Figure 2.

Amplification loops that contribute to an individual exceeding critical threshold 1 (Acute pancreatitis (AP)) and critical threshold 2 (severe AP) in the pathogenesis and progression of AP. While distinct, the loops interact and drive each other. (A) Toxins that increase the open probability of inositol trisphosphate receptor (IP₃R) and ryanodine receptor (RyR) Ca²⁺ channels induce release of Ca²⁺ from the endoplasmic reticulum (ER), raising the concentration of Ca²⁺ in the cytosol ([Ca²⁺]_i) and mitochondria ([Ca²⁺]_m) while lowering that in the ER ([Ca²⁺]_ER), which drives formation of stromal interaction molecule-calcium release-activated calcium channel-transient receptor potential canonical cation channel (STIM-ORAI-TRPC) puncta for Ca²⁺ entry. Continued elevation of [Ca²⁺]_m induces the mitochondrial permeability transition pore (MPTP) with loss of mitochondrial membrane potential and ATP production, which impairs Ca²⁺ clearance by the sarcoendoplasmic reticulum and plasma membrane Ca²⁺ ATPases (SERCA and PMCA) pumps, further increasing [Ca²⁺]_i and [Ca²⁺]_m. (B) Diminished ATP production induces defective autophagy, disordered endolysosomal trafficking, building up activated digestive enzymes and further driving intracellular and extracellular injury. (C) Sustained elevations of [Ca²⁺]_i and [Ca²⁺]_m induce nuclear factor of activated T cells (NFAT), nuclear factor kappa B (NF-κB) and the Nucleotide-binding oligomerisation domain, Leucine rich Repeat and Pyrin domain containing (NLRP) inflammasome system resulting in cytokine release, stimulating resident and infiltrating leucocytes, causing further parenchymal injury. (D) Acinar-ductal tango: ductal secretion may be diminished by inherited or acquired defects of cystic fibrosis transmembrane conductance regulator (CFTR) function or ductal obstruction that in turn injures acinar cells that release activated zymogens which further diminish ductal function. (E) Necrosis releases damage-associated molecular patterns (DAMPs, for example, histones, DNA) that attract and activate leucocytes which release cytokines, inflammatory mediators and neuropeptides. Parenchymal and circulating inflammatory mediators exacerbate local pancreatic and distant systemic organ injury resulting in further necrosis. (F) Inflammatory injury of the gut, lung and other organs damage mucosal and epithelial protective barriers, which bacteria breach to infect local and distant sites. Systemic sepsis impacts on organ function, prompting further inflammation and tissue injury.