BLT1 Mediates Bleomycin-Induced Lung Fibrosis Independently of Neutrophils and CD4+ T Cells.

Leukotriene B4 (LTB4) and its functional receptor BLT1 are closely involved in tissue inflammation by primarily mediating leukocyte recruitment and activation. Elevated LTB4 was reported in patients with lung fibrosis; however, the role of the LTB4/BLT1 axis in lung fibrosis remains unknown. In this study, we demonstrated that BLT1-/- mice exhibited significantly attenuated bleomycin (BLM)-induced lung fibrosis. Interestingly, BLT1 blockade with its specific antagonist U75302 in the acute injury phase (days 0-10 after BLM treatment) significantly attenuated lung fibrosis, which was accompanied by significant decreases in early infiltrating neutrophils and later infiltrating CD4+ T cells and the production of TGF-ß, IL-13, and IL-17A. In contrast, BLT1 blockade in the fibrotic phase (days 10-21 after BLM treatment) had no effect on lung fibrosis and TGF-ß production, although it significantly decreased CD4+ T cell infiltration. Furthermore, depletion of neutrophils or CD4+ T cells had no effect on BLM-induced lung fibrosis, suggesting the independence of profibrotic activity of the LTB4/BLT1 axis on BLT1-dependent lung recruitment of these two leukocytes. Finally, although BLT1 blockade had no effect on the recruitment and phenotype of macrophages in BLM-induced lung fibrosis, the LTB4/BLT1 axis could promote TGF-ß production by macrophages stimulated with BLM or supernatants from BLM-exposed airway epithelial cells in an autocrine manner, which further induced collagen secretion by lung fibroblasts. Collectively, our study demonstrates that the LTB4/BLT1 axis plays a critical role in acute injury phase to promote BLM-induced lung fibrosis, and it suggests that early interruption of the LTB4/BLT1 axis in some inflammatory diseases could prevent the later development of tissue fibrosis.

Comparison of the effects of e-cigarette vapor and cigarette smoke on indoor air quality.

CONTEXT: Electronic cigarettes (e-cigarettes) have earned considerable attention recently as an alternative to smoking tobacco, but uncertainties about their impact on health and indoor air quality have resulted in proposals for bans on indoor e-cigarette use. OBJECTIVE: To assess potential health impacts relating to the use of e-cigarettes, a series of studies were conducted using e-cigarettes and standard tobacco cigarettes. METHODS AND MATERIALS: Four different high nicotine e-liquids were vaporized in two sets of experiments by generic 2-piece e-cigarettes to collect emissions and assess indoor air concentrations of common tobacco smoke by products. Tobacco cigarette smoke tests were conducted for comparison. RESULTS: Comparisons of pollutant concentrations were made between e-cigarette vapor and tobacco smoke samples. Pollutants included VOCs, carbonyls, PAHs, nicotine, TSNAs, and glycols. From these results, risk analyses were conducted based on dilution into a 40 m³ room and standard toxicological data. Non-cancer risk analysis revealed "No Significant Risk" of harm to human health for vapor samples from e-liquids (A-D). In contrast, for tobacco smoke most findings markedly exceeded risk limits indicating a condition of "Significant Risk" of harm to human health. With regard to cancer risk analysis, no vapor sample from e-liquids A-D exceeded the risk limit for either children or adults. The tobacco smoke sample approached the risk limits for adult exposure. CONCLUSIONS: For all byproducts measured, electronic cigarettes produce very small exposures relative to tobacco cigarettes. The study indicates no apparent risk to human health from e-cigarette emissions based on the compounds analyzed.

Safety assessment of 1,2-glycols as used in cosmetics.

Caprylyl glycol and related 1,2-glycols are used mostly as skin and hair conditioning agents and viscosity agents in cosmetic products, and caprylyl glycol and pentylene glycol also function as cosmetic preservatives. The Cosmetic Ingredient Review (CIR) Expert Panel noted that, while these ingredients are dermally absorbed, modeling data predicted decreased skin penetration of longer chain 1,2-glycols. Because the negative oral toxicity data on shorter chain 1,2-glycols and genotoxicity data support the safety of the 1,2-glycols reviewed in this safety assessment, the Panel concluded that these ingredients are safe in the present practices of use and concentration described in this safety assessment.

Dermal peptide delivery using enhancer molecules and colloidal carrier systems--part I: carnosine.

Due to the lipophilic properties of the uppermost skin layer of the stratum corneum (SC), it is highly challenging to attain therapeutic concentrations of active substances; hydrophilic drugs, in particular, penetrate poorly. The purpose of this study was the improvement of the topical bioavailability of the hydrophilic dipeptides L-carnosine and its related compound N-acetyl-L-carnosine. Different strategies were investigated. On the one hand, an enhancer molecule, 1,2-pentylene glycol (PG), was added to a standard preparation, and on the other hand, a microemulsion (ME-PG) system was developed. Both were compared to the standard formulation without an enhancer molecule. For all 3 preparations, the penetration of the peptides in ex vivo human skin was investigated. This allows statements to be made regarding dermal penetration, localization and distribution of the active substances in each skin layer as well as the influence of vehicle variations, in this case, the addition of PG or the incorporation of N-acetyl-L-carnosine in an ME-PG system. For L-carnosine and N-acetyl-L-carnosine, the use of the standard preparation with PG resulted in a significant increase of the substance within the SC. Approximately 6-fold and higher dipeptide concentrations in the SC and in the viable skin layers were detected at all experimental periods compared to the formulation without the enhancer molecule and the ME-PG. High concentrations of the compounds were found after a short period of time in the viable skin layers after applying the enhancer molecule, even in concentrations of 5%. The application of the colloidal carrier system did not lead to a higher penetration rate of N-acetyl-L-carnosine in comparison to both standard preparations, although it must be said that the microstructure of the investigated ME-PG might not have been optimal for the hydrophilic properties of the dipeptide.

Intracerebroventricular injection of leukotriene B4 attenuates antigen-induced asthmatic response via BLT1 receptor stimulating HPA-axis in sensitized rats.

BACKGROUND: Basic and clinical studies suggest that hypothalamic-pituitary-adrenal (HPA) axis is the neuroendocrine-immune pathway that functionally regulates the chronic inflammatory disease including asthma. Our previous studies showed corresponding changes of cytokines and leukotriene B4 (LTB4) between brain and lung tissues in antigen-challenged asthmatic rats. Here, we investigated how the increased LTB4 level in brain interacts with HPA axis in regulating antigen-induced asthmatic response in sensitized rats. METHODS: Ovalbumin-sensitized rats were challenged by inhalation of antigen. Rats received vehicle, LTB4 or U75302 (a selective LTB4 BLT1 receptor inhibitor) was given via intracerebroventricular injection (i.c.v) 30 min before challenge. Lung resistance (RL) and dynamic lung compliance (Cdyn) were measured before and after antigen challenge. Inflammatory response in lung tissue was assessed 24 h after challenge. Expression of CRH mRNA and protein in hypothalamus were evaluated by RT-PCR and Western Blot, and plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were measured using the ELISA kits. RESULTS: Antigen challenge decreased pulmonary function and induced airway inflammation, evoked HPA axis response in sensitized rats. Administration of LTB4 via i.c.v markedly attenuated airway contraction and inflammation. Meanwhile, LTB4 via i.c.v markedly increased CORT and ACTH level in plasma before antigen challenge, and followed by further increases in CORT and ACTH levels in plasma after antigen challenge in sensitized rats. Expression of CRH mRNA and protein in hypothalamus were also significantly increased by LTB4 via i.c.v in sensitized rats after antigen challenge. These effect were completely blocked by pre-treatment with BLT1 receptor antagonist U75302 (10 ng), but not by BLT2 antagonist LY255283. CONCLUSIONS: LTB4 administered via i.c.v down-regulates the airway contraction response and inflammation through activation of the HPA axis via its BLT1 receptor. This study expands our concept of the regulatory role of intracranial inflammatory mediators in inflammatory diseases including asthma. The favourable effects of LTB4 on the HPA axis may help to explain the phenomenon of self-relief after an asthmatic attack.

Contact urticaria with systemic symptoms due to hexylene glycol in a topical corticosteroid: case report and review of hypersensitivity to glycols.

We report a case of severe contact urticaria with systemic involvement resembling an anaphylactic reaction, following the application of a topical corticosteroid. This was caused by hexylene glycol, an excipient in the formulation. Glycols are widely used in cosmetics, foods and topical and systemic drugs. In particular, glycols are present in many topical drugs used by dermatologists. To our knowledge, this is the first case in the literature of a potentially life-threatening immediate-type reaction in the context of a contact urticaria syndrome due to hexylene glycol. The classification of contact urticaria syndrome and the allergenic potential of glycols are reviewed. Dermatologists should be aware of the contact urticaria syndrome and of the increasing use of glycols in topical drug formulation in order to identify possible adverse reactions.

Therapeutic effect of 1,5-pentanediol for herpes simplex labialis: a randomized, double-blind, placebo-controlled clinical trial.

INTRODUCTION: Most episodes of recurrent herpes labialis are self-limited and mild, but can be troublesome when they occur frequently with painful and unsightly lesions. Therefore, there has been much interest in developing agents that can suppress outbreaks in addition to being therapeutically effective. The objective of the present study was to examine the prophylactic and therapeutic efficacy of 1,5-pentanediol (PD) gel in patients with recurrent episodes of herpes labialis. METHODS: In this placebo-controlled, randomized, double-blind clinical trial, a total of 105 patients with frequent episodes of recurrent herpes were randomized to either PD or placebo. During the 26-week prophylactic phase of the study, the patients applied PD gel or placebo gel twice daily to both lips. Upon recurrence of an episode, a 5-day therapy phase started during which the gel was to be applied eight times daily. After the therapy phase, the patient resumed prophylactic treatment twice daily until the next herpes episode. The main outcome measures were number of herpes episodes during the prophylactic phase of 26 weeks, and successful therapy of occurring herpes episodes with a 5-day treatment. RESULTS: There was no significant difference in recurrence rate between the two groups (P>0.05). During recurrence there was a statistically significant improvement regarding the therapeutic effect of the symptoms "blistering," "swelling," and "pain" in the PD group. The global evaluation of efficacy by the investigators and patients showed a statistically significant superiority for PD as opposed to placebo (P<0.001). CONCLUSION: Under the conditions used in the present study, PD did not show any prophylactic effect against recurrence of herpes episodes. A significantly better therapeutic effect of PD over placebo could be demonstrated on the symptoms "blistering," "swelling," and "pain." PD was very safe as no side effects were observed during the course of the study.

Glycol porphyrin derivatives as potent photodynamic inducers of apoptosis in tumor cells.

The design and synthesis of glycol-functionalized porphyrins that contain one to four low molecular weight glycol chains that are linked via ether bonds to the meta-phenyl positions of meso-tetraphenylporphyrin and the comparison of fluorinated and nonfluorinated para derivatives are reported. The cellular uptake and photodynamic activity significantly depend on terminal groups of the glycol substituent. Hydroxy glycol porphyrins, in contrast with methoxy glycol porphyrins, show efficient intracellular transport and a high induction of apoptosis in tumor cell lines in vitro . Furthermore, the ethylene glycol chain at the meta position exhibits a superior efficacy that leads to the permanent ablation of human breast carcinoma (MDA-MB-231) in nude mice. In addition, fluorination enhanced the photosensitizing potential of para-phenyl derivatives. The analysis of the cell-death mechanism revealed that glycol-functionalized porphyrins represent novel nonmitochondrially localized photosensitizers that have a profound ability to induce apoptosis in tumor cells that act upstream of caspase activation. The strong interaction with a tumor marker (sialic acid) indicates the preferential association of these compounds with tumor cells.

Self-assembled glycol chitosan nanoparticles for the sustained and prolonged delivery of antiangiogenic small peptide drugs in cancer therapy.

Antiangiogenic peptide drugs have received much attention in the fields of tumor therapy and tumor imaging because they show promise in the targeting of integrins such as alpha(v)beta(3) on angiogenic endothelial cells. However, systemic antiangiogenic peptide drugs have short half-lives in vivo, resulting in fast serum clearance via the kidney, and thus the therapeutic effects of such drugs remain modest. In this study, we prepared self-assembled glycol chitosan nanoparticles and explored whether this construct might function as a prolonged and sustained drug delivery system for RGD peptide, used as an antiangiogenic model drug in cancer therapy. Glycol chitosan hydrophobically modified with 5beta-cholanic acid (HGC) formed nanoparticles with a diameter of 230 nm, and RGD peptide was easily encapsulated into HGC nanoparticles (yielding RGD-HGC nanoparticles) with a high loading efficiency (>85%). In vitro work demonstrated that RGD-HGC showed prolonged and sustained release of RGD, lasting for 1 week. RGD-HGC also inhibited HUVEC adhesion to a beta ig-h3 protein-coated surface, indicating an antiangiogenic effect of the RGD peptide in the HGC nanoparticles. In an in vivo study, the antiangiogenic peptide drug formulation of RGD-HGC markedly inhibited bFGF-induced angiogenesis and decreased hemoglobin content in Matrigel plugs. Intratumoral administration of RGD-HGC significantly decreased tumor growth and microvessel density compared to native RGD peptide injected either intravenously or intratumorally, because the RGD-HGC formulation strongly enhanced the antiangiogenic and antitumoral efficacy of RGD peptide by affording prolonged and sustained RGD peptide delivery locally and regionally in solid tumors.

The in vitro activity of pentane-1,5-diol against aerobic bacteria. A new antimicrobial agent for topical usage?

Multi-resistance to antibiotic therapy and to biocides is becoming increasingly common, which has led to mounting concern worldwide regarding the future use of traditional antimicrobials. Diols or glycols also have antimicrobial effects. Pentane-1,5-diol has low oral toxicity, is essentially non-irritating to the skin and has high antimicrobial activities against bacteria, fungi and viruses. The effect of pentane-1,5-diol against both sensitive and multi-resistant Gram-positive and Gram-negative bacteria was tested in vitro against 85 bacterial strains showing minimal inhibitory concentrations in the range of 2.5 to 15.0% (vol/vol) against both antibiotic-susceptible and multi-resistant aerobic bacteria. The exact mechanism of action is unknown but probably pentane-1,5-diol sucks water out of the bacterial cells which then collapse, a mechanism to which it is probably very difficult to develop resistance. The high activity against multi-resistant bacteria makes pentane-1,5-diol an interesting new compound for topical antimicrobial therapy in humans.

Self-assembled nanoparticles containing hydrophobically modified glycol chitosan for gene delivery.

A self-assembled nanoparticle was prepared using a hydrophobically modified glycol chitosan for gene delivery. A primary amine of glycol chitosan was modified with 5beta-cholanic acid to prepare a hydrophobically modified glycol chitosan (HGC). The modified chitosan spontaneously formed DNA nanoparticles by a hydrophobic interaction between HGC and hydrophobized DNA. As the HGC content increased, the encapsulation efficiencies of DNA increased while the size of HGC nanoparticles decreased. Upon increasing HGC contents, HGC nanoparticle became less cytotoxic. The increased HGC contents also facilitated endocytic uptakes of HGC nanoparticles by COS-1 cells, which were confirmed by a confocal microscopy. The HGC nanoparticles showed increasing in vitro transfection efficiencies in the presence serum. In vivo results also showed that the HGC nanoparticles had superior transfection efficiencies to naked DNA and a commercialized transfection agent. The HGC nanoparticles composed of hydrophobized DNA and hydrophobically modified glycol chitosan played a significant role in enhancing transfection efficiencies in vitro as well as in vivo.

Detection of carboxylic acids and inhibition of hippuric acid formation in rats treated with 3-butene-1,2-diol, a major metabolite of 1,3-butadiene.

Epidemiological studies have indicated that 1,3-butadiene exposure is associated with an increased risk of leukemia. In human liver microsomes, 1,3-butadiene is rapidly oxidized to butadiene monoxide, which can then be hydrolyzed to 3-butene-1,2-diol (BDD). In this study, BDD and several potential metabolites were characterized in the urine of male B6C3F1 mice and Sprague-Dawley rats after BDD administration (i.p.). Rats given 1420 micromol kg(-1) BDD excreted significantly greater amounts of BDD relative to rats administered 710 micromol kg(-1) BDD. Rats administered 1420 or 2840 micromol kg(-1) BDD excreted significantly greater amounts of BDD per kilogram of body weight than mice given an equivalent dose. Trace amounts of 1-hydroxy-2-butanone and the carboxylic acid metabolites, crotonic acid, propionic acid, and 2-ketobutyric acid, were detected in mouse and rat urine after BDD administration. Because of the identification of the carboxylic acid metabolites and because of the known ability of carboxylic acids to conjugate coenzyme A, which is critical for hippuric acid formation, the effect of BDD treatment on hippuric acid concentrations was investigated. Rats given 1420 or 2272 micromol kg(-1) BDD had significantly elevated ratios of benzoic acid to hippuric acid in the urine after treatment compared with control urine. However, this effect was not observed in mice administered 1420 or 2840 micromol kg(-1) BDD. Collectively, the results demonstrate species differences in the urinary excretion of BDD and show that BDD administration in rats inhibits hippuric acid formation. The detection of 1-hydroxy-2-butanone and the carboxylic acids also provides insight regarding pathways of BDD metabolism in vivo.

[Efficacy of the combination of DEET (20%) and EHD (15%) against mosquito bites. Results of a study carried out in Senegal]. / Efficacité de l'association DEET (20%) et EHD (15%) contre les piqûres de moustiques. Résultats d'une étude de terrain effectuée au Sénégal.

The authors report the results of a survey on the efficacy against mosquito bites of a repellent, Mousticologne Spécial Zones Infestées (DEET 20%, EHD 15%). Two forms of the product, spray and gel, were tested in Senegal. Repellent efficacy was evaluated by exposing volunteers, both repellent-treated and untreated, to mosquito bites. The number of mosquito bites per person and per night was 0.63 in the spray treated group (group 1), 6.03 in the gel treated group (group 2) and 94.17 in the untreated group (group 3). The analysis of these results showed a significant difference between treated and untreated persons. Untreated persons were not protected against mosquito bites, persons treated with the spray were protected for 12 hours and those treated with the gel had over 8 hours' protection. We concluded that a single application of the repellent Mousticologne in the field is capable of ensuring all-night protection against mosquito bites.

Repeated exposure toxicity of 2-ethyl-1,3-hexanediol by cutaneous applications to the rat for 9 and 90 days.

2-Ethyl-1,3-hexanediol (EHD; CASRN 94-96-2), an industrial chemical and insect repellent, has a high potential for recurrent skin contact. Short-term (9 d) and subchronic (13 w) repeated epicutaneous contact studies were conducted to determine the potential for cumulative local skin irritation and systemic toxicity in Fischer 344 rats. Doses were 0.5, 2.0 or 4.0 ml/kg/d of undiluted EHD. There were no clinical signs and no treatment-related effects on hematology, clinical chemistry or histology of a large number of organs and tissues including the treated skin. The only effects where slight decreases in body weight gain for the high-dose males in the 9-d study and males and females of the high-dose group in the subchronic study; slight decreases in food consumption for females of all treatment groups in the subchronic study; and slight increases in relative liver weight for high-dose females in the 9-d study and high-dose males in the subchronic study, which is probably a compensatory hypertrophy for the metabolism of EHD. Thus, recurrent epicutaneous applications of undiluted EHD to the rat did not cause any local skin irritation or cumulative or organ-specific toxicity.

Attraction of mosquitoes to diethyl methylbenzamide and ethyl hexanediol.

Studies by prior workers have shown that insect repellents can act as attractants when present as low concentrations, deposits or residues. In the present study deet and ethyl hexanediol were tested in 2-fold serial doses from 1.9 X 10(-9) to 1.6 X 10(-2) mg/cm2 on the forearms of volunteers against colonized Anopheles albimanus, Aedes aegypti and Ae. taeniorhynchus. Both compounds were significantly repellent at the high end of the dose range, as expected. Neither was significantly attractant to An. albimanus in low doses. However, deet was significantly attractant to Ae. aegypti in the dose range 7.6 X 10(-9) to 1.2 X 10(-4) mg/cm2 and to Ae. taeniorhynchus in the dose ranges 1.9 X 10(-9) to 3.1 X 10(-8) mg/cm2 and 2.0 X 10(-6) to 2.5 X 10(-4) mg/cm2. Ethyl hexanediol was significantly attractant to Ae. taeniorhynchus in the dose range 1.9 X 10(-9) to 6.2 X 10(-5) mg/cm2. Based on these results and prior work of V.G. Dethier and C.N.E. Ruscoe, a model sequence of the effects of chemicals on insects with increasing dose was developed. It was concluded that the labels of commercial repellents should be amended to include instructions to wash off or reapply the repellent when it is no longer effective.

The acute toxicity and primary irritancy of 2-ethyl-1,3-hexanediol.

2-Ethyl-1,3-hexanediol (EHD), an insect repellant, was found to have acute peroral LD50 values in the rat of 9.85 ml/kg (males) and 4.92 ml/kg (females). Acute percutaneous LD50 values in the rabbit were 10.8 ml/kg (males) and 9.51 ml/kg (females). There were neither deaths nor signs of toxicity during or following a 6 hr exposure to a statically or dynamically generated substantially saturated vapor atmosphere. A 4 hr exposure to a high concentration (3.8 mg/liter) of a respirable aerosol of EHD (mass median aerodynamic diameter of 2.0 um) produced only minor signs of irritation during exposure, but no signs of toxicity. Occluded dermal contact with EHD on rabbits (4 and 24 hr) produced mild local erythema and, in several animals, edema. Contamination of the eye with EHD (0.005 to 0.1 ml) produced marked to severe conjunctivitis, with moderate iritis and diffuse corneal injury; healing occurred in most animals within 3 to 7 days. The major acute hazards with EHD are by swallowing and, to a greater extent, by contamination of the eye.