Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, acinar cell damage, and systemic inflammation in acute pancreatitis

Abstract

Seyhun E, Malo A, Schäfer C, Moskaluk CA, Hoffmann R, Göke B, Kubisch CH. Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, acinar cell damage, and systemic inflammation in acute pancreatitis.

Soluble Epoxide Hydrolase Pharmacological Inhibition Ameliorates Experimental Acute Pancreatitis in Mice

“…The mechanism by which sEH inhibition attenuates MAPK signaling is not clear and can be related to reduced inflammation. Moreover, sEH pharmacological inhibition correlated with decreased activation of ER stress, namely PERK/eIF2a and IRE1a sub-arms, and is in line with previous studies implicating ER stress in AP (Kubisch et al, 2006;Seyhun et al, 2011;Malo et al, 2013). Furthermore, sEH inhibition attenuates cerulein-and arginine-induced apoptotic and necrotic/cell death.…”

“…We evaluated activation of ER transmembrane proteins protein kinase R-like ERregulated kinase (PERK) and IRE1a, and their downstream targets a-subunit of eukaryotic translation initiation factor 2 (eIF2a) and XBP1, respectively (Ron and Walter, 2007;Hotamisligil, 2010). In line with previous reports (Seyhun et al, 2011;Malo et al, 2013;Bettaieb et al, 2014), cerulein and arginine administration induced ER stress in the pancreas (Fig. 5).…”

“…ER stress is implicated in AP (Kubisch et al, 2006;Seyhun et al, 2011;Malo et al, 2013). Given the capacity of sEH deficiency and inhibition to regulate ER stress response (Bettaieb et al, 2013), the effects of sEH pharmacological inhibition on ER stress in control and sEHI-treated mice were determined.…”

“…sEH inhibition attenuates high-fat diet-induced ER stress in vivo and chemical-induced ER stress in cultured cells (Bettaieb et al, 2013). Activation of ER stress is associated with AP (Kubisch et al, 2006), and treatment with ER chaperones mitigates the disease in animal models (Seyhun et al, 2011;Malo et al, 2013). Accordingly, sEH inhibition, through its capacity to modulate inflammatory and ER stress responses, impacts key signaling mechanisms previously implicated in AP.…”

Tauroursodeoxycholic acid inhibits apoptosis associated with ventilator-induced lung injury in rabbits

“…In contrast, TUDCA is a molecule with potent anti-apoptotic, pro-survival properties and limited side effects which appears to have protective effects in other type of injuries encountered in critically ill patients including acute kidney injury 44 , pancreatitis 45 , toxin induced myonecrosis 46 , acute brain injury 47 and others. Those effects together with the lack of known problematic side effects in the critically ill makes this drug well suited to study the contribution of apoptosis in models of critical illness and its modulation as a possible but yet uncertain therapeutic pathway that needs to be ultimately tested in humans.…”