Extending Horizon of Robotic Surgery to Bladder-Preserving Approach for Vesical Paraganglioma: Rare Case with Unusual Presentation.

Background: Vesical paraganglioma is rare and accounts for <0.1% of all urinary bladder tumors. They are mostly functional because of secretion of catecholamines and clinical presentation may mimic like a hyperfunctioning adrenal pheochromocytoma. They are easily misdiagnosed as urothelial malignancy and adequate perioperative attention is not provided. Case presentation: We hereby report a case of 55-year-old Indian lady with silent vesical paraganglioma at anatomically difficult location of bladder neck managed with robot-assisted excision of mass and bladder preservation. Conclusion: Surgery is the mainstay of the treatment that requires total excision of mass. However, minimally invasive bladder-preserving approach should be always kept as an option, if feasible. Robot assistance can help in bladder preservation even in difficult anatomic locations.

Retinoic acid inhibits induction of c-Jun protein by ultraviolet radiation that occurs subsequent to activation of mitogen-activated protein kinase pathways in human skin in vivo.

Human skin is exposed daily to solar ultraviolet (UV) radiation. UV induces the matrix metalloproteinases collagenase, 92-kD gelatinase, and stromelysin, which degrade skin connective tissue and may contribute to premature skin aging (photoaging). Pretreatment of skin with all-trans retinoic acid (tRA) inhibits UV induction of matrix metalloproteinases. We investigated upstream signal transduction pathways and the mechanism of tRA inhibition of UV induction of matrix metalloproteinases in human skin in vivo. Exposure of human skin in vivo to low doses of UV activated EGF receptors, the GTP-binding regulatory protein p21Ras, and stimulated mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38. Both JNK and p38 phosphorylated, and thereby activated transcription factors c-Jun and activating transcription factor 2 (ATF-2), which bound to the c-Jun promoter and upregulated c-Jun gene expression. Elevated c-Jun, in association with constitutively expressed c-Fos, formed increased levels of transcription factor activator protein (AP) 1, which is required for transcription of matrix metalloproteinases. Pretreatment of human skin with tRA inhibited UV induction of c-Jun protein and, consequently, AP-1. c-Jun protein inhibition occurred via a posttranscriptional mechanism, since tRA did not inhibit UV induction of c-Jun mRNA. These data demonstrate, for the first time, activation of MAP kinase pathways in humans in vivo, and reveal a novel posttranscriptional mechanism by which tRA antagonizes UV activation of AP-1 by inhibiting c-Jun protein induction. Inhibition of c-Jun induction likely contributes to the previously reported prevention by tRA of UV induction of AP-1-regulated matrix-degrading metalloproteinases in human skin.

Phorbol ester-mediated association of protein kinase C to the nuclear fraction in NIH 3T3 cells.

Treatment of intact NIH 3T3 cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) causes a rapid redistribution (stabilization) of protein kinase C to the particulate fraction. Part of the enzyme activity stabilized to the membrane fraction in response to TPA can be recovered associated with nuclear-cytoskeletal components. An apparently pure nuclear fraction prepared from NIH 3T3 cells was found to contain 25-30% of the total membrane-associated protein kinase C activity when isolated in the presence of Ca2+. In untreated control cells, most of this activity found with the nuclear fraction can be extracted by chelators. Phorbol ester (TPA) treatment of NIH 3T3 cells induces the tight association of protein kinase C to the nucleus; this tightly bound activity is not dissociable by chelators and can be recovered only by solubilization with detergent. Nuclei purified from untreated human promyelocytic leukemic HL-60 cells contain higher amounts of chelator-stable, detergent-extractable protein kinase C activity compared with control NIH 3T3 cells. However, TPA treatment of HL-60 cells does not enhance the amount of protein kinase C found tightly associated with the nuclear fraction. Immunohistochemical studies with polyclonal antibodies directed against protein kinase C further indicate that TPA treatment of NIH 3T3 cells does significantly enhance the amount of protein kinase C found tightly associated with the nucleus and cytoskeleton, whereas exposure of HL-60 cells to TPA does not appreciably alter the amount of protein kinase C observed to be associated with the nuclear fraction. The TPA-mediated association (activation) of protein kinase C to the nuclear and cytoskeletal fractions with NIH 3T3 cells is further supported by the enhanced phosphorylation of specific endogenous proteins noted when purified nuclei and cytoskeletal preparations are incubated with [gamma-32P]ATP. These results suggest that tumor promoters may induce association (activation) of protein kinase C with different subcellular components to alter the availability of endogenous substrates. This may result in differential responses by different cell types during exposure to tumor promoters.

Phosphatidic acid and phospholipase D both stimulate phosphoinositide turnover in cultured human keratinocytes.

Phosphatidic acid (PA) induced a rapid dose-dependent increase in production of inositol phosphates in cultured adult human keratinocytes, peaking at 30 s. Natural and dioleoyl PA were equally effective, while other phospholipid classes had no effect. Lipid A was also active. Lyso-PA also induced inositol phosphate production, but contamination of the PA preparation by lyso-PA could not account for the effect of PA. The effect of PA could not be reproduced by treatment of cells with calcium ionophore. PA-induced inositol phosphate production could be inhibited (> 50%) by pre-treatment of cells with either pertussis toxin or 12-O-tetradecanoylphorbol 13-acetate, suggesting the involvement of a GTP-binding protein and a protein kinase C-mediated negative feedback mechanism. PA also stimulated release of arachidonic acid from keratinocytes. Treatment of cells with exogenous phospholipase D similarly induced inositol phosphate production in the keratinocytes. Since PA may be formed by receptor-mediated activation of phospholipase D, or by phosphorylation of diacylglycerol, the results suggest that PA may play a significant role in signalling mechanisms of human keratinocytes.

Bradykinin induces phosphoinositide turnover, 1,2-diglyceride formation, and growth in cultured adult human keratinocytes.

The effects of bradykinin on activation of phosphoinositide turnover, 1,2-diglyceride formation, and growth of cultured adult human keratinocytes were investigated. Keratinocytes specifically bound [3H]bradykinin with high affinity (kd = 3.4 nM) and displayed 1.5 X 10(5) binding sites/cell. Bradykinin caused a rapid dose-dependent increase in inositol trisphosphate (IP3) inositol bisphosphate, and inositol monophosphate. IP3 was maximally increased (fivefold) at 30 s and remained elevated for at least 10 min. Half maximal stimulation of IP3 formation was observed at 27 nM bradykinin. IP3 accumulation was equally elevated by bradykinin and lys-bradykinin but was not stimulated by des-Arg9-bradykinin, indicating that phospholipase C in cultured keratinocytes is coupled to B2 bradykinin receptors. Treatment of keratinocytes with active phorbol ester (TPA) caused a significant inhibition (50%) of bradykinin-induced IP3 accumulation, suggesting negative regulation of phospholipase C by protein kinase C. Bradykinin also caused a significant elevation in 1,2-diacylglycerol (DAG) content. DAG content was maximally elevated (twofold) at 1 min and remained elevated for at least 10 min. Bradykinin also caused a significant (twofold, p less than 0.02) increase in keratinocyte growth. These data demonstrate that bradykinin is a potent agonist of the phospholipase C/protein kinase C signal transduction system in cultured adult human keratinocytes and that activation of this pathway by bradykinin is associated with increased keratinocyte growth.

Increased phospholipase C-catalyzed hydrolysis of phosphatidylinositol-4,5-bisphosphate and 1,2-sn-diacylglycerol content in psoriatic involved compared to uninvolved and normal epidermis.

Evidence suggests that the phospholipase C/protein kinase C signal transduction system participates in the regulation of epidermal cell growth and differentiation. Psoriatic epidermis is characterized by hyperproliferation, defective differentiation, and inflammation. In this report, we have determined the activity of phospholipase C-catalyzed hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) and 1,2-diacylglycerol content in normal and psoriatic involved and uninvolved epidermis. 1,2-diacylglycerol is formed from phospholipase C-catalyzed hydrolysis of PIP2 and is the physiologic activator of protein kinase C. PIP2 hydrolysis was assayed in soluble and particulate fractions prepared from keratome biopsies of normal and psoriatic skin. Total lipids were extracted from normal and psoriatic epidermis and 1,2-diradylglycerol (a mixture of 1,2-diacylglycerol and 1-ether, 2-acyl-glycerol) quantitated by enzyme assay. Because 1,2-diacylglycerol is a more potent activator of protein kinase C, the relative proportions of 1,2-diacyl and 1-ether, 2-acylglycerol in uninvolved and involved psoriatic epidermis were determined. This was accomplished by separation of acetate derivatives of 1,2-diacylglycerol and 1-ether, 2-acyl-glycerol by thin layer chromatography. Soluble and membrane-associated phospholipase C-catalyzed PIP2 hydrolysis were increased 3.7 times (p less than 0.001) and 3 times (p less than 0.004), respectively, in psoriatic involved compared to uninvolved and normal epidermis. 1,2-diradylglycerol content was also significantly elevated (3 times, p less than 0.01) in psoriatic involved versus uninvolved and normal epidermis. Analysis of the acetate derivatives of 1,2-diradylglycerol in psoriatic uninvolved and involved epidermis revealed that 1,2-diacylglycerol was the major species (86% and 95%, respectively). There were no significant differences in either phospholipase C-catalyzed PIP2 hydrolysis or 1,2-diacylglycerol content between uninvolved and normal epidermis. 1,2-diacylglycerol purified from normal and involved psoriatic epidermis was capable of activating protein kinase C from normal epidermis in vitro. In epidermal slices, activation of protein kinase C by addition of 12-0-tetradecanoylphorbol-13-acetate and 1,2-diacylglycerol (1,2-dioctanoylglycerol) resulted in subsequently decreased protein kinase C activity, a process termed down-regulation. These data are consistent with the possibility that the elevation in lesional 1,2-diacylglycerol content may account, in part, for the previously reported reduction of protein kinase C activity in psoriasis (Horn, Marks, Fisher, et al: J Invest Dermatol 88:220-222, 1987).

Agonist-induced hydrolysis of phosphoinositides and formation of 1,2-diacylglycerol in adult human keratinocytes.

The ability of a variety of agonists to induce formation of inositol phosphates and 1,2-diacylglycerol in cultured adult human keratinocytes has been investigated. Histamine, bradykinin, and thrombin significantly stimulated formation of inositol mono-, bis-, and trisphosphate and 1,2-diacylglycerol within 5 min after addition. Aluminum fluoride also caused a dose-dependent accumulation of inositol phosphates suggesting the participation of a GTP binding protein in the regulation of phospholipase C-catalyzed phosphoinositide hydrolysis. These data demonstrate that human keratinocytes possess the capacity for phospholipase C-mediated signal transduction and suggest that this pathway may participate in the regulation of keratinocyte function.

Reduced type I and type III procollagens in photodamaged adult human skin.

We have quantitatively assessed the relation between type I and type III procollagen precursor levels and the severity of clinical photodamage in human skin. Levels of procollagen, pN collagen (collagen without the carbroxypropeptide), and/or pC collagen (collagen without the aminopropeptide) were determined by radioimmunoassay, Western blot, and immunohistology in punch biopsy specimens from mildly and severely photodamaged forearm skin and from sunprotected underarm and buttock skin of the same subjects. Collagen precursor levels in forearm and underarm skin were expressed relative to buttock levels for comparison. In the mildly photodamaged group, collagen precursors in the forearm did not differ from those in the underarm by any measurement, except for type I collagen precursors measured by radioimmunoassay, which were reduced 16%. In severely photodamaged forearm skin, both type I and type III collagen precursor levels, measured by radioimmunoassay, were significantly reduced (approximately 40%). Western analysis revealed similar significant reductions in type I and type III collagen precursor levels in severely photodamaged forearm skin compared with the sun-protected underarm. Immunohistology localized both type I and III pN collagens predominantly to the extracellular papillary dermis. Relative staining intensities of type I and type III pN collagen were also significantly reduced in severely photodamaged forearm skin. Multiple linear regression modeling of all data demonstrated that reductions in collagen precursor levels were significantly correlated (p < 0.03) with the severity of photodamage, but not with chronologic age. These data demonstrate, by three independent methods, coordinate reductions of both type I and type III collagen precursors in photodamaged human skin, and the degree of reduction correlated with the degree of photodamage. It is likely that such changes in collagen precursors lead to reduced levels and/or altered organization of fibrillar collagen, and thus may contribute to the wrinkled appearance of photodamaged human skin.

Differential regulation of tyrosinase activity in skin of white and black individuals in vivo by topical retinoic acid.

Tyrosinase activity is a key determinant of melanin production in skin. Because retinoic acid regulates tyrosinase activity in melanoma cells, we analyzed modulation of pigmentation in vivo by retinoic acid. Black and white subjects were either not treated, or treated topically for 4 d under occlusion with vehicle, retinoic acid (0.1%), or the irritant sodium lauryl sulfate (2%). In untreated skin, tyrosinase activity and melanin content were significantly greater (2.3 times, and 3.2 times, respectively) in blacks versus whites. Four days of treatment with topical retinoic acid did not alter tyrosinase activity or melanin content in black skin. In contrast, retinoic acid treatment significantly induced (2.7 times, n = 8) tyrosinase activity, compared to vehicle treatment, in white skin. Melanin content, however, remained unchanged at 4 d. In separate experiments, tyrosinase activity in white subjects (n = 25) was increased 16% (p = 0.01) in sodium lauryl sulfate-treated skin, and 77% (p = 0.0005) in retinoic acid-treated skin, compared to vehicle-treated skin. The effect of retinoic acid on tyrosinase activity could be differentiated from non-specific irritation, because tyrosinase activity in retinoic acid-treated skin was significantly greater (52%, p = 0.004) than sodium lauryl sulfate-treated skin. Similar results were obtained with the dihydroxyphenylalanine reaction done on vehicle, sodium lauryl sulfate-, and retinoic acid-treated white skin. Northern analysis (n = 6) and semi-quantitative polymerase chain reaction (n = 6) demonstrated that retinoic acid treatment did not alter tyrosinase mRNA levels in white skin. Western analysis revealed that induction of tyrosinase activity by retinoic acid also was not associated with increased tyrosinase protein content (n = 9), indicating that regulation of tyrosinase activity by retinoic acid occurs through a post-translational mechanism. These data demonstrate that low tyrosinase activity in white skin in vivo is retinoic acid inducible and high tyrosinase activity in black skin in vivo is neither further induced nor reduced by retinoic acid.

Topical cyclosporine A inhibits the phorbol ester induced hyperplastic inflammatory response but not protein kinase C activation in mouse epidermis.

Cyclosporine A (CsA) is efficacious in the treatment of psoriasis. Although CsA is known to inhibit T-lymphocyte proliferation in vitro, whether this is its mode of action in psoriasis is uncertain. 12-0-tetradecanoylphorbol-13-acetate (TPA) induces an inflammatory, hyperplastic response in mouse skin, with many of the biochemical and histologic aberrations that occur in psoriatic epidermis. Protein kinase C is the major cellular phorbol ester receptor, and most responses of cells to TPA are mediated by PK-C, which is directly activated by TPA. We therefore have investigated the effects of CsA on pleiotypic responses induced by TPA and whether CsA acts in vivo as a direct inhibitor of PK-C. Simultaneous application of CsA (1.7 mumol) and TPA (10 nmol) to mouse skin significantly reduced inflammatory cell infiltration and increased epidermal thickness induced by TPA treatment alone. CsA had to be applied within 30 min of TPA application in order to have a significant inhibitory effect. Optimal doses of CsA inhibited TPA-induced ODC activity, TGase activity, arachidonic acid release, and interleukin-1 beta (IL-1 beta) mRNA to the same degree (approximately 80%), despite measurement at widely different times (30 min-12 h) required to obtain maximal induction by TPA. CsA did not, however, directly inhibit activation of PK-C by TPA. These data demonstrate that CsA blocks the pleiotypic responses of mouse skin to TPA treatment involving biochemical events, inflammatory cell infiltration, and epidermal hyperplasia. The molecular site(s) of action of CsA appears to be distal to the initial activation of PK-C by TPA and clearly inhibits PK-C inducible events. Furthermore, the above data suggest that CsA may directly affect keratinocytes in vivo.

Cellular, immunologic and biochemical characterization of topical retinoic acid-treated human skin.

Histologic and clinical improvement of sun-exposed skin following topical treatment with retinoic acid has been reported. Daily application of retinoic acid typically results within 2-5 d in an erythematous scaling reaction, which lessens with continued usage. The cellular, immunologic, and biochemical basis of this retinoid reaction and its role in the repair of photodamaged skin are not known. To investigate the retinoid reaction in man, we have treated non-sun-exposed skin with 0.1% retinoic acid cream (Retin-A, Ortho Pharmaceutical Corporation, Raritan, NJ) under occlusion for 4 d to induce erythema and then examined changes in 1) histology, 2) expression of cell-surface molecules, 3) the enzymes and second messengers of the phospholipase C/protein kinase C signal-transduction system, 4) levels of eicosanoids, and 5) levels of interleukin-1 protein and mRNA. These parameters were chosen for measurement both because they are indicators of epidermal function and previous studies suggest they may be responsive to retinoic acid treatment. Epidermal cell growth as judged by increased epidermal thickness and mitotic figures was significantly increased in retinoic acid-treated skin compared to vehicle-treated controls. Increased numbers of CD4+ T cells accompanied by prominence of dermal dendrocytes in the papillary dermis and focal keratinocyte expression of intercellular adhesion molecule-1 were observed in retinoic acid-treated biopsies. Phosphoinositide-specific phospholipase C activity and 1,2-diacylglycerol content were also elevated in retinoic acid-treated epidermis. Protein kinase C activity was reduced by one third in both the soluble and membrane fraction, suggesting down-regulation. Surprisingly, in view of the inflammatory nature of the retinoid reaction, no increases were observed in arachidonic acid, its metabolites, interleukin-1 alpha, or interleukin-1 beta. To examine the specificity of the retinoid reaction, subjects were treated with the irritant sodium lauryl sulfate, under conditions that resulted in a reaction clinically similar to that observed with retinoic acid. The histologic alterations induced by sodium lauryl sulfate were found to be indistinguishable from those induced by retinoic acid. These data indicate that, although a wide range of cellular and molecular alterations occur in retinoic acid-treated skin, these changes may not be necessarily specific or unique for retinoic acid.

Normalization of urinary oxalate by taurine in glycolate-fed rats.

Oral feeding of sodium glycolate (50 mg/d/rat for ten days) caused a significant (P less than 0.001) increase in oxalate and taurine excretion and a decrease in liver protein content (P less than 0.05), glycolic acid oxidase levels (P less than 0.01), and glycolic acid dehydrogenase levels (P less than 0.01) as compared to normal untreated rats. Taurine (100 mg/d/rat), when administered along with glycolate, prevented these effects of glycolate as evident from normal urinary excretion of oxalate, liver protein content, glycolic acid oxidase, and glycolic acid dehydrogenase levels in glycolate- plus taurine-fed animals.

Topical tretinoin (retinoic acid) improves early stretch marks.

BACKGROUND AND DESIGN: Stretch marks are disfiguring lesions usually caused by excessive stretching of skin. We investigated the response of early, clinically active stretch marks to topical 0.1% tretinoin (retinoic acid) cream. In a double-blind, randomized, vehicle-controlled study, 22 patients applied either 0.1% tretinoin (n = 10) or vehicle (n = 12) daily for 6 months to the affected areas. Patients were evaluated by physical examination monthly and by analysis of biopsy specimens of stretch marks obtained before and at the end of therapy in comparison with untreated normal skin. RESULTS: After 2 months, patients treated with tretinoin had significant improvements in severity scores of stretch marks compared with patients who received vehicle (P < .05). After 6 months, eight (80%) of the 10 tretinoin-treated patients had definite or marked improvement compared with one (8%) of the 12 vehicle-treated patients (P = .002). Targeted stretch marks in patients treated with tretinoin had a decrease in mean length and width of 14% and 8%, respectively, compared with an increase of 10% (P < .001) and 24% (P = .008), respectively, in patients who received vehicle. There were no significant differences in various measures of quality and quantity of dermal collagen and elastic fibers in stretch marks when tretinoin and vehicle treatments were compared. CONCLUSIONS: Topical application of tretinoin significantly improves the clinical appearance of early, active stretch marks. The processes that are responsible for the clinical improvement remain unknown.

Molecular mechanisms of photoaging in human skin in vivo and their prevention by all-trans retinoic acid.

Solar UV radiation damages human skin, affecting skin tone and resiliency and leading to premature aging (photoaging), the symptoms of which include leathery texture, wrinkles, mottled pigmentation, laxity and sallowness. We propose that photoaging results largely from UV induction of matrix metalloproteinases (MMP) that degrade skin collagen. We find that pretreatment of human skin with all-trans retinoic acid (tRA) inhibits UV induction of MMP, suggesting that tRA can protect against UV-induced collagen destruction and may therefore be able to lessen the effects of photoaging. The tRA prevents UV-induced accumulation of c-Jun protein, which is required for MMP gene expression. Activation of c-Jun transcriptional activity requires N-terminal phosphorylation. The majority of c-Jun in human skin in vivo is N-terminal phosphorylated. Topically applied tRA does not inhibit N-terminal phosphorylation by UV-induced c-Jun kinase activity in human skin. The tRA likely acts to reduce UV induction of c-Jun protein by stimulating its breakdown through the ubiquitin-proteasome pathway.

Effect of nucleoside-5'-phosphates on collagen-induced in vitro mineralization.

Nucleoside triphosphates (NTPs) at 4-10 microM concentrations were found to inhibit the rates of collagen-induced in vitro mineralization and ion exchange reactions. The sequential removal of the terminal phosphate groups caused a step-wise decrease in their inhibitory potency. The results suggest that NTPs inhibit the rates of ion uptake and exchange reactions at concentrations much lower than their intracellular physiological concentrations. Thus NTPs may be involved in the control of biological mineralization and the tissues which mineralize under physiological conditions develop a system to locally convert NTPs to NDPs and NMPs.

Effect of sodium glycolate and sodium pyruvate on oxalic acid biosynthesizing enzymes in rat liver and kidney.

Sodium glycolate feeding (50 mg/100 g body weight/day) to adult male rats for 7 days resulted in increased activities of glycolate oxidase in liver and lactate dehydrogenase in liver and kidney. However, the activity of glycolate dehydrogenase decreased both in liver and kidney. Treatment of sodium pyruvate (100 mg/100 g body weight/day) to the glycolate-fed rats resulted in lowered liver glycolate oxidase activity, and the glycolate dehydrogenase activity was further decreased as compared to glycolate-fed rats in both age groups. However, lactate dehydrogenase activity was not affected by pyruvate feeding in comparison to the glycolate-treated group. It is concluded that glycolate-induced oxalate biosynthesis in rats involves increased activity of liver glycolate oxidase, and pyruvate feeding inhibits glycolate oxidase, thereby decreasing oxalate biosynthesis.

Sodium glycolate absorption in rat intestine.

Absorption of sodium [1-14C]glycolate by rat intestine was studied by using the tissue accumulation technique with everted intestinal rings. Saturation kinetics was observed for the absorption of glycolate in the jejunoileal region, with a Km of 6.25 mM for glycolate and a Vmax of 5.56 mumole/30 min/g wet wt. The absorption was linear up to a period of 25 min at 37 degrees C. Jejunum and ileum showed significantly higher absorption of glycolate as compared to colon. Sulfhydryl binding agents, viz., p-chloromercuribenzoate and iodoacetate, and respiration inhibitors, e.g., KCN and 2,4-dinitrophenol, had no significant effect on glycolate uptake. However, glyoxylate and lactate showed significant inhibition at 6 mM concentration of the inhibitor. Pyridoxine deficiency had no effect on glycolate uptake by the rat intestine.

Differential activation of human skin cells by platelet activating factor: stimulation of phosphoinositide turnover and arachidonic acid mobilization in keratinocytes but not in fibroblasts.

Treatment of cultured adult human keratinocytes with platelet activating factor (PAF) resulted in a rapid, dose dependent accumulation of inositol phosphates. Inositol trisphosphate (IP3), inositol bisphosphate (IP2) and inositol phosphate (IP) were elevated within 15 seconds of exposure to PAF (1 microM). Lyso-PAF, phosphatidylcholine (PC) and lyso-PC had no effect on levels of inositol phosphates, indicating that the effect of PAF was specific. PAF also raised cellular 1,2-diacylglycerol content (2-fold) within two minutes of addition and stimulated mobilization of arachidonic acid (AA) and release of prostaglandin E2. In contrast, PAF did not stimulate phosphoinositide turnover or AA release in cultured dermal fibroblasts. These results suggest that the inflammatory effects of PAF in human skin result, at least in part, from its ability to directly activate keratinocytes and stimulate release of pro-inflammatory eicosanoids.