenuated this deposition and also attenuated intestinal tissue injury in a dose-dependent manner. In contrast, high doses of cytochalasin D failed to worsen the injury. These data indicate that ischemia-mediated aggregation of the actin cytoskeleton, rather than its disruption, results directly in the deposition of natural IgM and C3. We conclude that ischemia-mediated aggregation of the actin cytoskeleton leads to the deposition of natural IgM and the activation of complement, as well as tissue injury.
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. tshi@bidmc.harvard.edu
authors.forename: Tong
authors.initials: T
authors.lastname: Shi
authors.forename: Vaishali R
authors.initials: VR
authors.lastname: Moulton
authors.forename: Peter H
authors.initials: PH
authors.lastname: Lapchak
authors.forename: Guo-Min
authors.initials: GM
authors.lastname: Deng
authors.forename: Jurandir J
authors.initials: JJ
authors.lastname: Dalle Lucca
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D003167:Complement Activation; D003176:Complement C3 / Q000378:metabolism; D015933:Complement C3d / Q000378:metabolism; D015638:Cytochalasin D / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D007511:Ischemia / Q000150:complications / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007583:Jejunum / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control
chemical_list: D003176:Complement C3; D007075:Immunoglobulin M; D015638:Cytochalasin D; D015933:Complement C3d