PPAR gamma activation protects the brain against microvascular dysfunction in sepsis.
Sepsis is a severe disorder characterized by systemic inflammatory responses in the presence of an infection and may progress to multiple organ dysfunction and death. Alterations in cerebral microcirculation fulfill a crucial role in the pathogenesis of severe sepsis, and include a decrease in capillary density and disturbances in leukocyte movement along capillaries. Nevertheless, the mechanisms involved in sepsis-associated cerebral microcirculatory alterations have so far not been defined. We investigated the effect of the peroxisome proliferator-activated receptor gamma (PPARγ) selective agonist rosiglitazone on leukocyte/endothelial cell interaction and functional capillary density in the brain in the cecal ligation and puncture (CLP) model of sepsis. Anti-inflammatory effects of rosiglitazone on the cerebral microcirculation were marked. Functional capillary density increased and leukocyte rolling and adhesion were decreased in animals submitted to CLP and treated with rosiglitazone. Our data provide evidence for involvement of PPARγ activation in leukocyte-endothelium interactions and alterations in capillary density. Improved cerebral perfusion in animals treated with rosiglitazone, suggests that PPARγ activation is protective against cerebral microvascular dysfunction in sepsis.
Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
C V
CV
Araújo
V
V
Estato
E
E
Tibiriçá
P T
PT
Bozza
H C
HC
Castro-Faria-Neto
A R
AR
Silva
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001921:Brain / Q000098:blood supply*; D002432:Cecum / Q000601:surgery; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002561:Cerebrovascular Disorders / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D019610:Cytoprotection; D004195:Disease Models, Animal; D036904:Leukocyte Rolling / Q000187:drug effects; D008026:Ligation; D008297:Male; D051379:Mice; D008833:Microcirculation / Q000187:drug effects*; D055806:Microvessels / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011677:Punctures; D000077154:Rosiglitazone; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D045162:Thiazolidinediones / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone