Lansoprazole Protects and Heals Gastric Mucosa from Non-steroidal Anti-inflammatory Drug (NSAID)-induced Gastropathy by Inhibiting Mitochondrial as Well as Fas-mediated Death Pathways with Concurrent Induction of Mucosal Cell Renewal

Abstract

We have investigated the mechanism of antiapoptotic and cell renewal effects of lansoprazole, a proton pump inhibitor, to protect and heal gastric mucosal injury in vivo induced by indomethacin, a non-steroidal anti-inflammatory drug (NSAID). Lansoprazole prevents indomethacin-induced gastric damage by blocking activation of mitochondrial and Fas pathways of apoptosis. Lansoprazole prevents indomethacin-induced up-regulation of proapoptotic Bax and Bak and down-regulation of antiapoptotic Bcl-2 and Bcl xL to maintain the normal proapoptotic/antiapoptotic ratio and thereby arrests indomethacin-induced mitochondrial translocation of Bax and collapse of mitochondrial membrane potential followed by cytochrome c release and caspase-9 activation. Lansoprazole also inhibits indomethacin-induced Fas-mediated mucosal cell death by down-regulating Fas or FasL expression and inhibiting caspase-8 activation. Lansoprazole favors mucosal cell renewal simultaneously by stimulating gene expression of prosurvival proliferating cell nuclear antigen, survivin, epidermal growth factor, and basic fibroblast growth factor. The up-regulation of Flt-1 further indicates that lansoprazole activates vascular epidermal growth factor-mediated controlled angiogenesis to repair gastric mucosa. Lansoprazole also stimulates the healing of already formed ulcers induced by indomethacin. Time course study of healing indicates that it switches off the mitochondrial death pathway completely but not the Fas pathway. However, lansoprazole heals mucosal lesions almost completely after overcoming the persisting Fas pathway, probably by favoring the prosurvival genes expression. This study thus provides the detailed mechanism of antiapoptotic and prosurvival effects of lansoprazole for offering gastroprotection against indomethacin-induced gastropathy.Non-steroidal anti-inflammatory drugs (NSAIDs), 2 commonly used for the treatment of arthritis and other musculoskeletal disorders are considered to be one of the most important causative factors for gastric damage (1-3). Although various mechanisms have been suggested for NSAID-induced gastric ulcer (4 -7), recent studies suggest that increased apoptotic cell death and simultaneous block of mucosal cell renewal play major roles in the development of mucosal lesion (8 -10). Healthy gastric mucosa is always under equilibrium between cell death and cell renewal (11, 12) and mucosal injury is developed when this balance is disturbed due to an increase in apoptosis and/or inhibition of cell proliferation (11,12). NSAIDs are shown to induce apoptosis in gastric mucosal cells through reactive oxygen species generation, cytochrome c release, activation of caspase-3, inhibition of survivin expression, and induction of Ca 2ϩ signaling (8,10,13,14). Caspase-3 activation is generally mediated through two main pathways, viz. the mitochondrial (internal) and death receptor (external) pathways (15, 16). In the mitochondrial pathway, up-regulation or activation of pro-apoptotic proteins and/or down-regulation or inactivat...

Tryptamine-Gallic Acid Hybrid Prevents Non-steroidal Anti-inflammatory Drug-induced Gastropathy

“…(7) and lansoprazole (ED 50 ϭ 5.4 mg⅐kg Ϫ1 b.w.) (5). Although proton pump inhibitors are effective at a very low dose against NSAID-induced gastropathy (5), they have some adverse effects like diarrhea (57), linear mucosal defects, and friable mucosa associated with collagenous colitis (58,59), subacute cutaneous lupus erythematosus (60), Leydig cell tumors (61), acute nephritis (62), myopathy including polymyositis (63), and anaphylactic reactions (64).…”

“…Intramitochondrial free iron and ROS lead to MOS and consequent dysfunction (19 -25). MOS disrupts cellular integrity and promotes cell death (5,26,27), which ultimately leads to organ damage. The overproduction of ROS develops mitochondrial pathology (22,24,28,29), as indicated by the defect in electron transport chain and ATP synthesis, opening of mitochondrial permeability transition pore (MPTP), fall in transmembrane potential (⌬⌿ m ), oxidative damage of mitochondrial DNA, proteins, and phospholipids (30), and finally the activation of the mitochondrial pathway of apoptosis (6,31).…”

“…The rats were provided with water ad libitum. A gastric mucosal lesion was induced by indomethacin as described (5). Briefly, all of the animals were divided into control, indomethacin-treated, and drug-pretreated indomethacin-treated groups.…”

“…was given to the fasted animals to induce gastric injury. In the drug-pretreated groups, the animals were given SEGA (3a) (50,20,10,5,3, and 1 mg⅐kg Ϫ1 b.w. ), intraperitoneally 30 min prior indomethacin treatment.…”

Association of Heme Oxygenase 1 with the Restoration of Liver Function after Damage in Murine Malaria by Plasmodium yoelii

“…Apoptosis was determined by measuring the caspase-3 activity in cytosolic fractions of liver tissues by use of a commercially available kit (Sigma, St. Louis, MO) as mentioned previously (53,54,56,60). The instructions provided by the manufacturer were followed.…”