Sensory nerve-mediated immediate nasal responses to inspired acrolein. (17/473)

To investigate the role of sensory C-fiber stimulation and tachykinin release in the immediate nasal responses to the sensory irritant acrolein, the upper respiratory tract of the urethan-anesthetized male Fischer 344 rat was isolated via insertion of an endotracheal tube, and acrolein-laden air [2, 5, 10, or 20 parts/million (ppm)] was drawn continuously through that site at a flow rate of 100 ml/min for 50 min. Uptake of the inert vapor acetone was measured throughout the exposure to assess nasal vascular function. Plasma protein extravasation into nasal tissue and nasal lavage fluid was also assessed via injection of Evans blue dye. At 20 ppm, acrolein induced 1) a twofold increase in acetone uptake, indicative of vasodilation, followed by a progressive decline toward basal levels and 2) increased plasma protein extravasation, as indicated by dye leakage into nasal tissue and nasal lavage. These responses were inhibited by capsaicin pretreatment and the neurokinin type 1 antagonist N-acetyltrifluoromethyl tryptophan benzyl ester and were potentiated by the peptidase inhibitors phosphoramidon and captopril, suggesting that these responses were mediated by tachykinin. At lower exposure concentrations, acrolein was without effect on dye leakage but produced vasodilation, as indicated by increased acetone uptake. The responses at the lower concentrations were inhibited by capsaicin pretreatment, implicating nasal sensory C-fiber involvement, but were not influenced by N-acetyltrifluoromethyl tryptophan benzyl ester, phosphoramidon, or captopril, suggesting the involvement of a mediator other than the tachykinins substance P and neurokinin A.  (+info)

Upper airway reactivity and upper respiratory tract infection: effect of nebulized lidocaine. (18/473)

Patients presenting for elective anaesthesia and surgery may be suffering with, or recovering from, a recent upper respiratory tract infection. Airway reflexes are heightened and these individuals may be more likely to suffer airway complications on administration of general anaesthesia. We have examined the effect of nebulized lidocaine on upper airway reflexes in such subjects. Using dilute ammonia as a chemical stimulus to the upper airway, we measured upper airway reactivity in 15 volunteers (aged 22-43 yr) with symptoms of an upper respiratory tract infection for 4 days or less. The threshold concentration of ammonia producing a brief reduction in inspiratory flow was determined. Measurements were made before and after administration of a nebulized solution of 4% lidocaine 4 ml or saline. After a 2-h interval the procedure was repeated with the alternative solution. The order of administration was randomized. The observer was blind to the solution given. Ammonia threshold was found to increase in subjects after nebulized lidocaine, from a median value of 327 (range 76-878) ppm to 878 (251-1620) ppm (P = 0.0007, Wilcoxon); there was no significant change after nebulized saline. After a convalescence period of at least 4 weeks, with no return of symptoms in the preceding 2 weeks, ammonia threshold was reassessed. It was found to be increased in all 15 subjects. Comparison of the five different times of measurement showed a highly significant difference (P < 0.001, Friedman). Subsequent analysis showed significant differences (P < 0.05, Wilcoxon) between convalescent ammonia threshold and both baseline and post-saline nebulizer values. There was no significant difference between convalescent and post-lidocaine ammonia threshold. We conclude that in adult subjects, nebulized lidocaine attenuated the heightened airway reflex sensitivity associated with symptoms and signs of upper respiratory tract infection.  (+info)

Towards subunit-specific proteasome inhibitors: synthesis and evaluation of peptide alpha',beta'-epoxyketones. (19/473)

BACKGROUND: The proteasome is a large multicatalytic protease complex (700 kDa) involved in a number of highly regulated processes. It has three major catalytic activities: a chymotrypsin-like activity, a trypsin-like activity and a post-glutamyl peptide hydrolyzing (PGPH) activity. To be useful as molecular probes, which could help dissect the cellular functions of the proteasome, inhibitors should be specific for the proteasome, active in vivo and selectively block only one of the three catalytic activities. To date, few inhibitors fulfill these requirements so we set out to make novel proteasome inhibitors that incorporate these characteristics. RESULTS: A panel of amino-terminally acetylated peptide alpha',beta'-epoxyketones with leucine in P1 and various aliphatic or aromatic amino acids in P2-P4 were prepared and evaluated. Most compounds selectively inhibited the chymotrypsin-like activity, while only weakly inhibiting the trypsin-like and PGPH activities. After optimization, one inhibitor, Ac-hFLFL-epoxide, was found to be more potent and selective for the inhibition of the chymotrypsin-like activity than several previously described inhibitors. This inhibitor also exhibited strong in vivo anti-inflammatory activity. CONCLUSIONS: Optimization of amino-terminally acetylated peptide alpha',beta'-epoxyketones furnished a potent proteasome inhibitor, Ac-hFLFL-epoxide, that has an excellent selectivity for the chymotrypsin-like activity. The inhibitor also proved to be a potent antiproliferative and anti-inflammatory agent. The strong in vivo and in vitro activities suggest that this class of proteasome inhibitors could be both molecular probes and therapeutic agents.  (+info)

Prophylactic contraceptives for HIV/AIDS. (20/473)

The current pandemic of sexually transmitted human immunodeficiency virus (HIV) infection--the causative agent of acquired immunodeficiency syndrome (AIDS), has created an urgent need for a new type of contraceptive: one that is both a spermicide and a microbicide. Because most women at risk for HIV infection are of reproductive age (15-44 years), effective use of dual-function contraceptives is important to prevent HIV transmission and unintended pregnancies. In the absence of an effective prophylactic anti-HIV therapy or vaccine, new emphasis has been placed on the development of intravaginal microbicidal agents capable of reducing the transmission of HIV. Topical microbicidal spermicides would ideally provide a female-controlled method of self-protection against HIV as well as preventing pregnancy. However, several microbicides that are undergoing preclinical and human clinical trials contain detergent-type ingredients. The detergent-type spermicide, nonoxynol-9, the only recommended microbicide for protection against sexual transmission of HIV has been shown to cause lesions in vaginal and cervical epithelia leaving women more vulnerable to HIV infection. Therefore, a major challenge in microbicide research has been to design mechanism-based microbicides that are highly effective against pregnancy and HIV transmission while lacking detergent-type effects on epithelial cells and normal vaginal flora. We present an overview of current microbicide research and report on the identification and preclinical development of novel non-detergent spermicidal nucleoside and non-nucleoside inhibitors aimed at decreasing pregnancy and preventing sexual transmission of HIV.  (+info)

Studies of delayed systemic effects of ultraviolet B radiation (UVR) on the induction of contact hypersensitivity, 2. Evidence that interleukin-10 from UVR-treated epidermis is the critical mediator. (21/473)

Acute, low-dose ultraviolet B radiation (UVR) alters cutaneous immunity at the local site as well as systemically. Within 2-3 days of UVR exposure, recipient mice lose their capacity to develop contact hypersensitivity (CH) when hapten is painted on unexposed skin. This loss correlates temporally with a functional deficit among dendritic antigen-presenting cells within non-draining lymph nodes and spleen. In the experiments described, the delayed systemic immune deficiency following acute, low-dose UVR exposure was found to be eliminated with neutralizing anti-interleukin-10 (IL-10) antibody. Intracutaneous injection of IL-10 generated a deficiency of systemic immunity as well as a functional deficit among lymph node dendritic cells that was similar to that induced by UVR. The skin itself was found to be the source of the IL-10 responsible for these defects, and epidermis (presumably keratinocytes) rather than mast cells was found to be the source of IL-10 within UVR-exposed skin. The potential relationships are discussed between the delayed systemic immune deficit created by acute, low-dose UVR, and the systemic immune deficits caused by chronic, high-dose UVR and by a single, high-dose UVR exposure.  (+info)

Sensitivity to sunburn is associated with susceptibility to ultraviolet radiation-induced suppression of cutaneous cell-mediated immunity. (22/473)

Skin cancer incidence is highest in white-skinned people. Within this group, skin types I/II (sun sensitive/tan poorly) are at greater risk than skin types III/IV (sun tolerant/tan well). Studies in mice demonstrate that ultraviolet radiation (UVR)-induced suppression of cell-mediated immune function plays an important role in the development of skin cancer and induces a susceptibility to infectious disease. A similar role is suspected in humans, but we lack quantitative human data to make risk assessments of ambient solar exposure on human health. This study demonstrates that ambient levels of solar UVR, typically experienced within 1 h of exposure to noonday summer sunlight, can suppress contact hypersensitivity (CHS) responses in healthy white-skinned humans in vivo (n = 93). There was a linear relationship between increase in erythema and suppression of CHS (P < 0.001), and a moderate sunburn (two minimal erythema doses [2 MED]) was sufficient to suppress CHS in all volunteers by 93%. However, a single suberythemal exposure of either 0.25 or 0.5 MED suppressed CHS responses by 50 and 80%, respectively, in skin types I/II, whereas 1 MED only suppressed CHS by 40% in skin types III/IV. The two- to threefold greater sensitivity of skin types I/II for a given level of sunburn may play a role in their greater sensitivity to skin cancer.  (+info)

Protective and defensive airway reflexes evoked by nasal exposure to wood smoke in anesthetized rats. (23/473)

We investigated the airway responses evoked by nasal wood smoke in anesthetized Sprague-Dawley rats. Wood smoke (5 ml, 1.4 ml/s) was delivered into an isolated nasal cavity while animals breathed spontaneously. In study 1, nasal wood smoke triggered either an apneic response (n = 26) or a sniff-like response (n = 16) within 1 s after smoke exposure in 42 normal rats. Both airway responses were abolished by trigeminal nerve denervation and by nasal application of a local anesthetic or a hydroxyl radical scavenger, but they were not significantly affected by removal of smoke particulates or nasal application of a saline vehicle. In study 2, nasal wood smoke only triggered a mild apneic response in two rats neonatally treated with capsaicin and had no effect on breathing in the other six; the treatment is known to chronically ablate C fibers and some Adelta fibers. In contrast, nasal wood smoke evoked an apneic response in six rats neonatally treated with the vehicle of capsaicin and elicited a sniff-like response in the other two. These results suggest that the apneic and sniff-like responses evoked by nasal wood smoke result from the stimulation of trigeminal nasal C-fiber and Adelta-fiber afferents by the gas-phase smoke and that hydroxyl radical is the triggering chemical factor.  (+info)

Signal transducer and activator of transcription 6 is essential in the induction of contact hypersensitivity. (24/473)

Contact hypersensitivity (CHS) is thought to be mainly associated with the activation of T helper type 1 (Th1) cells. However, there is also evidence that Th2 cells or Th2 cytokines play a role in the development of CHS. To analyze the functional contribution of Th2 cytokines interleukin (IL)-4 and IL-13, signal transducer and activator of transcription 6 (STAT6)-deficient (STAT6(-/)-) and wild-type (wt) control C57BL/6 mice were contact sensitized with 5% 2,4,6-trinitrochlorobenzene (TNCB), 0.5% 2,4-dinitrofluorobenzene, or 5% 4-ethoxyl methylene-2-phenyl-2-oxazolin-5-one, and any skin reactions were examined. Ear swelling was significantly reduced with a delayed peak response in STAT6(-/)- mice compared with wt mice.A histological analysis revealed that the infiltration of both eosinophils and neutrophils in the skin challenged after 24 h in STAT6(-/)- mice decreased substantially compared with that in wt mice. The expression of Th2 cytokines (IL-4, IL-5) in TNCB-challenged skin tissues and the supernatants from T cells stimulated by 2,4,6-trinitrobenzene sulfonate-modified spleen cells, as well as the immunoglobulin (Ig)E and IgG1 response after challenge, were also profoundly reduced in STAT6(-/)- mice, whereas the expression of interferon gamma was the same in STAT6(-/)- and wt mice after challenge. Furthermore, adoptive transfer experiments revealed that STAT6(-/)- mice induced CHS after injection of lymph node cells obtained from sensitized wt mice. Our data suggest that the STAT6 signal plays a critical role in the induction phase of CHS.  (+info)