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While interleukin (IL)-1β is a potent pro-inflammatory cytokine involved in host defense, high levels can cause life-threatening sterile inflammation including systemic inflammatory response syndrome. Hence, the control of IL-1β secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1β is synthesized as a cytoplasmic inactive pro-form. Extracellular ATP originating from injured cells is a prototypical second signal for inflammasome-dependent maturation and release of IL-1β. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1β regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of AAT efficiently inhibit ATP-induced release of IL-1β from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1β release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1β release is independent of the anti-elastase activity of AAT. Signaling of AAT in monocytic cells involves the lipid scavenger receptor CD36, calcium-independent phospholipase A2β, and the release of a small soluble mediator. This mediator leads to the activation of nicotinic acetylcholine receptors, which efficiently inhibit ATP-induced P2X7 receptor activation and inflammasome assembly. We suggest that AAT controls ATP-induced IL-1β release from human mononuclear blood cells by a novel triple-membrane-passing signaling pathway. This pathway may have clinical implications for the prevention of sterile pulmonary and systemic inflammation.
Background. Arterial ex situ back-table perfusion (BP) reportedly reduces ischemic-type biliary lesion after liver transplantation. We aimed to verify these findings in a prospective investigation.
Methods. Our prospective, randomized, controlled, multicenter study involved livers retrieved from patients in 2 German regions, and compared the outcomes of standard aortic perfusion to those of aortic perfusion combined with arterial ex situ BP. The primary endpoint was the incidence of ischemic-type biliary lesions over a follow-up of 2 years after liver transplantation, whereas secondary endpoints included 2-year graft survival, initial graft damage as reflected by transaminase levels, and functional biliary parameters at 6 months after transplantation.
Results. A total of 75 livers preserved via standard aortic perfusion and 75 preserved via standard aortic perfusion plus arterial BP were treated using a standardized protocol. The incidence of clinically apparent biliary lesions after liver transplantation (n = 9 for both groups; P = 0.947), the 2-year graft survival rate (standard aortic perfusion, 74%; standard aortic perfusion plus arterial BP, 68%; P = 0.34), and incidence of initial graft injury did not differ between the 2 perfusion modes. Although 33 of the 77 patients with cholangiography workups exhibited injured bile ducts, only 10 had clinical symptoms.
Conclusions. Contrary to previous findings, the present study indicated that additional ex situ BP did not prevent ischemic-type biliary lesions or ischemia-reperfusion injury after liver transplantation. Moreover, there was considerable discrepancy between cholangiography findings regarding bile duct changes and clinically apparent cholangiopathy after transplantation, which should be considered when assessing ischemic-type biliary lesions.