However, the liver was different from skin, gut, and brain in tha

However, the liver was different from skin, gut, and brain in that integrins were often not involved and other

adhesion molecules were implicated. Indeed, anti-adhesion was demonstrated for VAP-1 in hepatic sinusoids in a model of hepatitis.[9] Adhesion molecules such as CD44/hyaluronic acid and Siglec-10/VAP-1 have also been implicated in interactions between leukocytes Selleck Kinase Inhibitor Library and endothelium in liver.[33-36] McDonald et al.[33] have shown that CD44 was responsible for reversible neutrophil adhesion to hyaluronic acid (HA) within liver sinusoids in vivo and the disruption of CD44-HA interactions reduced liver injury in response to bacterial lipopolysaccharides. The CD44-dependent adhesion was reversible and not replaced by other adhesive mechanisms or physical trapping, suggesting a key role for molecular adhesion in liver sinusoids.[33] Moreover, Siglec-10, a member of the family of sialic acid-binding Ig-like lectins (Siglecs), was first identified as

a leukocyte surface ligand and a substrate for VAP-1, which is important GPCR Compound Library datasheet in lymphocyte recruitment in liver.[35, 36] These findings are crucial for the development of new antiinflammatory therapy rather than traditional anti-integrin therapy. Herein, we provide further evidence that VAP-1 is a good target to ameliorate the autoimmune-induced hepatic injury by selectively regulating recruitment of CD4 Th2 but not Th1 lymphocytes. We analyzed the effect of anti-VAP-1 therapy for lymphocyte recruitment to the liver using a well-established Con A-induced hepatitis model.[4, 5, 7, 8] Con A treatment caused acute liver injury as assessed by increased serum transaminase level as early as 4 hours (data not shown) after intravenous administration and continued until 24 hours. Con A treatment is not specific for liver and causes injury elsewhere, including lung, where many neutrophils are recruited but anti-VAP-1 was ineffective (Supporting Fig. 4), indicating that VAP-1 does not affect neutrophil recruitment MCE公司 in lung or as previously reported

in liver.[9] VAP-1 functions as both an adhesion molecule and a generator of oxidants. Our data demonstrate that blocking a specific adhesion molecule holds some therapeutic promise, while inhibitors of the mono-oxidase activity showed marginal (25%) benefit. However, inhibiting both functions of VAP-1 reduced Con A-induced inflammation to the greatest extent, suggesting that targeting both functions of VAP-1 could have optimal benefit. The attenuated liver injury in anti-VAP-1-treated mice and VAP-1-deficient mice correlated with reduced CD4+ T cell recruitment and reduced numbers of IL-4 producing T cells. This is in line with the essential role of CD4+ T cells in induction of liver injury derived by Con A but our data point toward a Th2 subset.

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