cyclic-gmp and Dermatitis--Contact

The understanding of passive transfer of cell mediated-immune responses with transfer factor and other cell free materials has progressed to the point that investigators are seeking the chemical identity of the molecule(s) that are responsible for these effects and are working on their mechanisms of action. In addition, clinical trials are underway that should clarify the potential for use of transfer factor in treatment of infections, neoplastic and autoimmune diseases. This chapter will critically review the past and current data concerning the components of transfer factor and their effects on immunologic and inflammatory reactions. Some of the recently developed animal models will be described and evaluated, and the clinical studies that have provided conclusive data regarding efficacy will be reviewed.

Topics: Animals; Antibody Formation; Antineoplastic Agents; Bacterial Infections; Cattle; Chemotaxis, Leukocyte; Cyclic AMP; Cyclic GMP; Cytotoxicity, Immunologic; Dermatitis, Contact; Dogs; Guinea Pigs; Haplorhini; Humans; Hypersensitivity, Delayed; Immune System Diseases; Immunoglobulins; Lymphatic System; Lymphocyte Activation; Lymphokines; Macrophages; Mice; Mice, Inbred Strains; Mycoses; Neoplasms; Organ Size; Parasitic Diseases; Rosette Formation; Transfer Factor; Virus Diseases

Topics: Animals; Blood Platelets; Blood Vessels; Burns; Chemical Phenomena; Chemistry; Chemotaxis; Collagen; Cyclic AMP; Cyclic GMP; Dermatitis; Dermatitis, Contact; Humans; In Vitro Techniques; Leukocytes; Prostaglandins; Rabbits; Radioimmunoassay; Rats; Skin

1. Nitric oxide (NO) concentrations were measured in dialysate from healthy human skin, in vivo, both at rest and during the inflammatory response to intradermal histamine or bradykinin. Changes in dialysate NO concentration, measured by electrochemical detection, were related to changes in dermal vascular perfusion, measured using scanning laser Doppler imaging. 2. Basal NO concentration in dermal microdialysate was 0.60 +/- 0.14 microM (mean +/- s.e.m.). Following the intradermal injection of histamine, a transient, time-dependent increase in NO concentration was measured in areas of skin incorporating the weal and in others incorporating the flare. The increase in NO concentration was associated with an increase in dialysate cGMP concentration in both the weal and flare areas. 3. Addition of N G-nitro-l-arginine-methyl ester (L-NAME, 5 mM) to the probe perfusate resulted in an inhibition of the histamine-induced increase in NO and cGMP. Moreover, the reduction in dialysate NO concentration was associated with a reduction in dermal vascular flux, both under basal conditions and within the weal and flare response. 4. These results demonstrate, by the use of microdialysis, that vasoactive mediators can be measured in healthy human skin in vivo. They provide direct evidence that endogenous concentration of NO increases during the inflammatory weal and flare response to histamine and that the increase in dermal NO concentration is associated with increases in cGMP concentration and dermal vascular perfusion, thus confirming a role for NO in vasoregulation in human skin.

Topics: Adult; Bradykinin; Cyclic GMP; Dermatitis, Contact; Electrochemistry; Enzyme Inhibitors; Female; Histamine; Humans; Injections, Intradermal; Laser-Doppler Flowmetry; Male; Microdialysis; Middle Aged; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Regional Blood Flow; Skin

The immunomodulating properties of UVA radiation remain controversial. Here, we demonstrate in female inbred Skh:hr-1 mice that single subinflammatory UVA exposures between 1.61 and 580.5 kJ/m(2) are not immunosuppressive. Furthermore, UVA exposures between 16.13 and 580.5 kJ/m(2) provided dose-related immunoprotection against UVB-induced immunosuppression. Higher UVA exposures (870.8-1,161 kJ/m(2)) became inflammatory and immunosuppressive alone, and lost the photoimmunoprotective capacity. We previously reported that UVA photoimmunoprotection depends on the induction of cutaneous heme oxygenase-1, particularly its enzymatic product, carbon monoxide (CO). CO was suggested to activate cutaneous guanylyl cyclase (GC), as the specific GC inhibitor, 1H-(1,2,4)oxadiazolo-(4,3-a)quinoxalin-1-one (ODQ), abrogated CO photoimmunoprotection in the mouse. This study shows that cutaneous cyclic guanosine monophosphate (cGMP) concentration increased only following immunoprotective UVA doses, or immunoprotective topical CO treatment, and cGMP production was inhibited by ODQ. Conversely, cGMP concentration was increased by inhibition of its degradative phosphodiesterase (PDE) with topical sildenafil. The PDE-5 isoform was identified in normal mouse skin. Subsequently, a moderate concentration of sildenafil was shown to simulate the effect of UVA in protecting against photoimmunosuppression by solar-simulated UV radiation or its mediator cis-urocanic acid. Thus, cutaneous cGMP, controlled by its synthesis via CO-activated GC and its degradation by PDE-5, is strongly associated with UVA photoimmunoprotection.

Topics: Animals; Carbon Monoxide; Cyclic GMP; Dermatitis, Contact; Dose-Response Relationship, Radiation; Enzyme Activation; Female; Guanylate Cyclase; Immune Tolerance; Mice; Mice, Inbred Strains; Oxadiazoles; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Quinoxalines; Sildenafil Citrate; Skin; Sulfones; Ultraviolet Rays

Ten nickel-allergic patients and six healthy control subjects participated in a study of the morphology, kinetics and evolution of the cAMP and cGMP concentrations of migrated leukocytes, using an improved skin chamber technique. Also studied was the effect of nickel exposure in the chamber medium during development of an eczematous reaction in the nickel-allergic patients. Nickel exposure had a specific effect on the morphology, from the 24th hour to the end of the 48 h observation period, with a significant increase in the percentages of basophils, eosinophils and lymphocytes and a decrease of neutrophils. A significantly increased leukocyte migration rate (LMR) was observed from the 27th to 39th hour in six of the allergic patients exposed to nickel. There were no specific permanent changes in cAMP and cGMP concentrations during nickel exposure. The control chambers of the allergic patients and healthy controls had identical leukocyte morphology, LMR and leukocyte concentrations of cAMP and cGMP. However, no correlations were found between LMR, cAMP and cGMP in the eczema patients throughout the observation period.

Topics: Adult; Aged; Cell Movement; Chemotaxis, Leukocyte; Cyclic AMP; Cyclic GMP; Dermatitis, Contact; Female; Humans; Hypersensitivity, Delayed; Leukocytes; Male; Middle Aged; Nickel; Skin Tests