Immunomodulatory therapies for acute pancreatitis

Abstract

It is currently difficult for conventional treatments of acute pancreatitis (AP), which primarily consist of anti-inflammatory therapies, to prevent the progression of AP or to improve its outcome. This may be because the occurrence and progression of AP, which involves various inflammatory cells and cytokines, includes a series of complex immune events. Considering the complex immune system alterations during the course of AP, it is necessary to monitor the indicators related to immune cells and inflammatory mediators and to develop more individualized interventions for AP patients using immunomodulatory therapy. This review discusses the recent advances in immunomodulatory therapies. It has been suggested that overactive inflammatory responses should be inhibited and excessive immunosuppression should be avoided in the early stages of AP. The optimal duration of anti-inflammatory therapy may be shorter than previously expected (< 24 h), and appropriate immunostimulatory therapies should be administered during the period from the 3(rd) d to the 14(th) d in the course of AP. A combination therapy of anti-inflammatory and immune-stimulating drugs would hopefully constitute an alternative to anti-inflammatory drug monotherapy. Additionally, the detection of the genotypes of critical inflammatory mediators may be useful for screening populations of AP patients at high risk of severe infections to enable the administration of early interventions to improve their prognosis.

Keywords: Immunomodulatory therapy; Immunostimulation; Immunosuppression; Pancreatitis; Systemic inflammatory response syndrome.

Figures

Figure 1

Schematic presentation of the pathways involved in the inflammatory response during acute pancreatitis. Following lipopolysaccharide (LPS) stimulation, the inhibitors of κB (IκB) kinase are activated via the toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-dependent (blue) or -independent pathway (purple). Thereafter, IκBα is rapidly phosphorylated by IκB kinase and then degraded. This process allows nuclear factor-κB (NF-κB) to translocate into the nucleus and to increase the transcription of several important inflammatory genes, such as the genes encoding tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), adhesion molecules and chemokines. The up-regulation of these inflammatory mediators, in turn, either leads to further IκB kinase activation or mediates the migration of the inflammatory cells to the site of inflammation, thus amplifying the inflammatory response. Meanwhile, platelet-activating factor (released from active macrophages, endothelial cells or platelets) and endothelins (released from endothelial cells) are involved in the increased vascular permeability and extravasation of inflammatory cells. TNF R: Tumor necrosis factor receptor; IL-1 R: Interleukin-1 receptor; ICAM-1: Intercellularadhesionmolecule-1; PAF: Platelet-activating factor; ET: Endothelin.