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Fibrinogen modulates leukocyte recruitment in vivo during the acute inflammatory response
Publication . Almeida, V. Vitorino de; Herdade, A. Silva; Calado, A.; Rosário, H. S.; Saldanha, Carlota
Besides playing an important role in blood hemostases, fibrinogen also regulates leukocyte function in inflammation. Our previous in vitro studies showed that the adhesive behaviour of the neutrophil is modulated by soluble fibrinogen when present at a physiological concentration. This led us to propose that this plasma glycoprotein might further influence leukocyte recruitment in vivo and thus contribute to the inflammatory response. To address this in vivo, leukocyte recruitment was here investigated under acute inflammatory conditions in the absence of soluble fibrinogen in the blood circulation. For such, intravital microscopy on mesentery post-capillary venules was performed on homozygous fibrinogen α chain-deficient mice ((α-/-) mice). Acute inflammatory states were induced by perfusing platelet activating factor (PAF) over the exposed tissue. As control animals, two groups of mice expressing soluble fibrinogen in circulation were used, namely, C57BL/6 wild type animals and heterozygous fibrinogen α chain-deficient mice ((α+/-) mice). Under acute inflammatory conditions, an abnormal pattern of recruitment was observed for leukocytes in homozygous (α-/-) mice in comparison to both control groups. In fact, the former exhibited a significantly decreased number of rolling leukocytes that nevertheless, migrated with increased rolling velocities when compared to leukocytes from control animals. Consistently, homozygous mice further displayed a diminished number of adherent leukocytes than the other groups. Altogether our observations led us to conclude that leukocyte recruitment in homozygous (α-/-) mice is compromised what strongly suggests a role for soluble fibrinogen in leukocyte recruitment in inflammation.
An in vitro study on the modulation of the neutrophil adhesive behavior by soluble fibrinogen
Publication . Almeida, V. Vitorino de; Calado, A.; Herdade, A. S. Silva; Rosário, H. S.; Saldanha, Carlota
Fibrinogen constitutes an important plasma glycoprotein involved in hemostasis and in inflammation. Previously, we have shown that at physiological concentrations, soluble fibrinogen is able to modulate the pattern of neutrophil activation. This led us to propose that under these conditions, fibrinogen could as well interfere with the adhesive behaviour of circulating neutrophils which is of utmost importance in their recruitment to the vascular wall during inflammatory processes. To address our working hypothesis, in vitro adhesion assays were here performed in a flow chamber by using primary cultures of human umbilical vein endothelial cells (HUVEC) and neutrophils isolated from peripheral venous blood of healthy human donors. In the presence of a physiological concentration of soluble fibrinogen (300 mg/dL), we observed that despite the number of neutrophils rolling on an activated endothelium was not affected, their rolling velocity was increased in comparison to that of non-activated neutrophils. Consequently as expected, the number of fibrinogen-treated neutrophils adhering to activated HUVEC monolayers was significantly diminished. Overall, we have here demonstrated that at least in vitro, soluble fibrinogen under physiological concentrations is able to modulate the interaction of neutrophils with the vascular endothelium. In vivo studies will enable us in the future to study the physiological relevance of these findings and further to understand the mechanisms underlying this function.
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Fundação para a Ciência e a Tecnologia
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SFRH
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SFRH/BD/30145/2006