A Nanoconjugate Apaf-1 Inhibitor Protects Mesothelial Cells from Cytokine-Induced Injury

Abstract

BackgroundInflammation may lead to tissue injury. We have studied the modulation of inflammatory milieu-induced tissue injury, as exemplified by the mesothelium. Peritoneal dialysis is complicated by peritonitis episodes that cause loss of mesothelium. Proinflammatory cytokines are increased in the peritoneal cavity during peritonitis episodes. However there is scarce information on the modulation of cell death by combinations of cytokines and on the therapeutic targets to prevent desmesothelization.MethodologyHuman mesothelial cells were cultured from effluents of stable peritoneal dialysis patients and from omentum of non-dialysis patients. Mesothelial cell death was studied in mice with S. aureus peritonitis and in mice injected with tumor necrosis factor alpha and interferon gamma.Tumor necrosis factor alpha and interferon gamma alone do not induce apoptosis in cultured mesothelial cells. By contrast, the cytokine combination increased the rate of apoptosis 2 to 3-fold over control. Cell death was associated with the activation of caspases and a pancaspase inhibitor prevented apoptosis. Specific caspase-8 and caspase-3 inhibitors were similarly effective. Co-incubation with both cytokines also impaired mesothelial wound healing in an in vitro model. However, inhibition of caspases did not improve wound healing and even impaired the long-term recovery from injury. By contrast, a polymeric nanoconjugate Apaf-1 inhibitor protected from apoptosis and allowed wound healing and long-term recovery. The Apaf-1 inhibitor also protected mesothelial cells from inflammation-induced injury in vivo in mice.ConclusionCooperation between tumor necrosis factor alpha and interferon gamma contributes to mesothelial injury and impairs the regenerative capacity of the monolayer. Caspase inhibition attenuates mesothelial cell apoptosis but does not facilitate regeneration. A drug targeting Apaf-1 allows protection from apoptosis as well as regeneration in the course of inflammation-induced tissue injury.

Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease

“…The release of cytochrome c into the cytosol induces the formation of the apoptosome which, in turn, recruits and activates caspase-3. Proteolytic cleavage of calcineurin induces a loss of its calcium-calmodulin sensitivity 32 . This causes an increase in its phosphatase activity resulting in an increased dephosphorylation of GluR1 at Ser845, followed by substrates by caspase-3 cannot be excluded.…”

“…16). To confirm the effect of caspase-3 inhibition on GluR1 synaptic distribution we used the polyglutamic acid (PGA)-peptoid QM56 to inhibit the activity of the apoptosome 31 , a macromolecular complex activating caspase-3 and the mitochondrial-dependent apoptosis pathway 32 .…”

Peptide-Based Polymer Therapeutics

“…Although pro-apoptotic approaches are related with cancer therapy, anti-apoptotic strategies have also applications in regenerative medicine [96]. Vicent and coworkers designed the first anti-apoptotic polymeric nanomedicine: a PGA-based Apaf-1 inhibitor conjugate [97,98], which has shown to promote regeneration in the course of inflammation-induced tissue injury [99].…”

The value of CRP, IL-6, leptin, cortisol, and peritoneal caspase-3 monitoring in the operative strategy of secondary peritonitis

“…There is also a clear-cut correlation between caspase-3 levels and peritoneal mesothelial cell apoptosis. [16] With the above-mentioned literature data, monitoring of peritoneal fluid caspase levels in the treatment of peritonitis may add valid data to our clinical knowledge.…”