Inhibition of p38 MAP kinase as a therapeutic strategy

Lee, John C.; Kumar, Sanjay; Griswold, Don E.; Underwood, David C.; Votta, Bartholomew J.; Adams, Jerry L.

doi:10.1016/s0162-3109(00)00206-x

Cited by 442 publications

(315 citation statements)

References 133 publications

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“…59 This, too, is relevant to the development of pterygia because there is on-going debate as to whether there is a viral component to this disease. 60 -62 Alternatively, specific blockade of intracellular pathways downstream of EGFR activation such as targeting MAPK has been performed with some success in reducing disease severity 63 and inhibiting tumor cell invasiveness. 64 Finally, retinoic acid has been shown to inhibit the UVB-mediated induction of c-jun protein in human skin.…”

Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Receptor Signaling Is Partially Responsible for the Increased Matrix Metalloproteinase-1 Expression in Ocular Epithelial Cells after UVB Radiation

Girolamo

Coroneo

Wakefield

2005

The American Journal of Pathology

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Pterygia are inflammatory, invasive, and proliferative lesions of the human ocular surface in which the matrix metalloproteinase (MMP) collagenase-1 (MMP-1) is highly expressed. Pterygia development may involve MMP-1 activity against interstitial fibrillar collagen, an abundant extracellular matrix component of the cornea, and its induction by ultraviolet light (UVB). We examined the pathways responsible for enhanced expression of MMP-1 in pterygium epithelial cells after UVB exposure and/or treatment with chemical inhibitors of mitogen-activated protein kinases or epidermal growth factor receptor. The induction of MMP-1 by UVB was comparable to that mediated by heparin-binding epidermal growth factor-like growth factor and epidermal growth factor. The epidermal growth factor receptor inhibitor PD153035 partially blocked the UVB-mediated induction of MMP-1 and totally abrogated its production after stimulation with either heparin-binding epidermal growth factor-like growth factor or epidermal growth factor. UVB exposure enhanced the phosphorylated form of ERK1/2 in a time-dependent manner whereas the ERK1/2 inhibitor PD98059 decreased this induction by at least fivefold. Transcripts for c-jun and c-fos were detected as early as 2 hours after UVB exposure and were suppressed by PD98059. The identification of a specific intracellular signaling pathway responsible for the enhanced production of a key enzyme that denatures intact fibrillar collagen has important implications for understanding the pathophysiology and future therapy for pterygia. Pterygium is a condition of the ocular surface characterized by squamous cell metaplasia and goblet cell hyperplasia. The lesion consists of a wing-shaped mass of fibrovascular conjunctival tissue that invades the normal cornea. Other obvious pathological changes include activation of stromal fibroblasts, a persistent inflammatory component, elastotic degeneration, and destruction of collagenous barriers such as Bowman's layer. Pterygia are particularly prevalent in heavily sun-exposed individuals in whom extensive epidemiological studies link this disease to excessive ultraviolet (UV) radiation. 1-5 Despite this evidence, there is still controversy regarding the actual trigger for the development of pterygia and whether or not there is a genetic predisposition to this disease. 6 Recently, we have identified UVB as an environmental agent likely to be responsible for initiating molecular events that lead to the formation of pterygia. 7,8 From our hypothesis, 9 we postulate that UVB radiation activates cells at or near the limbus. This activation may cause 1) phenotypic alterations in a distinct population of epithelial cells, 2) production of proinflammatory and angiogenic cytokines 7 and growth factors, 8 and 3) increased invasiveness due to enhanced production of matrix metalloproteinases (MMPs) over and above their natural tissue inhibitors (TIMPs). 6,9 -12 To date, we 6,9 -12 and others [13][14][15][16][17] have accumulated data from in vitro culture and in vivo tissue-b...

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Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Receptor Signaling Is Partially Responsible for the Increased Matrix Metalloproteinase-1 Expression in Ocular Epithelial Cells after UVB Radiation

Girolamo

Coroneo

Wakefield

2005

The American Journal of Pathology

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“…Increased protein phosphorylation is a common finding in several diseases, which has positioned protein kinases as attractive drug targets and led to the emerging clinical utilization of kinase inhibitors for therapeutic purposes. 33,34 Increases in IF protein phosphorylation in disease states has been reported for neurofilaments in amyotrophic lateral sclerosis 35 and Alzheimer disease 36,37 ; desmin in animal and human cardiomyopathies 38 -40 ; lamin B2 in human leukemia cells 41 ; epidermal K5 and K6 in psoriasis and squamous cell carcinoma 19 ; K8/18 in Mallory bodies of human alcoholic liver disease and animal models with similar hyaline inclusions, 20 primary biliary cirrhosis, 22 in vascular smooth-muscle cells of atherosclerotic lesions and umbilical cord vessels 42 ; and vimentin after rat glomerular cell injury. 43 In most cases the increase in phosphorylation was demonstrated by immunofluorescence staining using phospho-specific antibodies.…”

Section: Discussionmentioning

confidence: 99%

Keratin 8 and 18 hyperphosphorylation is a marker of progression of human liver disease

Toivola

Resurreccion

et al. 2004

Hepatology

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Keratin 8 and 18 (K8/18) phosphorylation plays a significant and site-specific role in regulating keratin filament organization, association with binding proteins, and modulation of cell cycle progression. Keratin hyperphosphorylation correlates with exposure to a variety of stresses in cultured cells and in mouse models of liver, pancreatic, and gallbladder injury, and it is found in association with mouse and human Mallory bodies. We asked whether K8/18 phosphorylation correlates with human liver disease progression by analyzing liver explants and biopsies of patients with chronic noncirrhotic hepatitis C virus (HCV) or cirrhosis. We also examined the effect of HCV therapy with interleukin-10 on keratin phosphorylation. Using site-specific antiphosphokeratin antibodies we found keratin hyperphosphorylation on most K8/18 sites in all cirrhotic liver explants tested and in most liver biopsies from patients with chronic HCV infection. Immunofluorescence staining of precirrhotic HCV livers showed focal keratin hyperphosphorylation and limited reorganization of keratin filament networks. In cirrhotic livers, keratin hyperphosphorylation occurred preferentially in hepatic nodule cells adjacent to bridging fibrosis and associated with increased stress kinase activation and apoptosis. Histological and serological improvement after interleukin-10 therapy was accompanied by normalization of keratin hyperphosphorylation on some sites in 7 of 10 patients. In conclusion, site-specific keratin phosphorylation in liver disease is a progression marker when increased and a likely regression marker when decreased. (HEPATOLOGY 2004;40:459 -466.)

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“…More-specific inhibitors of certain intracellular molecular pathways have been developed recently. MAP kinase inhibitors are able to modify the expression of costimulatory molecules and may represent promising therapeutic weapons in the future (37). Trichostatin A, a histone deacetylase inhibitor, modulates the expression of many proteins at the transcriptional level by modifying the histone acetylation status.…”

Section: Discussionmentioning

confidence: 99%