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Acinar cell injury induces synthesis and release of proinflammatory cytokines [70,71] and of proinflammatory DAMPs (damage‐associated molecular patterns) including histones, high mobility group box 1 protein (HMGB1), nuclear and mitochondrial DNA, cyclophilin A, heat shock proteins, and ATP [14,72] that act in concert to initiate a cellular inflammatory response consisting primarily of neutrophils and monocytes (Figure 12.3). Nuclear DAMPs can be measured as early as four hours after induction of experimental AP [73,74] and act via common immune sensors, including toll‐like receptors (TLRs), nucleotide‐binding domain (NOD)‐like receptors (NLRs), and receptors for advanced glycation end‐products (RAGE), to initiate sterile inflammation [75]. Targeting these receptors ameliorates experimental AP. Genetic deletion of TLR4 [76] or TLR9 [77] has been shown to reduce disease severity, as has pretreatment with the TLR9‐specific antagonist IRS‐954 [77]. The RAGE ligand S100A9 directly affects pancreatic leukocyte infiltration, which in turn has been shown to limit the degree of intrapancreatic trypsin activation and tissue damage in cerulein‐induced AP [78]. Neutralizing antibodies to HMGB1 or histone H3 have ameliorated experimental AP in two models [79]. While there are no human trials targeting these mechanisms as yet, release and concentration of nuclear DAMPs directly correlates with disease severity in human AP [80,81].

Another approach for targeting inflammatory pathways in AP has derived from a focus on the kynurenine pathway of tryptophan metabolism, pursued by the Mole group at the University of Edinburgh in collaboration with GSK [82,83]. Kynurenine is converted into 3‐hydroxykynurenine and other downstream toxic metabolites that damage organs by the enzyme kynurenine‐3‐monooxygenase (KMO), a pathway that is upregulated in AP and which primes the immune system for the systemic inflammatory response [50]. Targeting this pathway with GSK’s KMO inhibitors [83] has been shown to prevent multiorgan dysfunction syndrome in experimental AP [82]. This work has gone forward into a Phase I trial, although a temporary halt has been placed on this work. It is hoped that any issues arising can be overcome with an adapted strategy so that this promising discovery can bear fruit in the treatment of AP.

Figure 12.3 Immune system/anti‐inflammatory strategies. Inflammation in AP may result directly from cell death‐dependent or ‐independent pathways. Acinar cell injury can result in direct cytokine and chemokine release that is then amplified by immune cells: interleukin (IL)‐1, IL‐2, IL‐6, IL‐8, IL‐12, IL‐18; platelet‐activating factor (PAF); tumor necrosis factor (TNF‐α). Cell death pathways resulting in cell membrane permeabilization or rupture (predominantly necrosis) of acinar cells, but also potentially neutrophils (NETosis), with the subsequent release of both mitochondrial and nuclear damage‐associated molecular patterns (DAMPs) also drives inflammation. Strategies inhibiting DAMPS (TLR‐9 with IRS‐954, monoclonal antibodies directed towards HMGB1 and histones), immune cell modulation such as by inhibiting NETosis (Cl‐amidine, chloroquine), or direct cytokine inhibition (infliximab, CytoSorb) all hold promise for AP. mtDNA, mitochondrial DNA; nDNA, nuclear DNA; TLR, toll‐like receptor; HSPs, heat shock proteins; HMGB1, high mobility group box 1.

Whereas release of DAMPs is thought to be primarily a passive process, pancreatic acinar cells also actively synthesize and release cytokines [70] and chemokines [84] and upregulate intercellular adhesion molecule (ICAM)‐1 [85] to promote neutrophil and monocyte infiltration [86,87]. Infiltrating inflammatory cells act together with activated peritoneal macrophages and hepatic Kupffer cells to amplify proinflammatory cytokines in the systemic circulation [88–90], manifesting clinically as the systemic inflammatory response syndrome (SIRS). Early intervention to reduce local and systemic AP injury is the basis of an ongoing randomized clinical trial of infliximab, a monoclonal anti‐tumor necrosis factor (TNF)‐α antibody, in early AP that is currently recruiting (RAPID‐I, ISRCTN16935761) as well as a pan‐cytokine absorption trial (PACIFIC [91]). With the exception of the use of nonsteroidal anti‐inflammatory agents in the prevention of pancreatitis post endoscopic retrograde cholangiopancreatography [92,93], these are the first trials in AP to directly target the inflammatory cascade since the lexipafant (platelet activating factor inhibitor) trials of the early 1990s [94], which despite promising preclinical results failed to demonstrate a benefit in human AP.

Neutrophils are among the earliest cellular responders to acinar cell injury and can be observed within the pancreas as early as one hour after initiation of experimental AP and after three hours in the lung [95]. Antibody‐mediated depletion of neutrophils ameliorates disease in experimental models [96–98], in particular with respect to associated lung injury. Knockout and/or inhibition of chemokines or their receptors can reduce inflammatory cell migration and has been shown to ameliorate AP in a variety of ways, including by inhibition of CXCR2 [99–101], CXCR4 [102], CXCL4 [103], and CXCL16 [104], but no human trials have been published to date. More recently, a novel mechanism of neutrophil toxicity has been described where neutrophils actively release nuclear chromatin, laced with proteases, in the form of web‐like structures termed neutrophil extracellular traps (NETs). NETs have been shown to promote the pathogenesis in experimental AP [105,106] and inhibition of NET release (NETosis) has been found to ameliorate AP by deletion of protein arginine deiminase type IV (PAD4), or through pharmacological inhibition with Cl‐amidine [107] or chloroquine [108]. Because of their highly regulated release and their effect on both pancreas and lung, NETs present a fantastic opportunity for the development of novel therapeutic agents.

Targeting immune‐based mechanisms has yet to be proven to be effective in the treatment of human AP, but the results of ongoing trials, notably RAPID‐I and PACIFIC, are awaited. The complex interactions and redundancies of immune pathways remain problematic, but the continuing discovery of new mechanisms, availability of novel investigative technologies, and a drive towards personalized medicine presents opportunities for yet untested strategies in this vital area.