Selective Cyclooxygenase-2 Inhibition Does Not Alter Keratinocyte Wound Responses in the Mouse Epidermis after Abrasion

Abstract

The cyclooxygenase isoforms, COX-1 and COX-2, are the rate limiting enzymes in the biosynthesis of prostaglandin E 2 , a major prostaglandin involved in epidermal homeostasis and repair. Epidermal injury results in transient hyperplasia and induction of COX-2 expression. The role of COX-2 in this hyperplasia is unknown, however. In this study, we characterized the epidermal expression of COX isozymes following wounding by abrasion in SKH-1 mice using immunohistochemistry, in situ hybridization, and Western analysis. In addition, we evaluated pivotal keratinocyte functions necessary for the reparative hyperplasia, including proliferation by 5-bromo-2Јdeoxy-uridine labeling and differentiation by the expression of involucrin, keratin 1, and keratin 6. Although COX-1 expression in keratinocytes remained unchanged during wound healing, COX-2 expression was induced coincidentally with keratinocyte proliferation and keratin 6 expression, suggesting a role for COX-2 in epidermal repair. The role of COX-2 was also evaluated using the selective COX-2 inhibitor SC-791 and the traditional COX inhibitors indomethacin and diclofenac. Neither inhibitor altered keratinocyte proliferation or differentiation following abrasion, in contrast to dexamethasone, which delayed these responses. Our results indicated that, although COX-2 expression was coincident with transient epidermal hyperplasia and keratinocyte proliferation/differentiation during the healing of epidermal injury, it does not play a pivotal role in this repair process.The epidermis is a stratified epithelium made up of basal, spinous, granular, and cornified layers. Under physiological situations, a precise balance between keratinocyte proliferation in the basal layer and the loss of corneocytes from the surface of the skin is maintained through a tightly regulated program of proliferation, differentiation, and vertical migration. Keratinocytes undergo distinct morphological changes during this program and initiate the synthesis of proteins that are differentially expressed in each epidermal layer (Eckert et al., 1997). For example, involucrin is expressed by keratinocytes in the late spinous and granular layers. Mechanical disruption of the epidermal cornified layer by tape stripping or mild abrasion results in increased keratinocyte proliferation, transient epidermal hyperplasia, and altered keratinocyte differentiation characterized by the abnormal expression of involucrin and the transient induction of the keratin 6/keratin 16 heterodimer (Bertsch et al., 1976;Eckert et al., 1993;Hatta et al., 1997;Ekanayake-Mudiyanselage et al., 1998). The signals that trigger changes in keratinocyte proliferation and differentiation following wounding are not completely understood. Disruption of the epidermal layer results in keratinocyte proliferation and induction of growth factors and cytokines, such as epidermal growth factor, interleukin-1, and tumor necrosis factor-␣, as well as the inducible form of cyclooxygenase (Tsai et al

Acquired Activation of the Akt/Cyclooxygenase-2/Mcl-1 Pathway Renders Lung Cancer Cells Resistant to Apoptosis

“…Here we show that suppressing COX-2 activity with chemical inhibitors and eliminating COX-2 protein with siRNA were equally effective in sensitizing the cells to apoptosis induced by different anticancer agents and was not accompanied by increases in DR5 (data not shown) as reported previously (Chen et al, 2007a). The difference in non-COX-2-related activity between our findings and those of others may be due to the use of different COX-2 inhibitors (Hardy et al, 2003;Malhotra et al, 2004). Nevertheless, our data clearly show that COX-2 has an antiapoptosis role in cancer cells with acquired apoptosis resistance.…”

The wound healing, chronic fibrosis, and cancer progression triad

“…For example, PGE2 inhibits hepatic fibrosis (23) as well as pulmonary fibrosis where it has been shown to limit fibroblast proliferation and myofibroblast differentiation (37, 187). Also, although COX-2 is expressed briefly in response to tissue injury (131), the use of COX-2 and prostaglandin inhibitors appears only to impart a modest effect over wound healing (131,244). Even though these types of inhibitors block inflammation, they exacerbate injury since they prevent wound healing especially in the intestine (354).…”

Glycine-extended gastrin inhibits apoptosis in Barrett's oesophageal and oesophageal adenocarcinoma cells through JAK2/STAT3 activation

“…We investigated the involvement of COX-2 by pre-treating the cells with either the non-selective COX-2 inhibitor indomethacin (10 mM) or two different COX-2 selective inhibitors (NS-398 (5 mM) or SC 791 (400 nM) (Hardy et al 2003)). All three agents induced a small but statistically insignificant increase in basal apoptosis in serum-starved cells (data not shown), but none of these COX inhibitors ameliorated the anti-apoptotic effects of G-Gly in OE33, BIC-1 or QhERT cells (Fig.…”