3.3 Pathophysiology
While the pathophysiology of CP is not fully defined，a number of factors have been proposed.These pathophysiological models，mostly originated from animal studies，will be briefly discussed below.
3.3.1 Trypsin Pathways
In this model，the balance between proteolytic enzymes and anti-protease defense mechanisms is disturbed，leading to premature activation of zymogens within pancreas and autodigestion of the organ.The supportive models of this theory are gene mutations and specifically，the breakthrough discovery of the PRSS1 gene in 1996（Le Bodic et al.1996；Pandya et al.1996；Whitcomb et al.1996a，b）.This discovery substantiated the decades-old observation of familial clustering of chronic pancreatitis（Comfort and Steinberg 1952）.The most common mutations in PRSS1 linked to hereditary pancreatitis are R122H and N29I，leading to autoactivation of trypsinogen（Whitcomb et al.1996b）.SPINK1 encodes a protein that is involved in preventing trypsin-catalyzed premature activation of zymogens within pancreas.Because 1-4%of the general population carry one SPINK1 mutation（most commonly N34S），this gene is regarded as a modifier of the inflammatory process possibly tilting the balance in favor of ARP/CP（Aoun et al.2010；Pfutzer et al.2000；Threadgold et al.2002；Witt et al.2000）.Of note，children with PRSS1 or SPINK1 mutations were more likely to present with CP compared with ARP in the INSPPIRE cohort，suggesting that these genes may influence the development of CP（Kumar et al.2016）.Another candidate gene is CFTR.If CFTR function is completely or almost completely lost，children are born with cystic fibrosis（CF），severe pancreatic damage and exocrine pancreatic insufficiency（EPI）.A subset of pancreatic-sufficient CF patients develop recurrent attacks of AP and patients with compound heterozygous CFTR mutations have higher likelihood for CP（Cohn et al.1998；Sharer et al.1998）.The pathogenesis of CFTR-associated pancreatic damage is not clear，but thickened and acidic secretions in pancreas causing zymogen activation have been proposed（Whitcomb 2013）.The risk of pancreatitis increases up to 900-fold in the presence of both CFTR and SPINK1 mutations（Noone et al.2001）.Other candidate gene variants and their association with pancreatitis in the trypsin pathway have been described，including chymotrypsin C（CTRC）and calcium sensing receptor（CASR）（Baudry et al.2010；Felderbauer et al.2006；Masson et al.2008b；Muddana et al.2008；Rosendahl et al.2008）.
3.3.2 Inflammatory Pathways(https://www.daowen.com)
This theory is supported by animal models lacking trypsinogen that still develop inflammation in their pancreas following an insult（Dawra et al.2011）.Sustained activation of inflammatory pathways by various stimuli may lead to of CP in animal models.Different mechanisms have been postulated to play a role，including regulatory T cells，CD28，TNF，NFxB，IL-6 and IL-8，complement pathways and TGF-β（Abu-El-Haija et al.2011；Huang et al.2013；Meagher et al.2008）.In Autoimmune pancreatitis（AIP），T helper cells，IgG4（+）cells may also be involved（Okazaki et al.2000；Zen et al.2007）.
Other pathogenic cellular events such as abnormal calcium signaling，mitochondrial dysfunction，endoplasmic reticulum stress，autophagy and impaired trafficking，lysosomal and secretory responses also synergize with inflammatory pathways（Sah et al.2012）.
3.3.3 Fibrosis
The hallmark of CP is fibrosis and acinar cell loss of.Stellate cell activation has been proposed to have a role in progression to CP（Masamune and Shimosegawa 2013）.Smoking have a role in activating pancreatic stellate cells through the nicotinic acetylcholine receptors，as an agent on its own，or that effect might be enhanced with alcohol exposure（Lee et al.2015）.Stellate cells may induce fibrogenesis by activating Transforming Growth factorβ1（TGFβ1）and inhibition of Matrix metalloproteinases（Shek et al.2002）.Understanding the pathways involved in stellate cell activation may lead to designing effective therapies that could halt the progression to CP（Apte et al.2015）.