Matrix metalloproteinase inhibitors reduce phorbol ester-induced cutaneous inflammation and hyperplasia

Holleran, Walter M.; Galardy, Richard E.; Gao, Wei; Lévy, Daniel; Tang, Peng; Elias, Peter M.

doi:10.1007/s004030050169

Cited by 41 publications

(32 citation statements)

References 34 publications

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“…In addition, we demonstrate a reduction in MPO activity in direct relation with BB-94 dosage, thus proving the decrease in the inflammatory infiltrate. These results are in line with previous studies that reported similar effects when using MMP inhibitors for other inflammatory diseases [8, 9, 19]. …”

Section: Discussionsupporting

confidence: 83%

“…In a recent report, Holleran et al [8]showed that GM 6001, a potent inhibitor of MMPs, decreased both the inflammatory cellular infiltrates and epidermal hyperalgesia in a rat model of induced inflammation, thus demonstrating that use of MMP antagonists might be a new therapeutic approach to controlling inflammatory response. In addition, MMPs, such as gelatinases, are produced by phagocytes and thought to play a critical role in cell transmigration and tissue remodeling processes.…”

Section: Introductionmentioning

confidence: 99%

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Beneficial Effects of Batimastat (BB-94), a Matrix Metalloproteinase Inhibitor, in Rat Experimental Colitis

Sebastiano

Mola²,

Artese³

et al. 2001

Digestion

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Background and Aims: Matrix metalloproteinases (MMPs) represent a group of enzymes that regulate cell-matrix composition playing a major role in the inflammatory response. In the present study we evaluated the ability of the MMP inhibitor Batimastat (BB-94) to modify the course of experimental colitis induced in the rat by trinitrobenzensulfonic acid (TNB). Methods: Colitis was induced in 40 rats by intracolonic administration of TNB. Animals were divided into four groups of ten rats each: group 1 received only intracolonic TNB, group 2 received TNB+5 mg/kg intraperitoneal BB-94, group 3 TNB+10 mg/kg BB-94 and group 4 TNB+20 mg/kg BB-94. The MMP inhibitor was administered 30 min before induction of colitis and twice daily until death. Ten rats receiving only intracolonic 0.9% saline served as controls. Animals were killed after seven days; segments of colon were removed and used for histological score of inflammation and myeloperoxidase (MPO) activity. Results: Rats receiving only intracolonic 0.9% saline showed no evidence of colitis. The inflammation score was 0.9, MPO activity 0.235 U/mg. Group 1 (TNB-treated rats) exhibited a high inflammation score (12.4) and MPO activity (0.715 U/mg). Conversely, BB-94-treated rats showed, compared to the TNB group, a significantly lower inflammation score and MPO activity in a dose-dependent fashion. Group 2: inflammatory score 10.1, MPO activity 0.474 (p < 0.05 vs. TNB); group 3: inflammatory score 8.3, MPO activity 0.287 (p < 0.01 vs. TNB); group 4: inflammatory score 5.0, MPO activity 0.256 (p < 0.01 vs. TNB). Conclusions: Treatment with BB-94 has dose-dependent beneficial effects on the inflammatory alterations in rat experimental colitis. Thus, the inhibition of MMPs may represent a novel therapeutic approach for treatment of intestinal inflammation.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Beneficial Effects of Batimastat (BB-94), a Matrix Metalloproteinase Inhibitor, in Rat Experimental Colitis

Sebastiano

Mola²,

Artese³

et al. 2001

Digestion

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“…Recently, much attention has been devoted to the stimulatory effect of AP-1 on the transcription of matrix metalloproteinase genes encoding collagenase, gelatinase and stromelysin. These zinc-dependent proteases appear to be involved in dermal matrix remodeling occurring during inflammation (Holleran et al 1997), wound healing (Saarialho-Kere et al 1993) and UV-induced skin damage (Fisher et al 1996). It has been suggested that metalloproteinase-mediated collagen destruction accounts, largely, for the connective tissue damage that occurs in photoaging and during natural skin aging (Varani et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D inhibits the activation of stress-activated protein kinases by physiological and environmental stresses in keratinocytes

Ravid

Rubinstein²,

Gamady³

et al. 2002

Journal of Endocrinology

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In addition to its known effects on keratinocyte proliferation and differentiation, the hormonal form of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), has been shown to protect keratinocytes from UV-and chemotherapy-induced damage. Epidermal keratinocytes contain both the machinery needed to produce 1,25(OH) 2 D 3 and vitamin D receptors. The activation of the stress-activated protein kinases (SAPKs), such as c-Jun N-terminal kinase (JNK) and p38, is an early cellular response to stress signals and an important determinant of cell fate. This study examines whether modulation of these SAPKs is associated with the effects of 1,25(OH) 2 D 3 on keratinocytes under stress. HaCaT keratinocytes were exposed to heat shock, hyperosmotic concentrations of sorbitol, the epidermal growth factor receptor tyrosine kinase inhibitor AG1487, the pro-inflammatory cytokine tumor necrosis factor , and H 2 O 2 . These stresses activated both SAPKs. Pretreatment with 1,25(OH) 2 D 3 inhibited the activation of JNK by all stresses and the activation of p38 by heat shock, AG1478 and tumor necrosis factor . Under the same conditions, treatment with 1,25(OH) 2 D 3 protected HaCaT keratinocytes from cytotoxicity induced by exposure to H 2 O 2 and hyperosmotic shock. The effect of 1,25(OH) 2 D 3 was dosedependent, already apparent at nanomolar concentrations, and time-dependent, maximal after a 24-h pre-incubation. We suggest that inhibition of SAPK activation may account for some of the well-documented protective effects of 1,25(OH) 2 D 3 on epidermal cells during exposure to UV or chemotherapy and may also be related to the anti-inflammatory actions of the hormone in skin.

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“…PP1 (Hanke et al, 1996) was purchased from BIOMOL Research Laboratories (Plymouth Meeting, PA). GM6001 (Holleran et al, 1997), PD158780, and SU6656 (Rewcastle et al, 1998;Blake et al, 2000) were purchased from Calbiochem (San Diego, CA). Unless stated specifically, all other chemicals were purchased from SigmaAldrich.…”

Section: Methodsmentioning

confidence: 99%

Src Family Kinase Inhibitors Block Amphiregulin-Mediated Autocrine ErbB Signaling in Normal Human Keratinocytes

Kansra¹,

Stoll²,

Johnson³

et al. 2004

Mol Pharmacol

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c-Src potentiates proliferation, survival, and invasiveness in response to epidermal growth factor (EGF) in human mammary carcinoma cells. Tyrosine (Tyr) 845 of ErbB1 is phosphorylated by Src and has been implicated in control of malignant behavior. Although several lines of evidence also suggest important interactions of ErbB and Src family kinase signaling in normal epithelial cells, little is known about the mechanism of this interaction. Studying normal human keratinocytes (NHKs), here we demonstrate strong expression of the Src family kinases Src, Yes, and Fyn; Src family kinase-dependent stimulation of Tyr 845 by EGF; and potent inhibition of NHK proliferation and migration by two Src family kinase inhibitors PP1 and PD173952. EGF-stimulated extracellular signal-regulated kinase (ERK) phosphorylation occurred at much lower concentrations of EGF than required to phosphorylate Tyr 845. Moreover, the effect of Src family kinase inhibitors on EGFstimulated ERK phosphorylation was transient, prompting a search for other targets of Src family kinase action. By enzymelinked immunosorbent assay analysis, we found that three different Src family kinase inhibitors [6-(2,6-, and 2-oxo-3-(4,5,6,7-tetrahydro-1H-indol-2-ylmethylene)-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (SU6656)] markedly inhibited elaboration of soluble amphiregulin by NHKs. The ErbB inhibitor PD158780 and the mitogen-activated protein kinase kinase inhibitor U0126 also markedly inhibited NHK proliferation, migration, and amphiregulin production. Together, these observations demonstrate that one or more Src family kinases act upstream as well as downstream of ErbB1 to promote amphiregulin-dependent autocrine stimulation of NHKs and suggest that autocrine NHK proliferation is more dependent upon ERK activation than upon Tyr 845 phosphorylation.

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Matrix metalloproteinase inhibitors reduce phorbol ester-induced cutaneous inflammation and hyperplasia

Cited by 41 publications

References 34 publications

Beneficial Effects of Batimastat (BB-94), a Matrix Metalloproteinase Inhibitor, in Rat Experimental Colitis

Beneficial Effects of Batimastat (BB-94), a Matrix Metalloproteinase Inhibitor, in Rat Experimental Colitis

Vitamin D inhibits the activation of stress-activated protein kinases by physiological and environmental stresses in keratinocytes

Src Family Kinase Inhibitors Block Amphiregulin-Mediated Autocrine ErbB Signaling in Normal Human Keratinocytes

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