Obesity exacerbates sepsis-induced inflammation and microvascular dysfunction in mouse brain.
OBJECTIVE
Obese patients with sepsis have higher morbidity and mortality than lean counterparts, but the mechanisms involved are unknown. The authors examined the inflammatory and thrombogenic responses of the cerebral microvasculature to sepsis induced by cecal ligation and perforation in obese and lean wild-type mice.


METHODS
Leukocyte and platelet adhesion in cerebral microvasculature and behavioral responses were measured in wild-type and obese mice 4 h postperforation. P-selectin expression in different vascular beds was assessed 6 h postperforation. The effects of immunoblockade of P-selectin, ICAM-1, and CD18 on leukocyte and platelet recruitment were evaluated in obese septic animals.


RESULTS
Cerebral venules of obese and wild-type mice assumed a proinflammatory and prothrombogenic phenotype 4 h post-perforation, with greatly exaggerated responses in obese mice compared to the lean counterparts. These enhanced responses were attenuated by blocking P-selectin, CD18, or ICAM-1. Obese mice also exhibited a more profound behavioral deficit after sepsis, which appears to be unrelated to the recruitment of leukocytes and platelets. Cecal ligation and perforation-induced P-selectin expression was greater in obese mice compared with lean counterparts.


CONCLUSIONS
These findings suggest that the increased morbidity to sepsis in obesity may result from exaggerated microvascular inflammatory and thrombogenic responses that include the activation of endothelial cells with subsequent expression of adhesion molecules, such as P-selectin.
Vachharajani
Vidula
V
Department of Critical Care Medicine, Louisiana State University Health Sciences Center, Shreveport 71130-3932, USA.
Russell
Janice M
JM
Scott
Keith L
KL
Conrad
Steven
S
Stokes
Karen Y
KY
Tallam
Lakshmi
L
Hall
John
J
Granger
D Neil
DN
D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000503:physiopathology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000032:analysis; D004730:Endothelium, Vascular / Q000473:pathology; D007249:Inflammation / Q000209:etiology*; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D008820:Mice, Obese; D008833:Microcirculation / Q000503:physiopathology*; D009043:Motor Activity; D009765:Obesity / Q000150:complications*; D019007:P-Selectin / Q000032:analysis; D010973:Platelet Adhesiveness; D018805:Sepsis / Q000150:complications*
D015815:Cell Adhesion Molecules; D019007:P-Selectin