Impaired mesenteric leukocyte recruitment in experimental portal hypertension in the rat

Abstract

Increased incidence of septic complications in human and experimental portal hypertension has been documented. Because development of an inflammatory response is essential in defense against infectious agents, the aim of this study was to assess leukocyte-endothelial cell interactions in an experimental model of portal hypertension. Intravital microscopy studies showed that under baseline conditions, leukocyte rolling, adhesion, and emigration in mesenteric venules were similar in control, sham operated (SO), and partial portal vein ligated (PPVL) rats. Compared with either control or SO rats, PPVL animals exhibited a markedly reduced recruitment of rolling, adherent, and emigrated leukocytes in response to leukotriene B₄ (LTB₄) stimulation. Similarly, platelet-activating factor (PAF) superfusion, which induced a large increment in leukocyte rolling and adherence in control and SO rats, was without any effect in PPVL animals. Endothelial P-selectin expression in control rats, as measured by the double radio-labeled monoclonal antibody (mAb) technique, was not modified by LTB₄, but significantly increased in response to PAF. PPVL rats had a significantly lower expression of P-selectin after stimulation with PAF. Neutrophils isolated from PPVL rats exhibited increased L-selectin shedding and CD11b up-regulation in response to PAF and LTB₄, compared with neutrophils isolated from SO rats. These observations indicate that portal hypertension is associated with a defective inflammatory response, which is manifested as a decreased recruitment of rolling leukocytes, and subsequently reduced adhesion/emigration. This defect appears to result from a reduced endothelial P-selectin up-regulation and increased L-selectin shedding.