Nonsteroidal Anti-Inflammatory Drug-Activated Gene-1 Plays a Role in the Impairing Effects of Cyclooxygenase Inhibitors on Gastric Ulcer Healing

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) can impair gastric ulcer healing. This study investigates the involvement of NSAIDactivated gene-1 (NAG-1) in ulcer repair impairment by cyclooxygenase (COX) inhibitors. Gastric ulcers were induced in rats by acetic acid. Four days later, animals received daily intragastric indomethacin (nonselective COX-1/COX-2 inhibitor; 1 mg/kg), 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560) (selective COX-1 inhibitor; 2.5 mg/kg), (5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl) phenyl-2(5H)-furanone (DFU) (selective COX-2 inhibitor; 5 mg/kg), celecoxib (selective COX-2 inhibitor; 1 mg/kg), and valdecoxib (selective COX-2 inhibitor; 1 mg/kg), for 1, 3, or 7 days. Ulcerated tissues were processed to assess: 1) COX-1, COX-2, NAG-1, proliferating cell nuclear antigen (PCNA), and activated caspase-3 expression; 2) ulcer area; and 3) prostaglandin E 2 (PGE 2 ) levels. COX-1 expression in ulcerated tissues was decreased, whereas COX-2 expression was enhanced. Ulcer healing was delayed by indomethacin, DFU, and SC-560, but not by celecoxib and valdecoxib. Ulcer PGE 2 levels were decreased by SC-560, DFU, celecoxib, valdecoxib, and indomethacin. NAG-1 was overexpressed in ulcerated tissues and further enhanced by indomethacin, DFU, and SC-560, but not by celecoxib or valdecoxib. PCNA expression in ulcerated areas was reduced by indomethacin, but not by the other test drugs. The expression of activated caspase-3 in ulcers was increased and enhanced further by indomethacin, DFU, and SC-560, but not by celecoxib and valdecoxib. These findings indicate that: 1) COX inhibitors exert differential impairing effects on gastric ulcer healing, through mechanisms unrelated to the inhibition of COX isoforms and prostaglandin production; and 2) NAG-1 induction, followed by activation of proapoptotic pathways, can contribute to the impairing effects of COX inhibitors on ulcer healing.

Schiff Base Metal Derivatives Enhance the Expression of HSP70 and Suppress BAX Proteins in Prevention of Acute Gastric Lesion

“…The gastric lesion indexing was performed as described by several works [ 38 – 41 ]. In brief, a dissecting microscope of the lesion area (mm 2 ) was measured.…”

Development of GI-safe NSAID; progression from the bark of willow tree to modern pharmacology

“…Retarded epithelial cell restitution Though the precise net outcome of NSAID action on cell proliferation remains unclear, NSAIDs and responsible gene, NSAID-activated gene-1 either confer inferior mucosal integrity or delay the epithelial restitution [17].…”

Early Epithelial Restitution by Nonsteroidal Anti-Inflammatory Drug–Activated Gene 1 Counteracts Intestinal Ulcerative Injuries

“…Although NAG-1 is involved in acute stress-induced apoptotic process (10), increasing recent evidences demonstrated that NAG-1 can trigger homeostatic cellular responses and play protective roles in both physiological and pathological states, including chronic inflammation and tumorigenesis (16)(17)(18)(19). In response to the cytotoxic NSAIDs, cells also can produce the survival signals.…”

“…Although most intestinal epithelial cells maintain a low level of NAG-1 expression, apoptotic mucosal surface epithelial cells can have relatively high levels of NAG-1 (15). Although NAG-1 is involved in acute stress-induced apoptotic process (10), increasing recent evidences demonstrated that NAG-1 can trigger homeostatic cellular responses and play protective roles in both physiological and pathological states, including chronic inflammation and tumorigenesis (16)(17)(18)(19). NAG-1, one of the major secreted proteins induced by p53, is thought to be important for promoting p53-mediated activity associated with cell cycle arrest and apoptosis (20).…”

“…However, the therapeutic uses of NSAIDs are frequently limited by the significant negative side effects, including ulceration, most notably in the gastrointestinal tract. Increasing evidence indicates that the ulcerogenic properties of NSAIDs are not exclusively the result of inhibition of protective cyclooxygenase metabolites (3,9,10). NSAID-activated gene 1 has been investigated as a potent mediator of cyclooxygenase-independent pathogenesis by NSAIDs (11,12).…”