4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1

TRPA1 is an excitatory ion channel expressed by a subpopulation of primary afferent somatosensory neurons that contain substance P and calcitonin gene-related peptide. Environmental irritants such as mustard oil, allicin, and acrolein activate TRPA1, causing acute pain, neuropeptide release, and neurogenic inflammation. Genetic studies indicate that TRPA1 is also activated downstream of one or more proalgesic agents that stimulate phospholipase C signaling pathways, thereby implicating this channel in peripheral mechanisms controlling pain hypersensitivity. However, it is not known whether tissue injury also produces endogenous proalgesic factors that activate TRPA1 directly to augment inflammatory pain. Here, we report that recombinant or native TRPA1 channels are activated by 4-hydroxy-2-nonenal (HNE), an endogenous alpha,beta-unsaturated aldehyde that is produced when reactive oxygen species peroxidate membrane phospholipids in response to tissue injury, inflammation, and oxidative stress. HNE provokes release of substance P and calcitonin gene-related peptide from central (spinal cord) and peripheral (esophagus) nerve endings, resulting in neurogenic plasma protein extravasation in peripheral tissues. Moreover, injection of HNE into the rodent hind paw elicits pain-related behaviors that are inhibited by TRPA1 antagonists and absent in animals lacking functional TRPA1 channels. These findings demonstrate that HNE activates TRPA1 on nociceptive neurons to promote acute pain, neuropeptide release, and neurogenic inflammation. Our results also provide a mechanism-based rationale for developing novel analgesic or anti-inflammatory agents that target HNE production or TRPA1 activation.

Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1.

Prostaglandins (PG) are known to induce pain perception indirectly by sensitizing nociceptors. Accordingly, the analgesic action of nonsteroidal anti-inflammatory drugs (NSAIDs) results from inhibition of cyclooxygenases and blockade of PG biosynthesis. Cyclopentenone PGs, 15-d-PGJ(2), PGA(2), and PGA(1), formed by dehydration of their respective parent PGs, PGD(2), PGE(2), and PGE(1), possess a highly reactive alpha,beta-unsaturated carbonyl group that has been proposed to gate the irritant transient receptor potential A1 (TRPA1) channel. Here, by using TRPA1 wild-type (TRPA1(+/+)) or deficient (TRPA1(-/-)) mice, we show that cyclopentenone PGs produce pain by direct stimulation of nociceptors via TRPA1 activation. Cyclopentenone PGs caused a robust calcium response in dorsal root ganglion (DRG) neurons of TRPA1(+/+), but not of TRPA1(-/-) mice, and a calcium-dependent release of sensory neuropeptides from the rat dorsal spinal cord. Intraplantar injection of cyclopentenone PGs stimulated c-fos expression in spinal neurons of the dorsal horn and evoked an instantaneous, robust, and transient nociceptive response in TRPA1(+/+) but not in TRPA1(-/-) mice. The classical proalgesic PG, PGE(2), caused a slight calcium response in DRG neurons, increased c-fos expression in spinal neurons, and induced a delayed and sustained nociceptive response in both TRPA1(+/+) and TRPA1(-/-) mice. These results expand the mechanism of NSAID analgesia from blockade of indirect nociceptor sensitization by classical PGs to inhibition of direct TRPA1-dependent nociceptor activation by cyclopentenone PGs. Thus, TRPA1 antagonism may contribute to suppress pain evoked by PG metabolites without the adverse effects of inhibiting cyclooxygenases.

Cytokines and chemokines in irritant contact dermatitis

Irritant contact dermatitis is a result of activated innate immune response to various external stimuli and consists of complex interplay which involves skin barrier disruption, cellular changes, and release of proinflammatory mediators. In this review, we will focus on key cytokines and chemokines involved in the pathogenesis of irritant contact dermatitis and also contrast the differences between allergic contact dermatitis and irritant contact dermatitis.

Woman's wrongs: a counter-irritant.

Mode of access: Internet.

TRPV4 is necessary for trigeminal irritant pain and functions as a cellular formalin receptor.

Detection of external irritants by head nociceptor neurons has deep evolutionary roots. Irritant-induced aversive behavior is a popular pain model in laboratory animals. It is used widely in the formalin model, where formaldehyde is injected into the rodent paw, eliciting quantifiable nocifensive behavior that has a direct, tissue-injury-evoked phase, and a subsequent tonic phase caused by neural maladaptation. The formalin model has elucidated many antipain compounds and pain-modulating signaling pathways. We have adopted this model to trigeminally innervated territories in mice. In addition, we examined the involvement of TRPV4 channels in formalin-evoked trigeminal pain behavior because TRPV4 is abundantly expressed in trigeminal ganglion (TG) sensory neurons, and because we have recently defined TRPV4's role in response to airborne irritants and in a model for temporomandibular joint pain. We found TRPV4 to be important for trigeminal nocifensive behavior evoked by formalin whisker pad injections. This conclusion is supported by studies with Trpv4(-/-) mice and TRPV4-specific antagonists. Our results imply TRPV4 in MEK-ERK activation in TG sensory neurons. Furthermore, cellular studies in primary TG neurons and in heterologous TRPV4-expressing cells suggest that TRPV4 can be activated directly by formalin to gate Ca(2+). Using TRPA1-blocker and Trpa1(-/-) mice, we found that both TRP channels co-contribute to the formalin trigeminal pain response. These results imply TRPV4 as an important signaling molecule in irritation-evoked trigeminal pain. TRPV4-antagonistic therapies can therefore be envisioned as novel analgesics, possibly for specific targeting of trigeminal pain disorders, such as migraine, headaches, temporomandibular joint, facial, and dental pain, and irritation of trigeminally innervated surface epithelia.

The relationship between angiogenesis and the immune response in carcinogenesis and the progression of malignant disease

Recent studies have demonstrated that angiogenesis and suppressed cell- mediated immunity (CMI) play a central role in the pathogenesis of malignant disease facilitating tumour growth, invasion and metastasis. In the majority of tumours, the malignant process is preceded by a pathological condition or exposure to an irritant which itself is associated with the induction of angiogenesis and/or suppressed CMI. These include: cigarette smoking, chronic bronchitis and lung cancer; chronic oesophagitis and oesophageal cancer; chronic viral infections such as human papilloma virus and ano-genital cancers, chronic hepatitis B and C and hepatocellular carcinoma, and Epstein- Barr virus (EBV) and lymphomas; chronic inflammatory conditions such as Crohn's disease and ulcerative colitis and colorectal cancer; asbestos exposure and mesothelioma and excessive sunlight exposure/sunburn and malignant melanoma. Chronic exposure to growth factors (insulin-like growth factor-I in acromegaly), mutations in tumour suppressor genes (TP53 in Li Fraumeni syndrome) and long-term exposure to immunosuppressive agents (cyclosporin A) may also give rise to similar environments and are associated with the development of a range of solid tumours. The increased blood supply would facilitate the development and proliferation of an abnormal clone or clones of cells arising as the result of: (a) an inherited genetic abnormality; and/or (b) acquired somatic mutations, the latter due to local production and/or enhanced delivery of carcinogens and mutagenic growth factors. With progressive detrimental mutations and growth-induced tumour hypoxia, the transformed cell, to a lesser or greater extent, may amplify the angiogenic process and CMI suppression, thereby facilitating further tumour growth and metastasis. There is accumulating evidence that long-term treatment with cyclo-oxygenase inhibitors (aspirin and indomethacin), cytokines such as interferon-α, anti-oestrogens (tamoxifen and raloxifene) and captopril significantly reduces the incidence of solid tumours such as breast and colorectal cancer. These agents are anti-angiogenic and, in the case of aspirin, indomethacin and interferon-α have proven immunomodulatory effects. Collectively these observations indicate that angiogenesis and suppressed CMI play a central role in the development and progression of malignant disease. (C) 2000 Elsevier Science Ltd.

Avaliação do desempenho in vivo do biovidro FastOs™

O conceito de bioatividade surgiu com a descoberta, no início década de 70, de que algumas composições vítreas (ex.: 45S5 Bioglass®), tinham a capacidade de estabelecer uma ligação direta e estável com os tecidos vivos. Desde então, este grupo de biomateriais tem vindo a receber uma atenção cada vez maior por parte dos investigadores, tendo como motivação principal a busca de novas composições com propriedades mais adequadas para a regeneração óssea do que as composições comercialmente disponíveis. Na presente tese, avaliou-se o desempenho in vivo de duas composições de biovidro do sistema diopsite (CaMgSi2O6) - fluorapatite (Ca5(PO4)3F) - fosfato tricálcico (3CaO•P2O5) aplicados em defeitos ósseos de tamanho não crítico em carneiros, tendo também sido avaliada a biocompatibilidade dos biomateriais através da aplicação subcutânea de placas dos mesmos vidros. O trabalho realizado também incluiu a avaliação dos materiais in vitro, através de estudos de biomineralização em fluido corporal simulado e estudos de degradação. Os biomateriais foram comparados com o biovidro 45S5 Bioglass®, sendo que em termos de bioatividade in vitro, as duas composições investigadas apresentaram um maior potencial bioativo, levando à formação de uma camada superficial de hidroxiapatite carbonatada, em contraste com a formação de calcite na composição comercial, sob condições idênticas. Os testes de degradação in vitro também apresentaram resultados melhores para as duas novas composições, traduzidos por variações de pH e taxas de degradação menores do que os observados no caso do 45S5 Bioglass®. A avaliação in vivo dos implantes subcutâneos permitiu apurar a biocompatibilidade dos biovidros testados, tendo sido considerados ligeiramente irritantes. Os resultados relativos à aplicação dos pós de vidro bioativo nos defeitos ósseos não foram obtidos em tempo útil de modo a poderem ser incluídos na presente tese. Considerando o desempenho in vitro e a biocompatibilidade dos materiais estudados, estes podem apontar-se como materiais promissores para aplicações em engenharia de tecidos, particularmente na regeneração do tecido ósseo.

Are coffee silverskin extracts safe for topical use? An in vitro and in vivo approach

Recent changes in regulatory requirements and social views on animal testing have incremented the development of reliable alternative tests for predicting skin and ocular irritation potential of products based on new raw materials. In this regard, botanical ingredients used in cosmetic products are among those materials, and should be carefully reviewed concerning the potential presence of irritant constituents. In particular, cosmetic products used on the face, in vicinity of the eyes or that may come in contact with mucous membranes, should avoid botanical ingredients that contain, or are suspected to contain, such ingredients. In this study, we aimed to evaluate the effect of a new cosmetic ingredient, namely, coffee silverskin (CS), with an in vitro skin and ocular irritation assay using reconstructed human epidermis, EpiSkin™, and human corneal epithelial model, SkinEthics™ HCE, and an in vivo assay. Three different extracts of CS were evaluated. The histology of the models after extracts applications was analysed. The in vitro results demonstrated that extracts were not classified as irritant and the histological analyses proved that extracts did not affect both models structure. The content of caffeine, 5-hydroxymethyl furfural and chlorogenic acid was quantified after the epidermal assay. The in vivo test carried out with the most promising extract (hydroalcoholic) showed that, with respect to irritant effects, these extracts can be regarded as safe for topical application.

A new alternative method for testing skin irritation using a human skin model: a pilot study.

Studies assessing skin irritation to chemicals have traditionally used laboratory animals; however, such methods are questionable regarding their relevance for humans. New in vitro methods have been validated, such as the reconstructed human epidermis (RHE) model (Episkin®, Epiderm®). The comparison (accuracy) with in vivo results such as the 4-h human patch test (HPT) is 76% at best (Epiderm®). There is a need to develop an in vitro method that better simulates the anatomo-pathological changes encountered in vivo. To develop an in vitro method to determine skin irritation using human viable skin through histopathology, and compare the results of 4 tested substances to the main in vitro methods and in vivo animal method (Draize test). Human skin removed during surgery was dermatomed and mounted on an in vitro flow-through diffusion cell system. Ten chemicals with known non-irritant (heptylbutyrate, hexylsalicylate, butylmethacrylate, isoproturon, bentazon, DEHP and methylisothiazolinone (MI)) and irritant properties (folpet, 1-bromohexane and methylchloroisothiazolinone (MCI/MI)), a negative control (sodiumchloride) and a positive control (sodiumlaurylsulphate) were applied. The skin was exposed at least for 4h. Histopathology was performed to investigate irritation signs (spongiosis, necrosis, vacuolization). We obtained 100% accuracy with the HPT model; 75% with the RHE models and 50% with the Draize test for 4 tested substances. The coefficients of variation (CV) between our three test batches were <0.1, showing good reproducibility. Furthermore, we reported objectively histopathological irritation signs (irritation scale): strong (folpet), significant (1-bromohexane), slight (MCI/MI at 750/250ppm) and none (isoproturon, bentazon, DEHP and MI). This new in vitro test method presented effective results for the tested chemicals. It should be further validated using a greater number of substances; and tested in different laboratories in order to suitably evaluate reproducibility.

Hazardous substances in frequently used professional cleaning products.

A growing number of studies have identified cleaners as a group at risk for adverse health effects of the skin and the respiratory tract. Chemical substances present in cleaning products could be responsible for these effects. Currently, only limited information is available about irritant and health hazardous chemical substances found in cleaning products. We hypothesized that chemical substances present in cleaning products are known health hazardous substances that might be involved in adverse health effects of the skin and the respiratory tract. We performed a systematic review of cleaning products used in the Swiss cleaning sector. We surveyed Swiss professional cleaning companies (n = 1476) to identify the most used products (n = 105) for inclusion. Safety data sheets (SDSs) were reviewed and hazardous substances present in cleaning products were tabulated with current European and global harmonized system hazard labels. Professional cleaning products are mixtures of substances (arithmetic mean 3.5 +/- 2.8), and more than 132 different chemical substances were identified in 105 products. The main groups of chemicals were fragrances, glycol ethers, surfactants, solvents; and to a lesser extent, phosphates, salts, detergents, pH-stabilizers, acids, and bases. Up to 75% of products contained irritant (Xi), 64% harmful (Xn) and 28% corrosive (C) labeled substances. Hazards for eyes (59%) and skin (50%), and hazards by ingestion (60%) were the most reported. Cleaning products potentially give rise to simultaneous exposures to different chemical substances. As professional cleaners represent a large workforce, and cleaning products are widely used, it is a major public health issue to better understand these exposures. The list of substances provided in this study contains important information for future occupational exposure assessment studies.

Studies on the prevalence of algal blooms along Kerala coast, India

Algal blooms are naturally occurring phenomena in the aquatic environment. These blooms cause mass mortalities of wild and farmed fish and shellfish, human intoxications which sometimes result in death, alteration of marine trophic structure through adverse effects on larvae and other life history stages of commercially important species and death of marine animals. Occurrences of harmful algal blooms and associated mortality have been reported along the coastal waters of India since the early period of the last century. The present study was taken up to study the dynamics of major phytoplankton blooms, which occur along the Kerala coast. The results of quantitative and qualitative analysis of phytoplankton in the coastal waters of Vizhinjam and Chombala, their species diversity and community structure is presented and the major algal blooms recorded along the coast of Kerala during the study period is described and their occurrence is related to the hydrographic and meteorological variations. There is a clear evident from these works in the Indian region that the fishes avoid areas where these harmful algae bloom, either due to the toxicity or due to some irritant property of the chemicals secreted by the algae. Taxonomic diversity studies indicated a change in the community structure of commercial finfishes, crustaceans and molluscs due to the bloom of C.marina and funnel plots indicated the deviation in taxonomic distinctness during the bloom period from theoretical mean for the region.

Determinación del perfil de exposición potencial a contaminantes químicos mediante el uso de metodologías de evaluación simplificada en trabajadores de autopartes en el barrio La Paz, Bogotá 2015

Las actividades de mantenimiento automotriz en el sector de autopartes conlleva el uso de agentes químicos bajo diversas circunstancias de exposición, tanto en las condiciones de manipulación de productos químicos como a las características propias de cada actividad de mantenimiento asociado a las tareas específicas del trabajo. Tradicionalmente la evaluación de contaminantes químicos desde la visión de la Higiene Ocupacional incluye la evaluación cuantitativa de la exposición mediante técnicas instrumentales concretas y estandarizadas, determinando el nivel de concentración en aire a la cual un trabajador se ve expuesto y que, en comparación con valores límites permisibles (VLPs), inducen el establecimiento de medidas de control y vigilancia, según el nivel de riesgo caracterizado. Sin embargo es evidente la limitación de la implementación de esta sistemática en particular en micros y pequeñas empresas que carecen de los recursos suficientes para abordar la problemática de forma objetiva. En este contexto diversas metodologías de evaluación cualitativa o subjetiva se han desarrollado por distintas organizaciones en el mundo con el fin de disminuir la brecha entre el establecimiento de medidas de control y la valoración del riesgo, ofreciendo alternativas confiables para la toma de decisiones preventivas sin la necesidad de acudir a mediciones cuantitativas. Mediante la presente investigación se pretende validar la efectividad en el uso de una herramienta de evaluación simplificada del riesgo químico propuesta por el INRS (Institut National de Recherche et de Sécurité Francés) mediante la determinación del perfil de exposición potencial a contaminantes químicos de la población laboral de 36 almacenes de autopartes ubicados en el barrio la Paz de la ciudad de Bogotá, Colombia, divididos según énfasis de actividades en Partes Externas, Partes Eléctricas e Inyección, Partes Mecánicas, Partes Múltiples, a través de un estudio de corte transversal. El estudio permitió Jerarquizar el riesgo potencial, valorar el riesgo vía inhalatoria y dérmica para finalmente construir el perfil de exposición potencial a contaminantes químicos de trabajadores. La información de las variables de análisis fue consolidada en una herramienta informática diseñada para tal fin, la cual facilito la administración de los datos y su respectivo análisis. Con base en los hallazgos fue posible establecer los productos químicos que de acuerdo a las condiciones de trabajo y circunstancias de exposición sugieren medidas específicas para la disminución del riesgo potencial de acuerdo a la calificación global de los agentes, permitiendo deducir la viabilidad de la aplicación de herramientas de valoración cualitativa para la evaluación del riesgo químico como estrategia de prevención primaria.