Lubiprostone Prevents Nonsteroidal Anti-Inflammatory Drug–Induced Small Intestinal Damage by Suppressing the Expression of Inflammatory Mediators via EP4 Receptors

Abstract

Lubiprostone, a bicyclic fatty acid derived from prostaglandin E 1 , has been used to treat chronic constipation and irritable bowel syndrome, and its mechanism of action has been attributed to the stimulation of intestinal fluid secretion via the activation of the chloride channel protein 2/cystic fibrosis transmembrane regulator (ClC-2/CFTR) chloride channels. We examined the effects of lubiprostone on indomethacin-induced enteropathy and investigated the functional mechanisms involved, including its relationship with the EP4 receptor subtype. Male Sprague-Dawley rats were administered indomethacin (10 mg/kg p.o.) and killed 24 hours later to examine the hemorrhagic lesions that developed in the small intestine. Lubiprostone (0.01-1 mg/kg) was administered orally twice 30 minutes before and 9 h after the indomethacin treatment. Indomethacin markedly damaged the small intestine, accompanied by intestinal hypermotility, a decrease in mucus and fluid secretion, and an increase in enterobacterial invasion as well as the up-regulation of inducible nitric-oxide synthase (iNOS) and tumor necrosis factor a (TNFa) mRNAs. Lubiprostone significantly reduced the severity of these lesions, with the concomitant suppression of the functional changes. The effects of lubiprostone on the intestinal lesions and functional alterations were significantly abrogated by the coadministration of AE3-208 [4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid], a selective EP4 antagonist, but not by CFTR(inh)-172, a CFTR inhibitor. These results suggest that lubiprostone may prevent indomethacin-induced enteropathy via an EP4 receptor-dependent mechanism. This effect may be functionally associated with the inhibition of intestinal hypermotility and increase in mucus/fluid secretion, resulting in the suppression of bacterial invasion and iNOS/ TNFa expression, which are major pathogenic events in enteropathy. The direct activation of CFTR/ClC-2 chloride channels is not likely to have contributed to the protective effects of lubiprostone.

NSAID-Induced Small Intestinal Damage - Roles of Various Pathogenic Factors

“…Other prostanoids such as ONO-NT-012 (an EP3 agonist) and ONO-AE1-329 (an EP4 agonist) provided dose-dependent protection against indomethacin-induced intestinal damage, whereas neither 17-phenyl PGE 2 (an EP1 agonist) nor butaprost (an EP2 agonist) had any effect on these lesions. Lubiprostone, a bicyclic fatty acid derived from PGE 1 [67], also prevented these lesions in the small intestine, and this effect was significantly abrogated by the co-administration of AE3-208, an EP4 antagonist, suggesting the involvement of EP4 receptors in these protective effects [57]. These findings support the importance of EP4 receptors in the protective effects of PGE 2 against NSAID-induced intestinal damage.…”

“…An RT-PCR analysis revealed that neither iNOS nor TNFα mRNAs was detected in the normal intestinal mucosa, but they were potently expressed in the mucosa as early as 3 h after the administration of indomethacin [56,57]. The upregulated expression of iNOS mRNA was similarly observed in the intestinal mucosa of animals given SC-560, but not rofecoxib [16].…”

“…Mucosal protective drugs were found to upregulate the expression of Muc2 and mucus secretion, thereby increasing the thickness of the mucus gel and hampering bacterial invasion following the administration of NSAIDs [35,39,55]. The secretion of intestinal fluid was also shown to prevent bacterial invasion by washing out the invading bacteria [10,35,56,57]. …”

“…Thus, controversy remains over the involvement of TNFα in the pathogenesis of NSAID-induced enteropathy. We reported that ampicillin, cinacalcet, or lubiprostone prevented the up-regulation of iNOS and TNFα as well as the invasion of enterobacteria in the intestinal mucosa following the administration of indomethacin, which suggested a close relationship between the mucosal invasion of enterobacteria and the upregulation of these cytokines [19,33,56,57]. …”

Lubiprostone in constipation: clinical evidence and place in therapy

“…Lubiprostone may be protective against nonsteroidal anti-inflammatory drug (NSAID) induced enteropathy via the EP4-dependent pathway. In rats, administration of lubiprostone significantly reduced indomethacin-induced damage to the small intestine, an effect that was eliminated in the presence of a selective EP4 antagonist [Hayashi et al 2014]. In a mouse model of cystic fibrosis, administration of lubiprostone increased proximal-and mid-intestinal mucin secretion [De Lisle, 2012].…”