icatibant and Dermatitis

The aim of the present study was to examine the contribution of the two kinin receptors B1 and B2 to the increased blood flow observed in response to bradykinin (BK) in a blister model under different injury conditions.. Young male Sprague-Dawley rats weighing 250-350 g were used.. A vacuum-induced blister was raised in the rat hind paw and blood flow measured in the superfused blister base under four different conditions including, early phase acute injury; late phase acute injury; recurrent injury and early phase acute injury in the setting of chronic nerve damage. BK (10 microM) was superfused alone, or in the presence of the B1 antagonist DesArg9Leu8BK (DALBK), (10 nM) and/or the B2 antagonist [D-Arg,Hyp3,Thi5 D-Tic7,Oic8] Bradykinin (HOE 140) (10 nM).. HOE 140 significantly inhibited the BK response in all models. Significant inhibition of BK-induced vasodilatation by DALBK was only observed in the late phase acute and recurrent injury models.. The results suggest that the involvement of the inducible B1 receptor in skin inflammation site is related to the site, duration and recurrence of the injury condition.

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Dermatitis; Male; Microcirculation; Nitroprusside; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin; Regional Blood Flow; Skin

1. Scald injury in Sv129+C57BL/6 mice induced a temperature and time dependent oedema formation as calculated by the extravascular accumulation of [(125)I]-albumin. Oedema formation was suppressed in NK(1) knockout mice compared to wildtypes at 10 (P<0.01) and 30 min (P<0.001). However, at 60 min a similar degree of extravasation was observed in the two groups. 2. Kinin B(1) (des-Arg(10) Hoe 140; 1 micromol kg(-1)) and B(2) (Hoe 140; 100 nmol kg(-1)) antagonists caused an inhibition of oedema in wildtype mice at 10 and 30 min (P<0.001), but not at 60 min or at 30 min in NK(1) receptor knockout mice. 3. The inhibition of thermic oedema by des-Arg(10) Hoe 140 was reversed by des-Arg(9) bradykinin (0.1 micromol kg(-1); P<0.01) and also observed with a second B(1) receptor antagonist (des-Arg(9) Leu(8) bradykinin; 3 micromol kg(-1); P<0.01). Furthermore des-Arg(10) Hoe 140 had no effect on capsaicin (200 microg ear(-1)) ear oedema, but this was significantly reduced with Hoe 140 (P<0.05). 4. Scalding induced a large neutrophil accumulation at 4 h, as assessed by myeloperoxidase assay (P<0.001). This was not suppressed by NK(1) receptor deletion or kinin antagonists. 5. These results confirm an essential role for the NK(1) receptor in mediating the early, but not the delayed phase of oedema formation or neutrophil accumulation in response to scalding. The results also demonstrate a pivotal link between the kinins and sensory nerves in the microvascular response to burn injury, and for the first time show a rapid involvement of the B(1) receptor in murine skin.

Topics: Administration, Topical; Animals; Bradykinin; Bradykinin Receptor Antagonists; Burns; Capsaicin; Cell Movement; Dermatitis; Edema; Hot Temperature; Injections, Intravenous; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Piperidines; Quinuclidines; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin; Receptors, Neurokinin-1; Tachykinins; Time Factors

Penetration of skin by cercariae of Schistosoma mansoni is associated with a local inflammatory response characterised by leukocyte accumulation and tissue swelling. The significance of the inflammation and its relevance to infection of the host is unknown. In this study, we have investigated the mechanisms of the local inflammatory response induced by injecting extracts of Schistosoma mansoni cercariae into guinea pig skin. Intradermal injection of cercarial homogenate or cercarial transformation fluid induced a dose-dependent increase in local edema formation and accumulation of intravenously injected 111In-labeled eosinophils and neutrophils. The responses were rapid in onset and independent of new protein synthesis. The capacity of extracts to induce edema formation and leukocyte accumulation correlated significantly with their proteolytic activity. In addition, extract-induced inflammation was reduced by co-injection with Trasylol, soybean trypsin inhibitor, PMSF, or heparin. A combination of PMSF and heparin virtually abolished extract-induced inflammation. The known inhibitory effect of Trasylol on kallikrein prompted an investigation into the role of kinins in inducing local edema formation. The bradykinin antagonist HOE 140 substantially reduced extract-induced edema whereas bradykinin itself was weak at inducing leukocyte accumulation. The cyclooxygenase inhibitor ibuprofen, the platelet-activating factor antagonist WEB 2086, and the 5-lipoxygenase inhibitor PF5901 had no effect on edema formation. In contrast, extract-induced eosinophil accumulation was reduced by WEB 2086 and PF5901, suggesting that endogenous PAF and leukotriene B4 were involved in recruiting these cells to inflammatory sites. Thus, cercarial proteases induce a local inflammatory response in guinea pig skin that can be attributed, in part, to known mediators of inflammation. It remains to be established whether the response is protective for the host or whether it is beneficial for the parasite. Further understanding of the underlying mechanisms may provide a target for the pharmacologic control of infection in schistosomiasis.

Topics: Animals; Bradykinin; Dermatitis; Edema; Eosinophils; Female; Guinea Pigs; Larva; Platelet Activating Factor; Protease Inhibitors; Schistosoma mansoni