calcipotriene and Hyperplasia

The type 2 cytokines IL-4 and IL-13 promote not only atopic dermatitis (AD) but also the resolution of inflammation. How type 2 cytokines participate in the resolution of AD is poorly known.. Our aim was to determine the mechanisms and cell types governing skin inflammation, barrier dysfunction, and resolution of inflammation in a model of AD.. Mice that exhibit expression of IL-4, IL-13, and MCPT8 or that could be depleted of basophils or eosinophils, be deficient in IL-4 or MHC class II molecules, or have basophils lacking macrophage colony-stimulating factor (M-CSF) were treated with calcipotriol (MC903) as an acute model of AD. Kinetics of the disease; keratinocyte differentiation; and leukocyte accumulation, phenotype, function, and cytokine production were measured by transepidermal water loss, histopathology, molecular biology, or unbiased analysis of spectral flow cytometry.. In this model of AD, basophils were activated systemically and were the initial and main source of IL-4 in the skin. Basophils and IL-4 promoted epidermal hyperplasia and skin barrier dysfunction by acting on keratinocyte differentiation during inflammation. Basophils, IL-4, and basophil-derived M-CSF inhibited the accumulation of proinflammatory cells in the skin while promoting the expansion and function of proresolution M2-like macrophages and the expression of probarrier genes. Basophils kept their proresolution properties during AD resolution.. Basophils can display both beneficial and detrimental type 2 functions simultaneously during atopic inflammation.

Topics: Animals; Basophils; Calcitriol; Cell Differentiation; Cytokines; Dermatitis, Atopic; Diphtheria Toxin; Edema; Eosinophils; Female; Gene Expression; Histocompatibility Antigens Class II; Hyperplasia; Keratinocytes; Male; Mice, Inbred C57BL; Mice, Transgenic; Skin

Topics: Calcitriol; Cell Proliferation; Dermatologic Agents; Down-Regulation; Epidermis; Humans; Hyperplasia; Interleukin-22; Interleukins; Keratinocytes; Receptors, Interleukin; Tissue Culture Techniques

A 4-week repeated percutaneous dose toxicity of calcipotriol (MC903), an anti-psoriasic agent, followed by a recovery for 4 weeks was studied in Slc:SD rats at doses of 4, 20 and 100 micrograms/kg/day as low, mid and high dose levels. 1. One male and female at high dose died probably due to stress and circulatory failure. One female at mid dose died with clonic convulsion considered to be results in attached error of a neck collar. Survival of rats showed reddish tear, reddening and desquamation of the skin at application site, and vocalization at all groups including control. Furthermore, abnormal gait, dirty hair, emaciation and opacity of the eyeball surface in both sexes were observed at high dose. 2. A decreased body weight and a slight increased water consumption in both sexes, and a decreased food consumption in males were observed at high dose. 3. An increased incidence of corneal opacity was noted significantly in both sexes as compared with control at high dose. Urinalysis revealed an increased Ca excretion in both sexes at more than mid dose, and lower pH in females at mid dose and in both sexes at high dose, and a decreased urinary volume in males at high dose. The increases of neutrophil and serum beta-globulin ratios in females, and serum Ca level in both sexes were observed at high dose. The increased mineralization of the cornea in males at mid dose and in both sexes at high dose, and of the Kidney in males at high dose were observed. At the skin of application site, cellular infiltration in the epidermis and dermis in both sexes at more than mid dose was observed. Furthermore, hyperplasia of the squamous cell in females, and hyperkeratosis in the epidermis and hypertrophy of the sebaceous gland in both sexes were observed at high dose. 4. After a 4-week recovery period, the changes related with application disappeared except for opacity of the eyeball surface and cornea, and mineralization of organs. 5. On the basis of results obtained in the present study, it is considered that 4 micrograms/kg/day is the no-toxic dose of MC903 applied percutaneously in both sexes of rats.

Topics: Administration, Cutaneous; Animals; Beta-Globulins; Body Weight; Calcitriol; Calcium; Corneal Opacity; Dermatologic Agents; Drug Administration Schedule; Female; Hyperplasia; Leukocyte Count; Male; Neutrophils; Rats; Rats, Sprague-Dawley; Skin

A 4-week repeated percutaneous dose toxicity of calcipotriol (MC903), an anti-psoriasic agent, followed by a 4-week recovery was studied in beagle dogs at doses of 0.04, 0.4 and 4 micrograms/kg/day. 1. In general conditions, reddening, desquamation, rash, and wet and hot skin were observed at the skin of application site at 4 micrograms/kg/day. 2. In urinalysis, a tendency to an increase in Ca level, was observed at 4 micrograms/kg/ day. In hematology, an increase in the segmented neutrophils and tendency to a decrease in the lymphocyte counts were observed at 4 micrograms/kg/day. In biochemistry of serum, an increase in gamma-globulin ratio, and decreases in A/G and albumin ratios were observed at 4 micrograms/kg/day. 3. In organ weights, tendency to decreases of the absolute and relative weights in the thymus was observed at 4 micrograms/kg/day. 4. Histopathological examination revealed squamous cell hyperplasia and hyperkeratosis at the skin of application site at 4 micrograms/kg/day. 5. The above changes disappeared after the 4-week recovery period and suggested that they were reversible. 6. On the basis of results obtained in the present study, it is considered that 0.4 microgram/kg/day is the no-toxic dose of MC903 applied percutaneously in both sexes of beagle dogs.

Topics: Administration, Cutaneous; Animals; Calcitriol; Calcium; Dermatologic Agents; Dogs; Drug Administration Schedule; Female; gamma-Globulins; Hyperplasia; Leukocyte Count; Male; Organ Size; Skin; Thymus Gland

A 26-week repeated percutaneous dose toxicity of calcipotriol (MC903), an anti-psoriasic agent, was studied in beagle dogs at doses of 0.04, 0.4 and 4 micrograms/kg/day. 1. In general conditions, reddening, rash, desquamation, pruritus, wet and hot skin at 4 micrograms/kg/day, reddening, rash and desquamation at 0.4 microgram/kg/day, pruritus and desquamation at 0.04 microgram/kg/day, were observed at the skin of application site. 2. In urinalysis, an increase or a tendency to an increase in Ca level, were observed at 4 micrograms/kg/day. 3. Histopathological examinations revealed squamous cell hyperplasia and parakeratosis at the skin of application site in both sexes at 4 micrograms/kg/day. However, these findings were not shown at the skin of application site at 0.4 and 0.04 microgram/kg/day. 4. On the basis of results obtained in the present study, it is considered that 0.4 microgram/kg/day is the no-toxic dose of MC903 applied percutaneously in both sexes of beagle dogs.

Topics: Administration, Cutaneous; Animals; Calcitriol; Calcium; Dermatologic Agents; Dogs; Drug Administration Schedule; Female; Hyperplasia; Keratosis; Male; Pruritus; Skin