Modulation of cutaneous SP receptors in atopic dermatitis after UVA irradiation.

Atopic dermatitis is a pruritic inflammatory skin disorder, involving immunological and non-immunological factors. Substance P seems to be involved in the pathogenesis of atopic dermatitis. Substance P-containing nerve fibers are increased in the lesional skin of patients with atopic dermatitis and a reduced weal and flare reaction to intradermal injection of substance P has been observed. We investigated the distribution of substance P receptors in the involved skin of patients before and after single or repetitive UVA irradiations. Our results indicate that substance P receptors of the NK-1 subtype are expressed on blood vessels and on epidermal keratinocytes of involved skin of patients with atopic dermatitis. UVA irradiations did not modify the epidermal distribution of substance P receptors but decreased their expression intensity on blood vessels. UVA irradiations seem to decrease skin inflammation through the modulation of NK-1 receptor expression on endothelial cells.

Binding and in vitro modulation of human epidermal Langerhans cell functions by substance P.

Substance P (SP) is distributed in both the central and peripheral nervous system. It has various effects on immunocompetent cells, such as macrophages and lymphocytes. The aim of our study was to search for the presence of SP receptors (SP-R) on human cutaneous Langerhans cells (LC), and to determine the effects of SP on LC immunological functions in a model of mixed epidermal cell-lymphocyte reaction (MELR). Radioligand binding studies showed that LC-enriched epidermal cell suspensions reversibly bound SP, and that the specific binding increased with the percentage of LC. Functional assays showed that SP had no effect when added at concentrations from 10(-6) M to 10(-12) M to the MELR. The addition of SP at concentrations of 10(-4) M and 10(-5) M was able to inhibit the allogeneic T-cell response (98.3 +/- 1.8% and 92.8 +/- 8.9% inhibition, respectively) without modifying the cell viability. This inhibition was through an effect of SP on both T-cell and LC function. We conclude that SP has receptors on LC and may inhibit antigen presentation.

Substance P and keratinocyte activation markers: an in vitro approach.

Substance P (SP) released by cutaneous C fibres is involved in the physiopathology of cutaneous lesions. As normal human keratinocytes have been reported to express SP receptors, we studied the effects of SP on keratinocyte activation markers such as ICAM-1 induction and cytokine production. Human keratinocytes derived from skin obtained during plastic surgery were cultured in defined medium (MCDB 153) and were stimulated by SP. Flow cytometry analysis showed that SP (10(-7) and 10(-5) M) as well as the specific NK1 agonist Sar9Met(O2)11SP (Sar Met) induced a slight but significant expression of ICAM-1 at the cell surface during treatment periods of 24 h and 48 h. SP (10(-5) M) also induced a significant but transient increase in the production of IL-1alpha, IL-1beta, IL-1 receptor antagonist and IL-8 which was detectable by ELISA techniques 6 h after stimulation. This elevation returned to constitutive levels 24 or 48 h postinduction. TNFalpha secretion was detected in stimulated cells only after 48 h. These results suggest that SP can activate keratinocytes and support its role in the local inflammatory reaction.

In vitro and in vivo biological activities of SR140333, a novel potent non-peptide tachykinin NK1 receptor antagonist.

(S)1-(2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)pip eridin-3- yl]ethyl)-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride (SR140333) is a new non-peptide antagonist of tachykinin NK1 receptors. SR140333 potently, selectively and competitively inhibited substance P binding to NK1 receptors from various animal species, including humans. In vitro, it was a potent antagonist in functional assays for NK1 receptors such as [Sar9,Met(O2)11]substance P-induced endothelium-dependent relaxation of rabbit pulmonary artery and contraction of guinea-pig ileum. Up to 1 microM, it had no effect in bioassays for NK2 ([beta Ala8]neurokinin A-induced contraction of endothelium-deprived rabbit pulmonary artery) and NK3 ([MePhe7]neurokinin B-induced contraction of rat portal vein) receptors. The antagonism exerted by SR140333 toward NK1 receptors was apparently non-competitive, with pD2' values (antagonism potency evaluated by the negative logarithm of the molar concentration of antagonist that produces a 50% reduction of the maximal response to the agonist) between 9.65 and 10.16 in the different assays. SR140333 also blocked in vitro [Sar9,Met(O2)11]substance P-induced release of acetylcholine from rat striatum. In vivo, SR140333 exerted highly potent antagonism toward [Sar9,Met(O2)11]substance P-induced hypotension in dogs (ED50 = 3 micrograms/kg i.v.), bronchoconstriction in guinea-pig (ED50 = 42 micrograms/kg i.v.) and plasma extravasation in rats (ED50 = 7 micrograms/kg i.v.). Finally, it also blocked the activation of rat thalamic neurons after nociceptive stimulation (ED50 = 0.2 micrograms/kg i.v.).

Effect of substance P and Sar9Met(O2)11-substance P on cutaneous capillary permeability in guinea pig skin.

The purpose of this study was to assess the effect of several drugs on the increase in cutaneous capillary permeability induced by intradermal injection of substance P (SP) and Sar9Met(O2)11-SP in guinea pig skin. On the one hand, the increase in cutaneous capillary permeability was partly reduced by spantide, promethazine, atropine or SR 40037, an inhibitor of the angiotensin-converting enzyme. On the other hand, norepinephrine and B3824, a B2-antagonist of bradykinin, showed an enhancing effect. Our results suggest that the effect of SP and Sar9Met(O2)11-SP in guinea pigs is partly mediated by histamine and acetylcholine, and that there is a relationship between tachykinins and bradykinin.

Effect of Endotelon (procyanidolic oligomers) on experimental acute lymphedema of the rat hindlimb.

Endotelon (Procyanidolic Oligomers, Sanofi-Labaz Laboratories) are recognized "angioprotectors" for human venous insufficiency. Using an operative experimental model of lymphedema, we sought pharmacological evidence for potential lymphagogue activity of Endotelon. After surgical interruption of hindlimb lymphatics, rats developed for 7 days, peripheral edema that represented a mean 24% increase in volume compared to the nonoperated hindlimb (control). In this experimental counterpart of acute lymphedema, Endotelon (400mg/kg/day p.o.) administered "prophylactically" (i.e., before, during, and 7 days after development of lymphedema) decreased rat hindlimb lymphedema by approximately 4.7%. When administered just before lymphedema became established (i.e., curatively), Endotelon and Coumarin (another "angioprotector") failed to affect hindlimb edema. These results suggest that Endotelon may reduce or prevent postoperative acute edema.