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Available from: Steven G Shimada, Mar 28, 2014
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    • "Four PAR subtypes PAR- 1 to PAR-4, have been identified so far [17] [18]. Tryptase acts on PAR-2 and on PAR-1, but only at high concentration, trypsin on PAR-1, PAR-2, and PAR-4 but not on PAR-3; thrombin acts on PAR-1, PAR-3, and PAR-4 but not on PAR-2, while kallikreins (KLK), mainly KLK5 and KLK14 act only on PAR-2 [18] [19]. Remarkably, PAR-2 has been recently shown to be involved in chronic itch, suggesting that proteases from apoptotic cells may partake in pruritus pathogenesis [17]. "
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    ABSTRACT: Lichen planus (LP) is an inflammatory mucocutaneous disease, showing a wide variety of clinical subtypes. The classic presentation of LP involves the appearance of polygonal, flat-topped, violaceous papules and plaques with reticulated white lines, termed "Wickham's striae". Cutaneous lesions tend to be extremely pruritic, and this symptom does not subside after common antipruritic treatment. Moreover, based on our previous pilot study, it could be stated, that itch is the most unpleasant and bothersome symptom of LP for majority of patients suffering from this disease. However, the underlying mechanisms of itch in lichen planus remain still unknown. In addition, there is no study on mediators of this sensation, but taking into account pathogenesis of LP there are some possible mediators implicated to transmit or modulate itch. In pathogenesis of LP important are such mechanisms as apoptosis, autoimmune reaction, and role of stress. With these pathways some, previously described in other diseases, itch mediators such as cytokines, proteases, and opioid system are connected. Whether these mechanisms are involved in pruritus accompanying LP requires further investigation. Limited knowledge of pruritus origin in lichen planus is responsible for the lack of the effective antipruritic treatments. Here, we describe possible mechanisms participating the pathogenesis of pruritus in lichen planus.
    07/2013; 2013:941431. DOI:10.1155/2013/941431
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    • "Cathepsin S (CTSS) is a lysosomal cysteine protease that can function as an elastase over a broad pH range in alveolar macrophages and may participate in the degradation of antigenic proteins to peptides for presentation on major histocompatibility complex (MHC) class II molecules. Recently , human CTSS was shown to activate human protease–activated receptor-2 (PAR-2), consistent with a possible pruritic role in inflammatory skin diseases such as AD (Reddy et al., 2010). PAR-2 is member of the G-protein–coupled receptor family (Vu et al., 1991). "
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    ABSTRACT: Atopic dermatitis (AD) is a chronically relapsing, noncontagious pruritic skin disease with two phases: acute and chronic. Previous studies have shown that the cysteine protease cathepsin S (CTSS) is linked to inflammatory processes, including atherosclerosis and asthma. The possibility that this or other cysteine proteases might cause itching or be part of a classical ligand-receptor signaling cascade has not been previously considered. Recently, CTSS was shown to be a ligand for proteinase-activated receptor-2 (PAR-2), which is associated with itching. In this study, we show that CTSS-overexpressing transgenic (TG) mice spontaneously develop a skin disorder similar to chronic AD. The results of this study suggest that CTSS overexpression triggers PAR-2 expression in dendritic cells (DCs), resulting in the promotion of CD4(+) differentiation, which is involved in major histocompatibility complex (MHC) class II expression. In addition, we investigated mast cells and macrophages and found significantly higher mean levels of T helper type 1 (Th1) cell-associated cytokines than T helper type 2 (Th2) cell-associated cytokines in CTSS-overexpressing TG mice. These results suggest that increased PAR-2 expression in DCs as a result of CTSS overexpression induces scratching behavior and Th1 cell-associated cytokine expression, and can trigger chronic AD symptoms.
    Journal of Investigative Dermatology 12/2011; 132(4):1169-76. DOI:10.1038/jid.2011.404 · 6.37 Impact Factor
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    • "Thus, our knowledge of endogenous itch mediators that may be implicated in producing most types of chronic, histamine-independent, itch is very limited. A potential candidate is the endogenous cysteine protease Cathepsin S, recently reported to elicit predominant sensation of itch accompanied by lesser nociceptive sensations in the absence of wheal or flare in human subjects (Reddy et al., 2010). Another candidate could be the BAM8–22 peptide that our results suggest can elicit itch in humans without releasing histamine. "
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    ABSTRACT: Chronic itch accompanying many dermatological, neurological, and systemic diseases is unresponsive to antihistamines. Our knowledge of endogenous chemicals that evoke histamine-independent itch and their molecular targets is very limited. Recently it was demonstrated in behavioral and cellular experiments that bovine adrenal medulla 8-22 peptide (BAM8-22), a proteolytically cleaved product of proenkephalin A, is a potent activator of Mas-related G-protein-coupled receptors (Mrgprs), MrgprC11 and hMrgprX1, and induces scratching in mice in an Mrgpr-dependent manner. To study the sensory qualities that BAM8-22 evokes in humans, we tested the volar forearm of 15 healthy volunteers with heat-inactivated cowhage spicules previously soaked in the peptide. BAM8-22 produced itch in each subject, usually accompanied by sensations of pricking/stinging and burning. The sensations were occasionally accompanied by one or more mechanically evoked dysesthesias, namely alloknesis, hyperknesis, and/or hyperalgesia, but no wheal or neurogenic flare in the skin surrounding the application site. The inactive truncated peptide BAM8-18 produced weak or no sensations. Pretreatment of the tested skin with an antihistamine cream (doxepin) inhibited histamine-induced sensations, dysesthesias, and skin reactions but not the sensations and dysesthesias evoked by BAM8-22. We show that BAM8-22 produces itch and nociceptive sensations in humans in a histamine-independent manner. Thus, BAM8-22 may be an endogenous itch mediator that activates, in humans, MrgprX1, a novel target for potential anti-itch treatments.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 05/2011; 31(20):7563-7. DOI:10.1523/JNEUROSCI.1192-11.2011 · 6.75 Impact Factor
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