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 B 4 (LTB 4 ) 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 LTB 4 , 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 LTB 4 , 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. (HEPATOLOGY 1999;30:445-453.)Patients with liver disease and portal hypertension are predisposed to develop spontaneous infections by enteric bacteria. These infective sequelae are responsible for serious and often fatal complications; however, the mechanism(s) underlying this high incidence of infection-related complications is not completely understood. One potential contributing factor is impaired neutrophil function. Neutrophilic superoxide anion production and the generation of both platelet-activating factor (PAF) and leukotriene B 4 (LTB 4 ) are reduced in alcohol-related 1 and non-alcohol-related cirrhosis. 2 In addition, demonstration of bacterial translocation to mesenteric ganglia in animal models of portal hypertension without liver disease 3,4 and the appearance of a unique septic complication such as spontaneous bacterial peritonitis in human cirrhosis with portal hypertension 5 suggest that there is a deficient host immune response in the mesenteric circulation directly related to portal hypertension.The adhesion of leukocytes to vascular endothelial cells is a critical early step in the development of an inflammatory response. This process is essential in isolating and eliminating infectious agents and in tissue repair. The inflammatory response involves sequential leukocyte...

Decreased leukocyte recruitment in the mesenteric microcirculation of rats with cirrhosis is partially restored by treatment with peginterferon: An in vivo study

“…A deficiency in one of the three steps of leukocyte recruitment can result in an inability of neutrophils to infiltrate in a region of inflammation. Impaired leukocyte recruitment has been reported previously in mesenteric venules of portal hypertensive rats [20,21] and in a model of acute cholestasis [22]. These findings support further the hypothesis of an altered anti-bacterial response in the splanchnic circulation.…”

“…However, other adhesion molecules, not studied in this experiment, could contribute to the deficient leukocyte recruitment in cirrhosis. Previously, it was already shown that there was a downregulation of L-selectin in portal hypertensive rats [20,21]. The reason why cirrhosis is associated with a decrease in expression of adhesion molecules on mesenteric venules is obscure.…”

“…Previous in vitro studies in an animal model of extrahepatic portal hypertension suggest that a decreased expression of selectins may contribute to the impaired leukocyte recruitment in this model [20,21]. Interferona is the only cytokine reported to increase cell-surface density of selectins [23][24][25].…”

The Molecular Basis of Susceptibility to Infection in Liver Cirrhosis

“…Portal hypertensive rats exhibit markedly reduced leukocyte rolling, adhesion, and migration in mesenteric venules in response to the lipid proinflammatory mediators, platelet-activating factor and leukotriene B4. This observation indicates that portal hypertension could be associated with a defective inflammatory response [27]. In an elegant experimental study, Pérez-del-Pulgar et al [28] demonstrated that partial portal vein ligation of rats changed the number of peripheral leukocytes from 7.0 10 6 to 3.6 10 6 cells/mL (P = 0.05).…”

Markers of bacterial translocation in end-stage liver disease

“…Patients with cirrhosis exhibit systemic immune alterations that may promote the development of infections and BT. Advanced cirrhosis is associated with decrease in the cellular and humoral components of immune response, decreased activity of the reticuloendothelial system, decreased phagocytic capacity of Kupffer cells, as well as restricted recruitment of leucocytes in response to inflammatory stimuli due to portal hypertension-associated splanchnic hyperaemia [16][17][18] . The inflammatory response induced by BT, with the synthesis of cytokines, particularly tumor necrosis factor-alpha (TNF-α), interleukins and nitric oxide (NO) also increases intestinal barrier permeability, which, in turn, favours BT, thus creating a feedback in which BT promotes its own causative mechanisms [5] .…”