The role of platelet-activating factor in musculocutaneous flap reperfusion injury.
Platelet-activating factor is an extremely potent lipid-inflammatory mediator implicated in the pathophysiologic mechanism of reperfusion injury in a variety of organs. The purpose of this study, employing a porcine latissimus dorsi flap model, was to (1) examine the expression of platelet-activating factor and (2) evaluate the possible benefit and mechanism of action of platelet-activating factor antagonism in musculocutaneous flap reperfusion injury. Experiment 1: In 6 pigs, bilateral flaps underwent 8 hours of arterial ischemia followed by 12 hours of reperfusion. Biopsies were collected sequentially and analyzed immunohistochemically for platelet-activating factor expression. Different processing techniques, however, were unable to detect specific tissue expression of platelet-activating factor. Experiment 2: In 11 pigs, bilateral flaps underwent 8 hours of arterial ischemia followed by 20 hours of reperfusion. A lipophilic platelet-activating factor receptor antagonist (L-659,989) was administered as a single dose to treated flaps by a local intraarterial route prior to reperfusion. This treatment augmented the survival of both muscle (48.3 versus 19.7 percent) and skin (49.8 versus 42.0 percent) components of the flaps in a statistically significant fashion (p = 0.001). Experiment 3: In 3 pigs, a radiolabeled structural analogue of L-659,989 (14C-L-680,573) was administered to flaps in a fashion similar to experiment 2. After 8 hours of ischemia, sequential full-thickness flap biopsies were collected over the initial 6 hours of reperfusion. The radio-labeled platelet-activating factor receptor antagonist was found to be highly concentrated within treated flaps, with gradual decay over the initial 6 hours of reperfusion. Experiment 4: Thirty minutes prior to completion of 8 hours of arterial ischemia, autologous neutrophils labeled with indium-111 were reintroduced into the systemic-circulation of 5 pigs. Prior to reperfusion, treated flaps received L-659,989 as in experiment 2. Over the initial 4 hours of reperfusion, the flaps were imaged in situ by a gamma camera at 3-minute intervals. The platelet-activating factor receptor antagonist was found to significantly attenuate the accumulation of radioactivity within treated flaps.


CONCLUSIONS
Platelet-activating factor expression within musculocutaneous flaps subjected to ischemia and reperfusion was non directly demonstrated in this study. Still, we have shown that (1) the specific platelet-activating factor receptor antagonist L-659,989 is beneficial to the survival of both muscle and skin flap components, (2) a single, prereperfusion local dose of this lipophilic drug remains concentrated within the flap during the early inflammatory phase of reperfusion, and (3) during reperfusion, platelet-activating factor antagonism is able to directly or indirectly diminish the accumulation of acute inflammatory cells in musculocutaneous flaps.
Stotland
M A
MA
Microsurgical Laboratories, Royal Victoria Hospital, Montreal, Quebec, Canada.
Kerrigan
C L
CL
D000818:Animals; D001158:Arteries; D001706:Biopsy; D002250:Carbon Radioisotopes; D005260:Female; D005663:Furans / Q000008:administration & dosage / Q000627:therapeutic use; D015870:Gene Expression; D006085:Graft Survival / Q000187:drug effects; D007150:Immunohistochemistry; D007205:Indium Radioisotopes; D007269:Injections, Intra-Arterial; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology; D007958:Leukocyte Count / Q000187:drug effects; D018482:Muscle, Skeletal / Q000098:blood supply / Q000000981:diagnostic imaging / Q000637:transplantation*; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D010972:Platelet Activating Factor / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D015424:Reperfusion; D015427:Reperfusion Injury / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D016038:Skin Transplantation / Q000000981:diagnostic imaging / Q000473:pathology*; D013524:Surgical Flaps / Q000098:blood supply / Q000473:pathology*; D013552:Swine
D002250:Carbon Radioisotopes; D005663:Furans; D007205:Indium Radioisotopes; D010972:Platelet Activating Factor; D019275:Radiopharmaceuticals; C054893:L 659989