Antiherpes activity of [E]-5-(1-propenyl)-2′-deoxyuridine and 5-(1-propenyl)-1-β-d-arabinofuranosyluracil

5-(1-Propenyl)-1-β-d-arabinofuranosyluracil has been synthesized, and this compound and [E]-5-(1-propenyl)-2′-deoxyuridine have been tested for inhibition of herpes virus multiplication. Only [E]-5-(1-propenyl)-2′-deoxyuridine was found to be an active inhibitor reducing by 50% the plaque formation of herpes simplex virus type 1 (HSV-1) at about 1 μM. A comparison to the bromovinyl derivatives showed the following order of decreasing activity; $\text{[}\text{E}\text{]-5-(2-}\text{bromovinyl}\text{)-2′-}\text{deoxyuridine}\text{> 5-(2-}\text{bromovinyl}\text{)-1-β-}\text{d}\text{-}\text{arabinofuranosyluracil}\text{≥ [}\text{E}\text{]-5-(1-}\text{propenyl}\text{)-2′-}\text{deoxyuridine}\text{> 5-(1-}\text{propenyl}\text{)-1-β-}\text{arabinofuranosyluracil}$. HSV-1 mutants lacking thymidine kinase or resistant against acycloguanosine were resistant against [E]-5-(1-propenyl)-2′-deoxyuridine. All compounds seemed to be phosphorylated by HSV-1 thymidine kinase in a cell-free assay. The compounds were phosphorylated to a lower extent by cellular or HSV-2 thymidine kinase, and the HSV-2 strains tested were inhibited by less than 50% at 100 μM in plaque assays. A selective inhibition of HSV-1 DNA synthesis by [E]-5-(1-propenyl)-2′-deoxyuridine was observed in infected cells indicating an effect on viral DNA polymerase. [E]-5-(1-Propenyl)-2′-deoxyuridine had a low cellular toxicity and a therapeutic effect when applied topically to HSV-1-infected guinea pig skin.     

Narrowband ultraviolet B treatment improves vitamin D balance and alters antimicrobial peptide expression in skin lesions of psoriasis and atopic dermatitis

Background Narrowband ultraviolet B (NB‐UVB) is a routine treatment for psoriasis and atopic dermatitis (AD) but its effect on vitamin D balance is not well studied. Objectives To examine whether NB‐UVB treatment in winter improves vitamin D balance in psoriasis and AD, and to study the effects of NB‐UVB on antimicrobial peptide and cytokine expression in the skin. Methods Eighteen adult patients with psoriasis, 18 with AD and 15 healthy subjects received a total of 15 NB‐UVB exposures on the whole body, given three times a week. Serum calcidiol (25‐hydroxyvitamin D) was measured by radioimmunoassay. Antimicrobial peptide and cytokine expression in skin lesions was examined by real‐time quantitative polymerase chain reaction. Results At onset 16 (89%) patients with psoriasis, 17 (94%) patients with AD and eight (53%) healthy subjects had vitamin D insufficiency (calcidiol < 50 nmol L^?1). NB‐UVB treatment significantly increased (P < 0·001) serum calcidiol. The increase was 59·9 nmol L^?1 (95% confidence interval, CI 53·5–66·9) in psoriasis, 68·2 nmol L^?1 (95% CI 55·4–80·1) in AD and 90·7 nmol L^?1 (95% CI 63·8–123·4) in healthy subjects. Psoriasis Area and Severity Index and SCORAD improved significantly (P < 0·001) but no correlation to the increase of serum calcidiol was found. Cathelicidin and human β‐defensin 2 (HBD2) expression was high in skin lesions of psoriasis. After six NB‐UVB treatments cathelicidin increased further while HBD2 expression decreased. A similar trend was observed in AD lesions. NB‐UVB caused a marked but nonsignificant decrease of interleukin (IL)‐1β and IL‐17 in psoriasis lesions. Conclusions The present study shows that in addition to a significant improvement of psoriasis and AD, NB‐UVB treatment effectively corrects vitamin D insufficiency. It also increases cathelicidin and decreases HBD2 levels in healing skin lesions of psoriasis and AD. This effect might be mediated by improved vitamin D balance and the local cytokine network.     

In vivo relationship between collagenase-2 and interleukin-8 but not tumour necrosis factor-alpha in chronic rhinosinusitis with nasal polyposis

BACKGROUND: The characteristic feature of chronic rhinosinusitis with nasal polyposis (CRSwNP) is eosinophilic inflammation of the sinus mucosa; a type of inflammation also seen in asthmatic airways. Similar histopathologic findings of airway remodelling are present in both diseases. Remodelling is tightly controlled by matrix metalloproteinases (MMP). Increase of collagenase-2 (MMP-8) expression in the bronchial epithelial cells has been described in asthmatic patients, but it has not been studied in CRSwNP. METHODS: The concentrations and degree of activation of MMP-8 were analysed by immunofluorometric assay and Western blotting, respectively, in sinus mucus samples from CRSwNP patients and in nasal lavages from healthy controls in relation to inductive cytokines interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha). RESULTS: Significantly elevated levels of MMP-8 and IL-8 but not TNF-alpha were found in CRSwNP patients relative to controls. In particular, the activation of mesenchymal-type MMP-8 but not polymorphonuclear-type MMP-8 was associated with elevated IL-8 levels. CONCLUSIONS: The IL-8 and MMP-8 seemingly form an inductive cytokine-proteinase cascade in CRSwNP pathogenesis. Together they provide a target for novel therapies and a diagnostic tool for monitoring CRSwNP treatment.     

Immunomodulatory Effects of Oak Dust Exposure in a Murine Model of Allergic Asthma

Repeated airway exposure to wood dust has been reported to causeadverse respiratory effects such as asthma and chronic bronchitis.In our recent study, we found that exposure of mice to oak dustinduced more vigorous lung inflammation compared to birch dustexposure. In the present study, we assessed the immunomodulatoryeffects of repeated intranasal exposure to oak dust both innonallergic and in ovalbumin-sensitized, allergic mice. Allergen-inducedinflux of eosinophils and lymphocytes was seen in the lungsof allergic mice. Oak dust exposure elicited infiltration ofneutrophils, lymphocytes, and macrophages in nonallergic mice.Interestingly, oak dust–induced lung neutrophilia as wellas oak dust–induced production of the proinflammatorycytokine TNF- and chemokine CCL3 were significantly suppressedin allergic mice. On the other hand, allergen-induced expressionof IL-13 mRNA and protein was significantly reduced in oak dust–exposedallergic mice. Finally, allergen-induced airway hyperreactivityto inhaled metacholine was significantly suppressed in oak dust–exposedallergic mice. The present results suggest that repeated airwayexposure to oak dust can regulate pulmonary inflammation andairway responses depending on the immunological status of theanimal.     

Morphological and functional changes of coronary vasculature caused by transcellular biosynthesis of sulfidopeptide leukotrienes in isolated heart of rabbit

Morphological and functional modifications occurring in Langendorff rabbit heart preparations perfused with purified human leukocytes (PMNL), as an organ model of sulfidopeptide-leukotrienes (sLT) transcellular biosynthesis, were studied. Coronary perfusion pressure (CPP), monitored as an index of coronary vasospasm, increased by 295% after challenge with the Ca(2+)-ionophore A-23187 (0.5 micromol/L) for 30', accompanied by a significant formation of sLT. Increase in CPP was prevented by PMNL pretreatment with the 5-lipoxygenase inhibitor MK-886 (1 micromol/L) or by heart pretreatment with LTD4-receptor antagonist SKF 104353, indicating a pivotal role of PMNL-derived 5-lipoxygenase (5- LO) products in the observed functional modifications. Similar effects were obtained using granulocyte macrophage-colony stimulating factor- primed PMNL challenged with the tripeptide n-formyl-methionyl-leucyl- phenylalanine. Scanning electron microscopy (SEM) of coronary arteries showed craters on the vessel luminal surface, PMNL adhering to endothelial cells (EC), increased number of microvilli on EC, presence of nonviable, desquamating, fusiform EC. SEM and transmission electron microscopy of myocardial microvessels, showed presence of perivascular and intermuscle edema, presence of activated PMNL and decreased number of patent microvessels. These morphological alterations were significantly blunted by MK-886 or SKF 104353. These data provide evidence of close interaction between PMNL and myocardial EC, resulting in enhanced sLT formation via transcellular biosynthesis, originating from transfer of PMNL-derived LTA4 to EC. These potent proinflammatory autacoids are responsible for coronary vasospasm and the morphological alternations observed.