Abstract
Small intestinal damage induced by nonsteroidal anti-inflammatory drugs (NSAIDs) remains an under-recognized clinical disorder. The incomplete understanding of the pathophysiology has hampered the development of prevention and treatment strategies leading to the high morbidity and mortality rates. NSAIDs are known to modulate macroautophagy, a process indispensable for intestinal homeostasis. Whether NSAIDs stimulate or repress macroautophagy and how this correlates with the clinical manifestations of NSAID enteropathy, however, remains unknown. The objectives of this study were to determine whether NSAIDs impaired macroautophagy and how this affects macroautophagy-regulated intestinal epithelial cell (IEC) processes essential for intestinal homeostasis (i.e., clearance of invading pathogens, secretion and composition of mucus building blocks, and inflammatory response). We show that NSAID treatment of IECs inhibits macroautophagy in vitro and in vivo. This inhibition was likely attributed to a reduction in the area and/or distribution of lysosomes available for degradation of macroautophagy-targeted cargo. Importantly, IEC regulatory processes necessary for intestinal homeostasis and dependent on macroautophagy were dysfunctional in the presence of NSAIDs. Since macroautophagy is essential for gastrointestinal health, NSAID-induced inhibition of macroautophagy might contribute to the severity of intestinal injury by compromising the integrity of the mucosal barrier, preventing the clearance of invading microbes, and exacerbating the inflammatory response.
Highlights
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used class of medications worldwide[1]
Intestinal epithelial cells (IECs) have evolved numerous strategies to prevent harmful reactions, including: (i) the secretion of mucin and antimicrobial peptides that shape the composition and location of the microbiota; (ii) suppressing the survival and dissemination of microorganisms that invade the mucosal layer; and, (iii) coordinating the responses of sub-epithelial immune cells[9]. All of these mechanisms are partly regulated by macroautophagy and its inhibition can negatively impact intestinal epithelial cell (IEC) function leading to microbial dysbiosis, invasion and dissemination of opportunistic pathogens, uncontrolled inflammatory responses and cell death[9]
The present study demonstrates that multiple classes of nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit autophagic flux in vitro by reducing the area and/or distribution of functional lysosomes in IECs
Summary
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used class of medications worldwide[1]. Intestinal epithelial cells (IECs) have evolved numerous strategies to prevent harmful reactions, including: (i) the secretion of mucin and antimicrobial peptides that shape the composition and location of the microbiota; (ii) suppressing the survival and dissemination of microorganisms that invade the mucosal layer; and, (iii) coordinating the responses of sub-epithelial immune cells[9] All of these mechanisms are partly regulated by macroautophagy and its inhibition can negatively impact IEC function leading to microbial dysbiosis, invasion and dissemination of opportunistic pathogens, uncontrolled inflammatory responses and cell death[9]. Harada et al, demonstrated that indomethacin treatment of IECs uncontrollably activates autophagy leading to cell death and small intestinal injury in rats[14] While both studies demonstrate the effects of indomethacin on autophagy, one suggests that indomethacin leads to uncontrolled autophagy activation and cell death, while the other suggests that initially indomethacin induces autophagy but results in inhibition of autophagic flux prompting cell apoptosis. IEC functions essential for intestinal homeostasis and partly regulated by autophagy, were dysfunctional in the presence of NSAIDs both in vitro and in vivo, suggesting that NSAIDs disrupt intestinal homeostasis as a result of autophagy inhibition
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