mezerein and Inflammation

Topics: Alkynes; Animals; Anthralin; Arachidonic Acid; Cantharidin; Capsaicin; Carrageenan; Croton Oil; Dermatitis; Disease Models, Animal; Diterpenes; Edema; Foot; Inflammation; Irritants; Male; Mice; Models, Animal; Mustard Plant; Otitis Externa; Plant Extracts; Plant Oils; Rats; Reproducibility of Results; Terpenes; Tetradecanoylphorbol Acetate; Zymosan

Chemically induced epidermal carcinogenesis is often divided into two stages: initiation, which involves the conversion of some epidermal cells into latent neoplastic cells, and promotion, which allows the evolution of this neoplastic change into the formation of a neoplasm. The hallmark of epidermal tumor promotion is the transformation of the normal epidermis into a hyperplastic epidermis. A major unanswered question about epidermal tumor promotion is whether the epidermal hyperplasia that characterizes promoted skin is a regenerative epidermal hyperplasia resulting from damage produced by the promoter. The opinion currently held is that the epidermal hyperplasia produced by tumor promoters is not simply a regenerative epidermal hyperplasia and possesses characteristics which a regenerative hyperplasia does not have, enabling it to evolve into an epidermal neoplasm. The purpose of this review is to present recent evidence which strongly suggests that promoter-induced epidermal hyperplasia is a regenerative hyperplasia. Three principal lines of evidence are reviewed. The first demonstrates that an epidermal regenerative hyperplasia repeatedly produced by wounding or abrasion can promote epidermal carcinogenesis in the initiated skin of mice. The second line of evidence demonstrates that the epidermal hyperplasia produced by the application of 12-O-tetradecanoyl-phorbol-13-acetate (TPA), the most powerful and widely used promoter of skin carcinogenesis, is preceded by damage to the epidermis. This strongly suggests that the epidermal hyperplasia which ensues is a regenerative hyperplasia. Thirdly, evidence is presented which demonstrates that hyperplasia-producing agents which do not promote, produce an epidermal hyperplasia which is different from that produced by tumor promoters. Finally, the review discusses the evidence which suggests that the production of a hyperplasia may be the mechanism for tumor promotion in other organs, such as the liver, bladder, and intestine.

Topics: Acetates; Acetic Acid; Animals; Carcinogens; Cell Differentiation; Connective Tissue Cells; Diterpenes; Epidermal Cells; Humans; Hyperplasia; Inflammation; Models, Biological; Regeneration; Skin Neoplasms; Terpenes; Tetradecanoylphorbol Acetate; Time Factors

The mechanisms by which lipoxin A(4) (LXA(4)) inhibit skin inflammation remain unclear. In the present studies, the ear inflammatory model was induced by topical application of mezerein. Treatment of the mouse ear with LXA(4) exhibited the inhibitory effects on oedema, neutrophil infiltration, vascular permeability, expressions of interleukin (IL)-1, IL-6 and IL-8 mRNA, DNA-binding activity of nuclear factor-kappaB (NF-kappaB), and on dermal hyperplasia. NF-kappaB reporter activities and nuclear translocations of NF-kappaB p65 in cultured keratinocytes stimulated by mezerein were inhibited by pretreatment of the cells with LXA(4). LXA(4) reduced degradation, but not phosphorylation of IkappaBalpha in cultured keratinocytes stimulated by mezerein, suggesting that LXA(4)-attenuated IkappaBalpha degradation may restore the mezerein-blocked inhibitory effects of IkappaB on nuclear translocation and DNA-binding activity of NF-kappaB. Our results demonstrated that LXA(4) displays the anti-inflammatory and anti-proliferative role on ear inflammatory model induced by mezerein and these effects were related with downregulation of DNA-binding activity of NF-kappaB.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carcinogens; Cell Line; Cytokines; Dermis; Disease Models, Animal; Diterpenes; Female; Humans; Hyperplasia; Inflammation; Keratinocytes; Lipoxins; Mice; Mice, Inbred Strains; NF-kappa B

Lipoxins and 15-epi-lipoxins are counter-regulatory lipid mediators that modulate leukocyte trafficking and promote the resolution of inflammation. To assess the potential of lipoxins as novel anti-inflammatory agents, a stable 15-epi-lipoxin A(4) analog, 15-epi-16-p-fluorophenoxy-lipoxin A(4) methyl ester (ATLa), was synthesized by total organic synthesis and examined for efficacy relative to a potent leukotriene B(4) (LTB(4)) receptor antagonist (LTB(4)R-Ant) and the clinically used topical glucocorticoid methylprednisolone aceponate. In vitro, ATLa was 100-fold more potent than LTB(4)R-Ant for inhibiting neutrophil chemotaxis and trans-epithelial cell migration induced by fMLP, but was approximately 10-fold less potent than the LTB(4)R-Ant in blocking responses to LTB(4). A broad panel of cutaneous inflammation models that display pathological aspects of psoriasis, atopic dermatitis, and allergic contact dermatitis was used to directly compare the topical efficacy of ATLa with that of LTB(4)R-Ant and methylprednisolone aceponate. ATLa was efficacious in all models tested: LTB(4)/Iloprost-, calcium ionophore-, croton oil-, and mezerein-induced inflammation and trimellitic anhydride-induced allergic delayed-type hypersensitivity. ATLa was efficacious in mouse and guinea pig skin inflammation models, exhibiting dose-dependent effects on edema, neutrophil or eosinophil infiltration, and epidermal hyperproliferation. We conclude that the LXA(4) and aspirin-triggered LXA(4) pathways play key anti-inflammatory roles in vivo. Moreover, these results suggest that ATLa and related LXA(4) analogs may have broad therapeutic potential in inflammatory disorders and could provide an alternative to corticosteroids in certain clinical settings.

Topics: Administration, Cutaneous; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Calcimycin; Cell Movement; Chemotaxis, Leukocyte; Croton Oil; Disease Models, Animal; Diterpenes; Female; Guinea Pigs; Humans; Hydroxyeicosatetraenoic Acids; Hypersensitivity, Delayed; Iloprost; Inflammation; Leukotriene B4; Lipoxins; Mice; Phthalic Anhydrides; Skin; Terpenes

It has been demonstrated that neutrophils from healthy donors or from patients with inflammatory disorders can bind immunoglobulin (Ig) E proteins through binding to Mac-2/epsilon bp. Functional responses to allergens were assessed by measuring the respiratory burst and intracellular Ca2+ levels, and binding of allergens to neutrophils was assessed by flow cytometry analysis and fluorescence microscopy. In this article, we demonstrate that neutrophils sensitized to specific allergens (from allergic patients), but not from healthy donors, are sensitive to allergens of the same type as those that produce clinical allergic symptoms. The activation of neutrophils was analyzed by the induction of a respiratory burst that was detected with luminol-dependent chemiluminescence. Intracellular Ca2+ levels increased parallel to those of the inducing allergens. In addition, the specific binding of allergens on the cell surface was revealed by flow cytometry and allergen-FITC-labeled staining analyses. The present data suggest a restricted recognition of allergen by sensitive neutrophils, probably associated with the specific binding of the allergen to its corresponding IgE molecule, which is bound to the Mac-2/epsilon bp structure. These findings demonstrate a functional role of allergen-associated neutrophils during the allergic state.

Topics: Allergens; Antigens; Antigens, Differentiation; Carcinogens; Diterpenes; Galectin 3; Humans; Hypersensitivity; Immunoglobulin E; Inflammation; Membrane Glycoproteins; Neutrophils; Poaceae; Reference Values; Terpenes

Reactive oxygen species (ROS) have been implicated as being involved in tumor promotion processes. However, the mechanism by which ROS modulate tumor promotion has not as yet been elucidated. In this report, we show that phorbol ester-type tumor promoters (12-O-tetradecanoylphorbol-13-acetate [TPA], mezerein and 12-O-retinoylphorbol-13-acetate [RPA]), which vary in their in vivo potencies, also differ in their effect on formation of hydrogen peroxide (H2O2) and oxidation of normal bases to 5-hydroxymethyl-2'-deoxyuridine [HMdU] and 8-hydroxyl-2'-deoxyguanosine [8-OHdG] in the DNA of SENCAR mouse epidermis, though they are equipotent in causing infiltration of polymorphonuclear leukocytes (PMNs). Treatment of SENCAR mice with the chemopreventive agents (-)-epigallocatechin gallate or tamoxifen (6.5 nmol) prior to application of TPA (6.5 nmol) diminished PMN infiltration, and formation of H2O2, HMdU and 8-OHdG. These results strengthen the evidence that ROS are involved in tumor promotion, and that generation of ROS and the subsequent oxidative DNA modification are related to the tumor-promoting potencies of the different phorbol ester-type promoters.

Topics: Animals; Carcinogens; Catechin; Diterpenes; DNA; DNA Damage; Female; Hydrogen Peroxide; Inflammation; Mice; Mice, Inbred Strains; Neutrophils; Oxidation-Reduction; Phorbol Esters; Skin; Tamoxifen; Terpenes; Tetradecanoylphorbol Acetate

Tumor-promoting phorbol esters are potent inflammatory agents for mouse skin, and the potential mechanistic role of inflammation in tumor promotion is under active investigation. We have shown previously that resiniferatoxin, a uniquely irritant phorbol-related diterpene, acts as a capsaicin analogue to induce and then to block neurogenic inflammation. We report here that pretreatment of CD-1 mice with resiniferatoxin blocked the early (3 h) erythema and edema (6 h) in response to phorbol 12-myristate 13-acetate (PMA), whereas the edema at later times (12-24 h) was only partially blocked. Since the efficiency of resiniferatoxin pretreatment decreased as a function of time if PMA was applied 24, 48, or 96 h after resiniferatoxin administration, the late edema response to PMA may be a combination of increasing edema of nonneurogenic origin and the recovering neurogenic response due to the decreasing desensitization. For other phorbol esters, 12-deoxyphorbol mono- and diesters, and mezerein, differing kinetics of edema and differing degrees of blockade of edema following resiniferatoxin pretreatment were observed, as expected from the discrepancies between their inflammatory and tumor-promoting activities. PMA-induced skin hyperplasia, unlike edema, was not inhibited by resiniferatoxin pretreatment, suggesting that the early component of neurogenic inflammation was not essential for hyperplasia under our conditions. Distinction between inflammatory mechanisms may help to clarify the role of inflammation in tumor promotion.

Topics: Administration, Topical; Animals; Diterpenes; Dose-Response Relationship, Drug; Erythema; Female; Hyperplasia; Inflammation; Mice; Mice, Inbred Strains; Phorbol Esters; Skin; Terpenes; Tetradecanoylphorbol Acetate

The production of megakaryocytic colony-stimulating activity (MEG-CSA) was assayed in acetic acid extracts of skin from mice topically treated with inflammatory and tumor-promoting agents. A rapid induction of MEG-CSA was found in skin treated both with phorbol 12-myristate 13-acetate (PMA), a strong tumor promoter, and with mezerein, a weak tumor promoter, but no induction was found in untreated skin. The time course of induction of MEG-CSA following treatment of skin with PMA or mezerein was very similar to that previously demonstrated for the induction of granulocyte-macrophage colony-stimulating activity in mouse skin by these agents. The induced MEG-CSA was found in both the epidermis and the dermis. Pretreatment of the skin with beta-methasone abrogated the MEG-CSA induction. The cell number response curve suggests that the MEG-CSA acts directly on the progenitor cells of the megakaryocyte colonies. That topical administration of diterpene esters results in the rapid, local induction of MEG-CSA which can be blocked by beta-methasone pretreatment suggests a mechanism for the thrombocytosis associated with some inflammatory states. The indirect action in which diterpene esters induce in certain cells the production or release of growth regulatory factors for other cell types may also aid in understanding their carcinogenic properties.

Topics: Animals; Betamethasone; Diterpenes; Dose-Response Relationship, Drug; Growth Substances; Inflammation; Megakaryocytes; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Skin; Skin Physiological Phenomena; Terpenes; Tetradecanoylphorbol Acetate; Thrombocytosis

Topics: Alkaloids; Antipain; Cocarcinogenesis; Diterpenes; Humans; Indoles; Inflammation; Lyngbya Toxins; Neutrophils; Oxygen; Phorbol Esters; Phorbols; Superoxides; Terpenes; Tetradecanoylphorbol Acetate; Tretinoin; Vitamin A