Regulation of leukocyte adhesion to heart by the tripeptides feG and feG(NH₂)

Abstract

The role of the D-isomeric form of the salivary gland tripeptide FEG (feG) and its carboxyl-amidated derivative, feG(NH2), in regulating leukocyte adherence to nonfixed atrial slices from Sprague-Dawley rats was examined under static conditions. Optimal binding of the leukocytes was seen if the leukocytes were treated with platelet activating factor (PAF; 10(-9)M). The increased adherence of PAF-treated peripheral blood leukocytes was totally inhibited by both feG and feG(NH2) (10-9M), as well as by antibodies against CD18 and CD49d. In contrast, the binding of peritoneal leukocytes was blocked only by CD49d antibody. Circulating leukocytes obtained from lipopolysaccharide (LPS) treated (2 mg/kg ip) rats did not bind to atrial slices obtained from normal hearts, but readily bound to atrial slices obtained from LPS-treated rats. This leukocyte binding was inhibited by in vivo feG treatment (100 microg/kg ip, 24 h before harvest) or by treating the isolated cells with feG (10(-9)M). The amidated peptide feG(NH2) reduced neutrophil accumulation in the atrium elicited by ip injection of LPS, whereas feG was ineffective. The reduction in neutrophil infiltration into the myocardium by feG(NH2) and the prevention of leukocyte interaction with myocytes seen with both feG and feG(NH2) probably results in hindered leukocyte migration in the inflamed heart, resulting in less tissue damage. The inhibition by these tripeptides on neutrophil adhesion to myocytes suggests that salivary glands hormones regulate the severity of cardiac inflammation.

Frontline: Inhibition of allergen‐induced pulmonary inflammation by the tripeptide feG: a mimetic of a neuro‐endocrine pathway

“…A recent study showed that feG blocks CD49d-mediated leukocyte adhesion in the heart [21]. Our data suggest that, in contrast to PMN, Eo and MU rely on ICAM-1 for recruitment to the airways.…”

The tripeptide analog feG ameliorates severity of acute pancreatitis in a caerulein mouse model

“…The beneficial effects of feG in reducing inflammation in other systems have been previously demonstrated for allergic inflammation (6) and endotoxin-provoked perturbation of intestinal motility and inflammation (23). These effects are probably mediated by feG's ability to regulate calcium and phospholipid-dependent protein kinase C (known to regulate the release of superoxide) in circulating neutrophils (6) and neutrophil adhesion (21), two neutrophil functions that are increased in AP patients (1,37).…”

“…A single dose of either tripeptide (100 g/kg ip) was administered at 0 h or at 3 h post-AP onset. This dose of feG was commonly used in previous studies (6,21,23).…”

“…feG has also been shown to restrict neutrophil movement and chemotaxis of human and rat neutrophils (24) and to reduce the production of superoxide production by activated neutrophils (25). The ability of feG to prevent PAF-induced upregulation of CD 11B and CD 16B (low-affinity IgG receptor), which are known to be involved in the activation of leukocytes and chemotaxis, has also been demonstrated (21). These properties of feG led us to hypothesize that this peptide may be beneficial in the treatment of AP.…”

A New Conformationally Restricted Mimetic of Dipeptide EG – Synthesis of an Analogue of FEG

“…[9] On the other hand, feG has anti-inflammatory [ properties in allergic airways inflammation in BrownNorway rats, [10] reduces endotoxin-provoked perturbation of intestinal motility and inflammation [11,12] and regulates leukocyte adhesion to the heart. [13,14] Thus, at first we devised that compound 2, having a (3R,4S) configuration, which was recently synthesized in our laboratory, [15] could be an attractive starting material for the preparation of a conformationally restricted dipeptide EG (Glu-Gly) suitable for the insertion in FEG, in order to change or improve its biological activity. In fact it is well known that insertion of a γ-lactam moiety into a peptide chain leading to severe conformational constrictions can give rise to significant changes in both the potency and biological activity.…”