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Review ARticle
10
Acute pancreatitis: pathogenesis and emerging
therapies
Saif Zamana, Fred Gorelicka,b,c,*
Abstract
Acute pancreatitis is a severe inflammatory disorder with limited treatment options. Improved understanding of disease mecha-
nisms has led to new and potential therapies. Here we summarize what we view as some of the most promising new therapies for
treating acute pancreatitis, emphasizing the rationale of specific treatments based on disease mechanisms. Targeted pharmaco-
logic interventions are highlighted. We explore potential treatment benefits and risks concerning reducing acute injury, minimizing
complications, and improving long-term outcomes. Mechanisms associated with acute pancreatitis initiation, perpetuation, and
reconstitution are highlighted, along with potential therapeutic targets and how these relate to new treatments.
Keywords: Acinar cell, Acute pancreatitis, Calcium signaling, Transporters, Treatment
Introduction
Acute pancreatitis (AP), a sudden inammatory disease of
the pancreas, can range from mild discomfort to a severe,
life-threatening illness. It is one of the most common causes of
gastrointestinal disease-related hospitalizations in the United
States.[1] Past AP annual expenditures in the United States were
estimated to be $2.6 billion.[2] Globally, the pooled incidence of
AP is approximately 34 cases per 100,000 general population,
making it a signicant concern for public health.[3] Moreover,
the global incidence of AP is increasing, with an estimated aver-
age annual percent increase of approximately 3% between 1961
and 2016.[4]
There is considerable morbidity and mortality as well as med-
ical costs associated with AP. Globally, there were approximately
115,000 AP deaths in 2019.[5] In its most severe form, AP can
result in systemic inammatory response syndrome (SIRS), mul-
tiple organ failure (MOF), increased infection rates, and mor-
tality rates of up to 30% in those with severe disease.[6] Though
most AP patients survive the disease, they can experience long-
term consequences, including recurrent AP, chronic pancreatitis,
exocrine and endocrine insufciency, and an increased risk of
pancreatic cancer.[7–9]
Although the risks associated with AP are well known, cur-
rent treatment strategies for AP are supportive and include uid
resuscitation, pain management, and nutritional support.[10]
Current treatment paradigms do not target the underlying
pathophysiological mechanisms of this disease. Investigators
have anticipated that understanding AP’s natural history and
mechanisms will lead to new therapeutic strategies to reduce
this debilitating disease’s short-term and long-term burden;
these goals are just being met. This article aims to delve into
the most foundational mechanisms underlying AP and explore
related new potential treatments that could improve patient
outcomes.
Goals of therapy
The primary goals of AP therapy are multifaceted and aim to
reduce the severity of the acute injury and its complications,
shorten intensive care unit (ICU) and hospital stays, reduce mor-
tality, and decrease the associated medical and quality of life
costs. An unresolved question is whether limiting acute and short-
term injury will reduce the emerging longer-term complications
such as pancreatic exocrine insufciency, diabetes, and pancreatic
cancer. For example, research has highlighted the role of inter-
leukin (IL)-6 as an early predictive marker for severe pancreati-
tis.[11] Other studies have underscored the importance of IL-6 in
driving the progression of preneoplastic pancreatic lesions.[12,13]
These ndings prompt an intriguing question of whether ther-
apies targeting IL-6 in the short-term could potentially reduce
the risk of pancreatic cancer or other long-term complications
in patients with AP and prompt the question of the timing and
length of therapy needed to do so. The potential negative effects
of treatments also need to be considered. For example, what is the
risk of reducing acute inammatory responses to an extent that
might increase the risk of infection or change healing responses?
Thus, the duration of treatment and balance between managing
the acute phase and preventing short-term and long-term compli-
cations need to consider potential off-target effects of treatments.
Mechanisms of pancreatitis injury and recovery vary
over time
Our mechanistic knowledge of pancreatitis comes largely
from in vivo rodent studies and ex vivo studies in rodent and
human pancreatic tissue slices and isolated pancreatic cells.
Conrmation of mechanisms described in rodents in human tis-
sues has been limited. In brief, the initiating event most often
occurs in the pancreatic acinar cell, where multiple forms of
injury can lead to abnormal intracellular calcium signaling.[14]
Though less studied, injury responses also occur in the pancre-
atic duct and endothelial cells early in the disease and contribute
aDepartment of Internal Medicine, Yale School of Medicine, New Haven, CT
06511, bVeteran’s Administration Healthcare System, West Haven, CT 06516,
cDepartment of Cell Biology, Yale School of Medicine, New Haven, CT 06511
Data sharing not applicable to this article as no datasets were generated or
analyzed during the current study.
* Corresponding author: Fred Gorelick, VA Connecticut HealthCare System, Yale
School of Medicine Clinical Campus, 950 Campbell Ave, West Haven, CT 06516.
E-mail: fred.gorelick@yale.edu
Copyright © 2023 The Chinese Medical Association, Published by Wolters
Kluwer Health, Inc. This is an open-access article distributed under the terms of
the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0
(CCBY-NC-ND), where it is permissible to download and share the work provided
it is properly cited. The work cannot be changed in any way or used commercially
without permission from the journal.
Journal of Pancreatology (2024) 7:1
Received: 29 September 2023; Accepted 25 December 2023.
Published online 2 January 2024
http://dx.doi.org/10.1097/JP9.0000000000000168
11
Zaman and Gorelick • Journal of Pancreatology (2024) 7:1 www.jpancreatology.com
to disease initiation and perpetuation.[15] Changes in acinar
cell calcium signaling can coordinate pathologic responses in
mitochondria and autophagic pathways,[16] activate digestive
enzymes within the acinar cell, misdirect secretion, and drive
the production of inammatory mediators. A complex-ordered
inammatory cascade follows in the pancreas, likely beginning
with platelets, then neutrophils and inammatory macrophages.
The resolution of AP requires suppressing the acute inamma-
tory cells and activating an anti-inammatory cascade. Other
factors, such as reduced blood ow, vascular injury, vessel occlu-
sion, tissue hypoxia, and neurogenic inammation, can modu-
late the injury’s severity and recovery effectiveness.
Less is known about the factors regulating the AP recov-
ery phase than those mediating early phases of injury or how
the acute therapies discussed below might affect recovery and
long-term AP sequelae. However, in addition to the mechanisms
previously described, one key aspect of tissue recovery is the
clearance of necrotic debris and revascularization.[17] This pro-
cess is mediated by macrophages, which phagocytize necrotic tis-
sue and facilitate recovery.[18] One group has demonstrated that
M1 macrophages dominate during the proinammatory phase
of AP, while M2-like macrophages dominate during pancreas
repair and regeneration. Depletion of M2-like macrophages
during the recovery phase delayed inammation resolution.[19]
The precise mechanisms and signaling pathways governing
the regenerative processes in the pancreas following AP remain
incompletely understood. Furthermore, the long-term conse-
quences of AP, such as the development of new-onset diabetes
and pancreatic insufciency, are areas of growing concern and
active research.[20] In a review of 24 prospective clinical studies
involving 1102 patients with a rst episode of AP, newly diag-
nosed diabetes mellitus developed in 15% of individuals within
12 months after the rst episode of AP.[21] One meta-analysis
of 1795 patients from 39 studies demonstrated that 35% of
patients studied had exocrine pancreatic insufciency after AP
on follow-up after hospital discharge.[9] It remains unclear how
early intervention in AP, particularly strategies aimed at avoid-
ing SIRS, might inuence long-term outcomes such as these.
This has led to initiatives like the Diabetes RElated to Acute
Pancreatitis and its Mechanisms (DREAM) Study, a prospective
cohort study designed to investigate and provide the evidence
needed to screen for, prevent, and treat DM after AP.[22] There
remains a need for continued research into the immediate man-
agement of AP and the long-term monitoring and treatment of
patients to mitigate these secondary complications.
Pathologic responses of the acinar cell that drive AP
and therapeutic targeting
Calcium signaling
There is a consensus that acinar cell calcium signaling changes
usually initiate AP.[14,23] In acinar cells, physiologic cytosolic
calcium signals oscillate, are transient, and are essential for
regulated digestive enzyme secretion. However, in the early
phase of AP, acinar cell cytosolic calcium levels are elevated
above physiologic responses (5–20-fold), prolonged, and
physiologic calcium oscillations disappear. These patholog-
ical, sustained elevations in cytosolic calcium are an early
event in models of AP and are seen in rodent and human aci-
nar cells.[24,25] The changes in cytosolic calcium signaling can
drive mitochondrial dysfunction with the opening of the mito-
chondrial transition pore and subsequent reductions in ATP
levels, intracellular trypsinogen activation,[26] disordered auto-
phagy,[27] endoplasmic reticulum (ER) stress,[28] reduced api-
cal and enhanced basolateral zymogen granule exocytosis,[29]
and tight-junction disruption.[30] Though the direct targets of
this elevated calcium remain unclear and may be manifold, a
role for the calcium-activated phosphatase, calcineurin, in the
pathogenesis of AP has been conrmed by using calcineurin
inhibitors and mice with calcineurin deletions.[31,32] However,
the direct cellular targets of calcineurin that transduce signals
and ultimately mediate acinar pancreatitis responses have yet
to be identied.
Cellular calcium transporters regulate physiologic calcium
homeostasis and can contribute to the early disordered acinar
cell calcium signaling in pancreatitis (Fig. 1). Many transport-
ers are important for calcium homeostasis in pancreatic aci-
nar and are shared by inammatory cells. Intracellularly, the
ER-associated inositol 1,4,5-tris-phosphate receptors (IP3Rs)
and ryanodine receptors (RYRs) enable calcium to move from
the ER stores into the cytosol.[14] Mediators of calcium import
on the plasma membrane include store-operated calcium entry
(SOCE) channels such as the Orai proteins (particularly Orai1)
and transient receptor potential cation (TRPC) channels such
as transient receptor potential cation channel subfamily V 1
(TRPV1) and TRPV6. The discrete homeostatic mechanisms
that regulate calcium entry across the plasma membrane, cal-
cium release from ER stores, and mitochondrial calcium and
lysosomal uxes modulate cytosolic calcium levels under physi-
ologic conditions and during AP (Fig. 1). Lysosomal, mitochon-
drial, and nuclear calcium uxes may modify these responses.
Following a stimulus, acinar cell cytosolic calcium levels are pri-
marily reduced by extrusion across the plasma membrane and
re-uptake into the ER.
Calcium efux across the acinar cell plasma membrane is
critical for lowering cytosolic calcium levels and largely medi-
ated Ca2+ ATPases (PMCA) family of transporters.[33] Na+/Ca2+
exchange has little to no role in acinar cell calcium homeosta-
sis. The primary calcium-regulatory mechanisms are largely
conserved among various cell types, including inammatory
and stellate cells.[23] Knowledge of the regulatory pathways for
calcium entry and extrusion has led to new approaches for AP
treatment. Agents that inhibit Ca2+ entry or enhance Ca2+ extru-
sion are summarized below and, in Figure 2, have shown con-
siderable promise for reducing AP severity.
Figure 1. Schematic representation of cellular Ca2+ transporters and their
role in Ca2+ homeostasis. Multiple transporters and proteins regulate acinar
cell calcium signaling and are relevant to early acute pancreatitis responses.
The schematic illustrates key transporters involved in calcium entry (Orai1,
Piezo, TRPV4), intracellular calcium regulation (RYR, IP3R), and calcium
extrusion (PMCA). These transporters play a crucial role in maintaining cal-
cium balance in pancreatic acinar cells and inflammatory cells, and their dys-
regulation can contribute to early disordered signaling in the pathogenesis
of acute pancreatitis. IP3R = inositol 1,4,5-tris-phosphate receptor, PMCA
= plasma membrane calcium ATPase, RYR = ryanodine receptor, TRPV =
transient receptor potential cation channel subfamily V.
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Zaman and Gorelick • Journal of Pancreatology (2024) 7:1 Journal of Pancreatology
Calcium entry (stromal interaction molecule 1, TRPV,
Piezo)
SOCE responds to decreases in ER calcium by increasing cal-
cium inux through the calcium release-activated calcium
channel Orai1 and its sensor stromal interaction molecule 1
(STIM1), which are located on the plasma membrane and ER,
respectively. When ER calcium is depleted, STIM1 oligomerizes
and translocates to ER-plasma membrane junctions, where it
binds and gates Orai1 to activate SOCE, resulting in calcium
entry into the cell.[34] The prominent role of calcium signaling
in AP’s pathogenesis has focused investigators on regulators of
calcium ion ux as potential AP therapeutic targets. For exam-
ple, CM4620, GSK-7975A, and CM128 are small molecule
inhibitors of Orai1, a component of SOCE channels formed
by STIM1 and Orai complexes that facilitate Ca2+ entry into
pancreatic acinar cells. The Orai1 inhibitors CM4620, GSK-
7975A, and CM128 can signicantly reduce the severity of AP
in rodent models by inhibiting SOCE in pancreatic acinar cells,
conferring substantial therapeutic benets in rodent AP mod-
els.[35,36] This has moved into human trials for AP therapy. In a
phase-2, open-label, dose-response study, 21 patients with AP,
SIRS, and hypoxemia were randomized to receive low-dose or
high-dose CM4620 plus standard of care (SOC) or SOC alone.
CM4620 showed a positive safety prole in this study without
increasing serious adverse events compared to SOC. Patients
treated with CM4620 displayed improved AP severity, better
tolerance to solid foods, reduced persistent SIRS, and decreased
hospitalization durations.[37] These are promising preliminary
ndings.
TRPC channels mediate a signicant portion of the receptor-
stimulated Ca2+ inux. The vanilloid receptor-1 (TRPV1)
was the rst member of the TRPV subgroup within the TRP
family to be discovered, consisting of 6 mammalian members
that act as Ca2+ entry channels responsive to diverse physical
and chemical triggers.[38] Furthermore, mechanical stressors
(trauma, gallstones) can initiate AP responses by stimulating
calcium inux through these channels. The mechanosensitive
ion channel Piezo1 is expressed in pancreatic acinar cells and
plays a key role in pressure-induced pancreatitis. Pressure-
induced activation of the Piezo1 ion channel can trigger the
opening of the TRPV4 channel, resulting in toxic calcium
overload and AP.[39] Elevating pressure in the mouse pancreatic
duct leads to pancreatitis; this can be prevented by blocking
or deleting Piezo1. The Piezo1 antagonist GsMTx4 reduces
the severity of AP in murine models.[40] Additionally, inhibit-
ing Piezo1 function is sufcient to prevent pressure-induced
AP, while activating Piezo1 can induce pancreatitis in normal
mice but not in mice where Piezo1 has been deleted from aci-
nar cells.[40] These ndings suggest that blocking Piezo1 could
prevent pancreatitis caused by trauma, gallstones, or medical
procedures such as endoscopic retrograde cholangiopancrea-
tography (ERCP) that increase pressure in the pancreas. To our
knowledge, there are no clinical trials yet that target Piezo1 or
TRVP channels.
Calcium release from intracellular stores (IP3Rs, RYR)
****RyRs are channel proteins in the ER that facilitate the
release of Ca2+ from ER calcium reservoirs into the cytosol.
Additionally, IP3Rs are channels that regulate the release of Ca2+
from the ER into the cytosol.[41] Our group reported that in rats,
zymogen activation is driven by Ca2+ release regulated by the
RYR.[42] Experimental data demonstrated that blocking RYR or
depleting its Ca2+ pools curtailed zymogen activation without
affecting enzyme secretion.[42] Thus, RYR’s role in mediating
zymogen activation, not enzyme release, underscores its poten-
tial involvement in AP. It was later demonstrated that inhibiting
RYR reduces early pancreatitis injury. Using the RYR inhibi-
tor dantrolene in mice, it was observed that pretreatment sub-
stantially reduced cerulein-induced pancreatitis.[43] Specically,
dantrolene decreased pancreatic trypsin activity and serum amy-
lase levels and improved the overall pancreatic histology and
evidence of cellular damage.[43] Though these ndings suggest
RYR’s activation may have a signicant role in pancreatitis, to
our knowledge, its inhibition has not yet been used prospec-
tively in a clinical setting in the setting of AP. However, dantro-
lene has been used in human clinical trials in phase Ib/IIa trials
of patients with Type 1 Wolfram syndrome, a disorder of ER
calcium homeostasis.[44]
Other small molecules, such as caffeine, have been investi-
gated in the setting of calcium signaling in AP. Caffeine and
its metabolites inhibit pathological IP3R-mediated calcium
signaling in pancreatic acinar cells, a response implicated in
AP initiation. Caffeine reduced the severity of experimentally-
induced AP by cerulein, taurolithocholate acid, and fatty acid
ethyl esters in mice. The protective effects were likely due to
inhibition of IP3R calcium signaling rather than other potential
mechanisms like phosphodiesterase inhibition. However, high
doses of caffeine, up to 25 mg/kg, were required for protective
effects in the animal models, which are not practical for clini-
cal use in humans. The ndings suggest methylxanthine-based
compounds like caffeine might be suitable starting points for
Figure 2. There are multiple potential calcium-regulatory targets for acute pancreatitis therapy. This schematic illustrates the intricate pathways of calcium
homeostasis, highlighting the transporters and key signaling molecules involved. In addition, the schematic displays select drugs that target the indicated Ca2+
regulators, showcasing potential pancreatitis therapies. Many of these calcium-signaling targeted agents have been shown to attenuate acinar cell responses
in acute pancreatitis and reduce AP severity in preclinical rodent models. A few have advanced to clinical trials. AP = acute pancreatitis, IP3R = inositol
1,4,5-tris-phosphate receptor, PMCA = plasma membrane calcium ATPase, TRPV = transient receptor potential cation channel subfamily V.
13
Zaman and Gorelick • Journal of Pancreatology (2024) 7:1 www.jpancreatology.com
drug discovery efforts targeting abnormal IP3R calcium signal-
ing as an AP therapy.[45]
Calcium extrusion
Two major mechanisms remove calcium from the cytosol.
A calcium ATPase pumps the ion from the cytosol into the
ER, and plasma membrane calcium extrusion ATPases of the
ATP2B4 family move cytosolic Ca2+ into the extracellular space.
Stimulation of Ca2+ extrusion has strong potential for targeted
AP treatment, as summarized below.
Pancreatic acinar cells and duct cells receive high concen-
trations of islet hormones, most relevantly insulin, through an
islet-to-acinar cell portal system. As seen in a T1DM model and
an insulin-receptor knockout mouse, insulin signaling deciency
sensitizes to AP development. Insulin protects acinar cells in
pancreatitis by providing glycolytically derived ATP to drive the
plasma membrane calcium ATPase (PMCA) pumps that lower
cytoplasmic calcium. However, it may have additional effects on
ER calcium pumps. However, the effective insulin dose for pro-
tecting acinar cells against experimental pancreatitis is higher
than the insulin doses needed to maximally enhance peripheral
glucose uptake in mouse models. Because this would predis-
pose to hypoglycemia and require the use of an insulin clamp
if applied therapeutically, its clinical use for AP therapy is not
practical.[46,47]
Insulin appears to protect acinar cells indirectly by inducing
Akt-mediated phosphorylation of 6-phosphofructo-2-kinase/
fructose-2,6-biphosphatase 2 (PFKFB2), which boosts glycol-
ysis and the ATP generation need to drive calcium export by
a PMCA. This reveals a potential therapeutic strategy to acti-
vate PFKFB2 phosphorylation, eliminating the need for sys-
temic insulin administration.[47] There are several potential
agents in early-phase development, though none have entered
clinical trials.[47] It may be relevant that a recent publication
on insulin therapy for AP suggested that it might reduce the
duration of hospitalization and lower ICU-related disease sever-
ity scores (Acute Physiology and Chronic Health Evaluation II
[APACHE-II]).[48]
Work from Jason Bruce’s group has hypothesized that the
severity of AP might be linked to the progressive loss of insu-
lin secretion, a consequence of collateral damage to pancreatic
β cells.[46] This insulin deciency could subsequently reduce
insulin-driven pancreatic antimicrobial peptide expression
(AMP) and secretion into the gut, leading to gut dysbiosis,
decreased mucous secretion, inammation, bacterial translo-
cation, infected pancreatic necrosis, sepsis, and consequently,
a more severe progression of AP. Although detailed ndings
await publication, the group is exploring a correlative study
between plasma insulin levels and gut AMPs throughout AP.
Such studies aim to discern differences in insulin loss between
severe and mild AP cases, potentially highlighting therapeu-
tic opportunities with insulin mimetics or antimicrobial pep-
tides (Jason I. E. Bruce, PhD, unpublished data, 2019–2022,
Manchester, UK).
The secretory protein renalase, a prosurvival and anti-
inammatory factor, directly activates the PMCA PMCA4b.[49]
PMCA4b stimulation by renalase enhances calcium egress from
the acinar cell cytosol (Gorelick, MD, Desir, MD, unpublished
data, 2013) and also coupled to other cell signals such as AKT
and ERK recombinant human renalase (rRNLS) reduces the
severity of experimental murine pancreatitis in vivo.[50] It also
reduces pancreatitis injury in isolated pancreatic acinar cells
in a PMCA4b-dependent manner.[50] These results demonstrate
the potential of renalase as a therapeutic agent for pancreati-
tis by promoting calcium extrusion and reducing cell injury.
Additionally, it has been demonstrated that amino acids 220-
239 of human renalase1 exhibit the protective effects found
in intact renalase in murine models of acute kidney injury.[51]
Renalase peptides containing human renalase 1 aa220-239 site
are now being investigated for potential therapeutic benets in
preclinical AP models.
Calcium target: calcineurin
In pancreatic acinar cells, increased cytosolic Ca2+ activates cal-
cineurin, a phosphatase that is central to the pathogenesis of
AP.[52,53] Calcineurin inhibitors, such as tacrolimus (FK506) and
cyclosporine A, are often used to manage autoimmune condi-
tions.[54] Past studies have demonstrated that these calcineurin
inhibitors, or the genetic deletion of calcineurin, decrease the
severity of experimental pancreatitis, including in a post-ERCP
model.[55] Targeted deletions of calcineurin suggested distinct
cell-specic roles for the enzyme. Specically, the expression
of calcineurin in hematopoietic cells and neutrophils contrib-
utes to the development of lung inammation associated with
pancreatitis. In contrast, calcineurin’s expression in the pan-
creas contributes to local inammation.[32] As such, the bene-
cial effects observed from blocking or deleting calcineurin
in mitigating pancreatitis depend on the site of its expression.
This observation led to further murine studies investigating the
local effects of calcineurin inhibitors in the pancreatic duct.
Introducing calcineurin inhibitors tacrolimus and cyclosporine
A with radiocontrast into the pancreatic duct in a post-ERCP
AP model dramatically reduced injury without apparent tox-
icity.[55] Additionally, preclinical intraductal delivery of calci-
neurin inhibitor formulations was safe and well tolerated in
mice.[56] This initial work has led to human clinical trials. One
prospective pilot study involved patients who had undergone
ERCP; patients were randomized into a control group and a
group receiving tacrolimus at 8 on the day preceding ERCP
and at 8 on the day of ERCP. Patients randomized to the
tacrolimus group underwent ERCP 2 hours after the morning
tacrolimus dose. All patients were monitored for post-ERCP
pancreatitis using clinical symptoms of worsening abdominal
pain and increased pancreatic enzymes. This trial demonstrated
that oral tacrolimus at a cumulative dose of 4 mg signicantly
decreases the incidence of post-ERCP pancreatitis.[57]
The Rectal INdomethacin, oral TacROlimus, or their com-
bination for the prevention of post-ERCP pancreatitis (INTRO
Trial) is an ongoing randomized, controlled, double-blinded trial
that will assess the role of tacrolimus in post-ERCP pancreati-
tis prophylaxis and pharmacologically optimize this therapeutic
strategy. The trial plans to randomize 4874 patients undergoing
ERCP to receive either 5 mg oral tacrolimus or oral placebo 1 to
2 hours before ERCP. It will follow patient’s post-ERCP for 30
days to assess the incidence of post-ERCP pancreatitis.[58] This
trial has begun and is planned to end in December 2024.
Organelle dysfunction
The initial changes in cytosolic calcium and other cytoplasmic
signaling molecules trigger a coordinated, interrelated series of
pathologic responses in acinar cell organelles. The most criti-
cal involves mitochondria and the autophagic-lysosomal path-
way, each making distinct contributions to acinar cell damage.
Relevant to this review, specic agents may be useful in targeting
individual organelles.
Mitochondrial dysfunction
Mitochondrial dysfunction drives AP through multiple patho-
logic mechanisms, including the generation of reactive oxy-
gen species (ROS) and reactive nitrogen species, reduced ATP
generation, and release of cytochrome C.[59–61] Oxidative stress
damages cell membranes and proteins while activating proin-
ammatory transcription factors like active protein 1 (AP-1)[62]
and nuclear factor kappa-light-chain-enhancer of activated
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Zaman and Gorelick • Journal of Pancreatology (2024) 7:1 Journal of Pancreatology
B cells (NF-kB).[63] Additionally, oxidative stress can damage
mitochondrial proteins and DNA, impairing mitochondrial
function and ultimately causing ATP depletion, which results
in further imbalances in oxidative stress and ion regulation.
Oxidative damage and mitochondrial dysfunction contribute
signicantly to pancreatic acinar cell injury and death in AP.[64]
The mitochondrial permeability transition pore (MPTP) plays
a critical role in the pathogenesis of AP by inducing mitochon-
drial dysfunction and necrosis upon its opening. Its opening
leads to the loss of mitochondrial membrane potential, swelling
of the mitochondria, and necrotic cell death. This process is
particularly relevant in AP. Small molecule inhibitors of cyclo-
philin D, a regulator of the MPTP implicated in AP, have been
investigated in preclinical models. One cyclophilin D inhibi-
tor signicantly protected mitochondrial membrane potential
and reduced necrosis in murine and human pancreatic acinar
cells.[65]
Autophagocytic-lysosomal
In addition to mitochondrial dysfunction, the dysfunction of
other cellular organelles, such as defective autophagy and lyso-
somal function, and dysregulation of vesicular transport and
trafcking pathways can trigger AP. Autophagy is linked to
the activation of pancreatic digestive proteases. Trypsinogen
activation to trypsin is an important early event in the patho-
genesis of AP and occurs along the secretory pathway and
in endolysosomal vacuoles (see “Zymogen activation” sec-
tion).[66–68] Some have proposed that this generation of active
trypsin can cause pancreatic “autodigestion,” which is central
to pancreatitis development.[69] Others, using murine models,
see generation of pancreatic trypsin as less essential to the
pathogenesis of AP.
Experimental and genetic models demonstrate that impaired
autophagy and lysosomal function in pancreatic acinar cells
play a foundational role in the initiation and development of AP.
While mechanistically complex, disruptions at multiple steps,
including defective cathepsin processing, reduced lysosomal
enzyme activities, altered vacuolar H+-ATPase localization,
decreased levels of the lysosomal membrane lysosome-associated
membrane protein (LAMP) proteins, impaired autophagosome
clearance, and blocked lysosomal enzyme targeting, contribute
to dysfunction in this pathway. Regardless of whether dysfunc-
tion occurs during autophagosome formation or completion of
autophagy, the resultant inhibition of autophagic ux leads to
the accumulation of active trypsin in the acinar cell, cytoplasmic
vacuolization, metabolic changes including reduced ATP pro-
duction, and pancreatitis.[70,71]
One group investigated the interaction between premature
intracellular activation of digestive proteases within pancreatic
acini and the systemic inammatory response during severe pan-
creatitis in mice. They found that not only acinar cells but also
inltrating macrophages can activate digestive proteases during
endocytosis of zymogen-containing vesicles, a process depen-
dent on pH and cathepsin B (CTSB), leading to macrophage
activation through NF-κB, ultimately contributing to systemic
inammation and pancreatitis severity.[72] It is possible that tryp-
sinogen in macrophages may account for the generation of pan-
creatic trypsin long after disease onset, with the acinar cell being
its initial source.
Dysfunction in one organelle impacts others through their
metabolic interdependence and signaling crosstalk, ultimately
leading to key features of pancreatitis like intrapancreatic
trypsinogen activation, inammation, and cell death. Targeted
genetic disruption of organelle components like the lysosomal
protein LAMP2 can cause spontaneous pancreatitis in mice,[73]
further demonstrating organelle dysfunction’s key role in dis-
ease pathogenesis.[16] As such, therapeutics to broadly restore
organelle homeostasis might effectively treat pancreatitis.
Inflammatory mediators
Changes in circulating and tissue levels of proinammatory
cytokines (tumor necrosis factor-α [TNF-α], IL-1β, IL-6, IL-8)[74]
and anti-inammatory cytokines (eg, IL-10)[75] during AP have
been well-documented in rodents and shown in human disease.
One such report characterized the trajectories of key proinam-
matory (angiopoietin-2, IL-6, IL-8, monocyte chemoattractant
protein [MCP]-1, resistin) and anti-inammatory (hepatocyte
growth factor [HGF], soluble tumor necrosis factor-alpha recep-
tor 1 [sTNF-αR1]) cytokines over the rst 5 days after onset in
a prospective cohort of AP patients. The study found that proin-
ammatory cytokines were signicantly elevated early in severe
acute pancreatitis (SAP) compared to mild forms but exhibited
a downward trajectory after day 1 in SAP versus milder forms
with at or upward trajectories.[76] Anti-inammatory cytokines
increased over time in mild and severe disease. The ndings indi-
cate that proinammatory cytokine responses occur rapidly and
are time-dependent in SAP. This highlights the need to enroll
SAP subjects early in the disease when investigating immune
mechanisms or designing trials targeting cytokines.
Resistin is a small adipokine implicated in obesity. A
meta-analysis of 11 studies involving 892 AP patients found
that circulating resistin levels were signicantly higher in
patients with SAP than those with mild AP, suggesting that ele-
vated resistin levels may predict AP.[77]
Activin A, a member of the TGF-β superfamily, has recently
emerged as a signicant potential mediator of inammation in
AP. Activin A is released into the bloodstream during inamma-
tory events and modulates inammatory responses.[78] In the set-
ting of AP, serum activin A levels correlate with disease severity
in murine models and patient cohorts,[79] suggesting its potential
as a predictive clinical marker and therapeutic target for severe
cases. Moreover, activin A predictive capability of AP severity
occurs independently of other risk factors such as body mass
index.[80] Follistatin is a protein that specically binds to and
inhibits the actions of activin A.[81] One recent study in murine
models demonstrated that following bacterial lipopolysaccha-
ride administration, activin A rapidly increases in circulation,
predominantly sourced from bone marrow–derived cells, espe-
cially neutrophils, while circulating Follistatin shows a delayed
increase.[82] Additionally, inhibiting activin A with a neutralizing
antibody in mice with AP decreased disease severity.[80] These
results raise the question of whether activin inhibition could be
a viable treatment strategy for AP; to our knowledge, no clinical
studies in human subjects have been done to test the effective-
ness of activin inhibition for AP treatment.
The role of proinammatory cytokines in the pathogenesis of
AP raises the question of whether anti-inammatory molecules
that suppress oxidative stress or inammation reduce AP sever-
ity and its complications.[83] One study found that by suppress-
ing NF-κB proinammatory signaling, resveratrol pretreatment
could attenuate pancreas injury, inammation, and oxidative
stress in a mouse model of hyperlipidemia-induced AP. Whether
this translates to human AP remains to be seen.[84]
As the understanding of cytokine involvement in AP continues
to evolve, the mixed lineage kinase domain-like protein (MLKL)
function emerges as a research focus. MLKL and its activated
form, p-MLKL, were upregulated in the pancreas in a mouse
model of AP, independent of RIPK3, the canonical upstream
activator of MLKL. Knockout of MLKL, but not Ripk3, reduced
the severity of pancreatitis in mice by promoting M2 “healing”
macrophage polarization in the pancreas.[85] This suggests a pro-
tective role for M2 macrophages in AP. This effect was mediated
in part by reducing the release of the chemokine (C-X-C) ligand
(CXCL10) from injured pancreatic acinar cells, which normally
act to polarize macrophages toward the proinammatory M1
phenotype. Neutralization of CXCL10 reduced macrophage
M1 polarization and pancreatitis severity in mice.[85] This sug-
gests inhibition of the MLKL-CXCL10-macrophage axis as
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a potential therapeutic approach in AP and highlights a non-
canonical inammation-related role for MLKL separate from its
canonical necroptotic function.
TNF-α inhibition has been demonstrated to reduce injury in
experimental AP. Antibody inhibition of TNF-α reduced dis-
ease severity and improved survival in mouse and rat models
of AP.[86,87] Importantly, delaying TNF-α inhibition until after
pancreatitis onset was more protective than early prophylactic
treatment, suggesting that its role may be time-dependent.[87]
Later studies demonstrated that the TNF-α inhibitor, iniximab,
enhanced the therapeutic effectiveness of octreotide by reducing
biochemical markers of injury, improving organ function, and
reducing pathology scores in a rat model.[88] The results support
the potential of anti–TNF-α therapy as an AP therapy and the
Randomised treatment of Acute Pancreatitis with Iniximab:
Double-blind multi-centre trial (RAPID-I trial), a phase IIb, ran-
domized, double-blind, placebo-controlled, multicenter trial of
iniximab in patients with AP. The RAPID-I is one of the rst
clinical trials in AP that involves a degree of precision medicine.
The trial plans to use transcriptomics to elucidate any genetic
factors in patients that may be linked to improved response to
iniximab.[89]
Recently, lactate has been identied as an inammatory mod-
ulator in acute inammatory pancreatic and liver injury. Hoque
et al[90] demonstrated that lactate, through the lactate receptor
Gi-protein–coupled receptor 81 (GPR81), counteracts the acti-
vation of the NLRP3 inammasome by negatively regulating
Toll-like receptors, leading to reduced inammation and organ
damage. Given its protective effects in mouse models, lactate
and its receptor GPR81 are potential targets of immunomodula-
tory therapy for patients with AP and other acute organ injuries.
This information has provided a mechanistic rationale for clini-
cal studies comparing post-ERCP pancreatitis and AP outcomes
in patients given intravenous lactated Ringer or normal saline
for treating AP. In post-ERCP AP, a clear benet for aggres-
sive hydration with lactated Ringer during ERCP and post-
procedure has been shown.[91] Though small preliminary studies
suggest a therapeutic advantage of intravenous lactated Ringer
over normal saline in hospitalized patients with AP, large pro-
spective clinical studies are planned.
Zymogen activation
A characteristic early AP response is the activation of protease
zymogens, particularly trypsinogen, in the pancreatic acinar cell.
Trypsinogen can also be activated outside the acinar cell after
entering the interstitial space through acinar cell death, baso-
lateral exocytosis, or back diffusion from the pancreatic duct
lumen through disrupted tight junctions, which can become
endocytosed and activated in macrophages. This activation
enhances their inammatory state.[72] Trypsinogen activation in
the acinar cell likely occurs in a non-zymogen granule compart-
ment along the secretory pathway[67,92] and within endocytic ves-
icles.[93] Chvanov et al[94] have demonstrated that large endocytic
vacuoles containing trypsin are formed in experimental models
of AP. These endocytic vacuoles are predicted to rupture and
release trypsin into acinar cell cytosol or exocytosis of trypsino-
gen into the extracellular space.[94] The result is predicted to lead
to inappropriate intracellular protease activity, and trypsin acti-
vation of other digestive proenzymes such as chymotrypsino-
gen, proelastase, procarboxypeptidase, and prophospholipase
A2 could contribute to AP injury.
There is a consensus that lysosomal hydrolases are central to
trypsinogen activation. The “co-localization hypothesis” posits
that in the initial phases of AP, acinar cell digestive zymogens,
such as trypsinogen, actively mix with lysosomal hydrolases
within vesicular compartments in the acinar cell. This merg-
ing is proposed to facilitate trypsinogen activation by the
lysosomal hydrolase CTSB, which can activate trypsinogen in
an acidic environment.[95] Research involving AP mice with a
targeted deletion in the CTSB (gene supports its role). When
subjected to experimental secretagogue-induced pancreatitis,
the CTSB-decient mice exhibited a signicant reduction in
trypsin activity—over 80% less than their wild-type counter-
parts. Correspondingly, the manifestation of pancreatic dam-
age, measured by serum amylase and lipase activities, as well
as the degree of acinar tissue necrosis, was halved in the CTSB-
decient mice.[96] This evidence underpins the role of CTSB in
activating intrapancreatic trypsinogen, thereby supporting the
co-localization hypothesis. However, selective compartmental
acidication may also be important.
Notably, pancreatic protease zymogen activation has not
proven a useful therapeutic target. Whether this reects chal-
lenges to appropriately time the therapy, inability to inhibit
relevant proteases, or lack of importance of intrapancreatic
zymogen activation in mediating AP severity remains unclear.
Pathologic responses of the non-acinar cell that drive
AP and therapeutic targeting
Fat cells and triglycerides
Fat cells and their triglyceride content can modulate AP sever-
ity. Specically, hypertriglyceridemia can cause severe pancre-
atitis. Blood levels of triglycerides directly relate to the risk of
developing AP.[97] Lipases hydrolyze triglycerides to generate
free fatty acids, which can vary in their ability to damage the
pancreas. Unsaturated fatty acids are particularly harmful and
can cause mitochondrial dysfunction, calcium overload, and
the generation of inammatory mediators in pancreatic acinar
cells.[98–100] Additionally, hypertriglyceridemia worsens outcomes
in AP, regardless of the initial cause.[101] This effect appears to
be increased in obese patients and mice, likely due to lipolysis
of intrapancreatic fat.[98] One group found that during AP, pan-
creatic triglyceride lipase (PNLIP) leaks into visceral adipose
tissue, causing excessive lipolysis independent of adipocyte-
autonomous adipose triglyceride lipase, leading to increased non-
esteried fatty acids, more severe organ failure, and reduced
survival. In contrast, this mechanism does not occur in acute
diverticulitis, indicating a specic role of PNLIP-induced lipolysis
in the pathogenesis of organ failure during pancreatitis.[99] These
results suggest that treatments that lower triglycerides or inhibit
relevant lipases could potentially reduce the severity of AP.
Insights into the mechanisms of lipid toxicity are appearing.
In human patients and mouse models, increased free unbound
fatty acids, especially unsaturated fatty acids like linoleic and
oleic acid, can enter and damage immune cells by interacting
with cell membrane phospholipids and mitochondrial mem-
branes. This impairs immune cell functions like phagocyto-
sis, reduces bacterial clearance, and increases susceptibility to
infections during pancreatitis.[102] Additionally, some work has
suggested lipotoxicity from peri-pancreatic fat necrosis is a key
factor in converting mild to severe AP in obesity.[103] These stud-
ies suggest that preventing an increase in unbound fatty acids or
promoting their binding to albumin could reduce infections in
and severity of AP. Inhibition of lipolysis using the lipase inhib-
itor orlistat in an obese mouse model of pancreatitis reduced
pancreatic necrosis, systemic inammation, lung and kidney
injury, hypocalcemia, and mortality.[98] These ndings suggest
that lipotoxicity mediated by UFAs contributes to the severe
outcomes in obese patients with pancreatitis and that treatment
modalities that reduce lipolysis could reduce AP severity.
Pancreatic triacylglycerol lipase and pancreatic lipase-related
protein 2 (PNLIPRP2) may be suitable targets for drug devel-
opment. These 2 proteins are present in fat necrosis in human
and experimental pancreatitis and can efciently hydrolyze tri-
glycerides to toxic unsaturated free fatty acids that cause injury.
In cell models, pancreatic triacylglycerol lipase and PNLIPRP2
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Zaman and Gorelick • Journal of Pancreatology (2024) 7:1 Journal of Pancreatology
caused lipotoxic injury.[104] In mouse models, PNLIP activ-
ity increased during AP, generating excess non-esteried fatty
acids.[99] These ndings suggest pancreatic triacylglycerol lipase
and PNLIPRP2 contribute to local and systemic lipotoxic injury
in severe AP. This further supports pancreatic lipase inhibition
as a potential therapeutic approach in AP and that pancreatic
triacylglycerol lipase and PNLIPRP2 may be suitable drug tar-
gets for this strategy.
Previous studies have examined the potential effects of dietary
factors on AP. Obese individuals who consume more saturated
fat have more saturated visceral fat triglycerides that are resis-
tant to hydrolysis by pancreatic lipase. This reduces the genera-
tion of free fatty acids that can cause lipotoxic injury. In contrast,
in leaner individuals who consume more unsaturated fat, the
more unsaturated visceral triglycerides are readily hydrolyzed
by lipase. This generates high lipotoxic-free fatty acid levels that
worsen inammation and organ failure.[100] The ndings provide
a potential explanation for the “obesity paradox” in AP, where
obesity sometimes seems protective. The results suggest dietary
fat saturation, not just the amount of body fat, contributes to
pancreatitis severity through effects on lipotoxicity.
Although the role of triglycerides in AP pathogenesis
is well established, the impact of the removal of circulat-
ing triglycerides in treating AP remains unclear. In a recent
multicenter cohort study of patients with hypertriglyceridemia-
associated AP (HTG-AP), plasmapheresis, while effective in low-
ering plasma triglycerides, was not linked to reduced incidence
or duration of AP-associated organ failure but was associated
with increased ICU admissions.[105] Other studies have high-
lighted the lack of advantages of apheresis compared to insulin
infusion. In a study comparing continuous insulin infusion and
apheresis in 48 patients, apheresis resulted in a rapid 78.5%
reduction in triglyceride levels after the rst session. In contrast,
insulin infusion led to a 44.4% reduction in the rst 24 hours.
However, despite the effectiveness of apheresis treatments, they
did not offer a distinct advantage over insulin infusion in terms
of prognosis and associated complications for HTG-associated
pancreatitis.[106]
As such, the optimal treatment for lowering triglyceride
levels in patients with HTG-AP is undetermined. There may
be negative consequences, such as ICU admissions, associated
with apheresis and systemic issues, including the lack of wide-
spread availability of apheresis. Larger clinical trials are cur-
rently being conducted to help resolve these questions. The
EarLy Elimination of Fatty Acids iN hypertriglyceridemia-
induced acuTe pancreatitis (ELEFANT) trial is an open-label,
multicenter, adaptive randomized clinical trial that is investi-
gating early elimination of triglycerides and free fatty acids in
hypertriglyceridemia-induced AP in a minimum of 495 patients.
The ELEFANT trial will randomize patients to plasmapheresis,
insulin-heparin treatment, or standard uid therapy within 48
hours of symptom onset. The primary endpoint is a compos-
ite of severe AP or mortality.[107] The results will provide high-
quality evidence on whether early removal of triglycerides and
free fatty acids improves outcomes in hypertriglyceridemia-
induced pancreatitis. This could establish a new treatment
approach targeting the inciting factors in this subset of patients.
Other potential targets
Store-Operated Calcium Entry Associated Regulatory Factor
(SARAF) regulates calcium signaling in pancreatic acinar cells.
In mouse models of AP, SARAF levels initially increase but then
decrease over time, leading to excessive calcium inux into aci-
nar cells and worsening pancreatitis. SARAF knockout mouse
models had more severe pancreatitis, while mice overexpressing
SARAF were protected.[108] This suggests that strategies to stabi-
lize or restore SARAF levels in acinar cells could be a potential
new therapeutic approach for treating AP.
MicroRNAs may serve as a critical target in the treatment
of AP. The microRNA miR-26a is crucial in regulating calcium
signaling and overload in pancreatic acinar cells. MiR-26a levels
are reduced in experimental mouse models and human samples
of AP. Mechanistically, miR-26a directly targets and inhibits
the calcium channels TRPC3 and TRPC6, thereby restricting
pathological calcium elevations and protecting against pancre-
atitis. miR-26a deciency in mice worsened pancreatitis, while
miR-26a overexpression, globally or in acinar cells, markedly
reduced pancreatitis severity. Additionally, administering a miR-
26a mimic mitigated cerulein-induced pancreatitis.[109] This
work highlights miR-26a as an intrinsic checkpoint on acinar
cell calcium overload. It demonstrates its therapeutic potential
to alleviate AP by normalizing pathological calcium signaling,
suggesting the need to investigate further other miRNAs that
may be involved in calcium signaling or other mechanisms
underlying AP development.
Anticoagulants
Heparin and its non-anticoagulant derivatives can protect against
SAP in mouse models. The drugs reduced pancreatic necrosis,
inammation, and macrophage inltration in SAP, independent
of anticoagulant function.[110] Release of high mobility group
box 1 (HMGB-1) from pancreas macrophages, which can drive
inammation and multi-organ damage in SAP, is inhibited by
this drug class and independent of their anticoagulant function.
Reduced HMGB-1 release is associated with reduced intestinal
barrier dysfunction and, lung injury and decreased mortality.[110]
With regard to non-heparin anticoagulants, one group found
that orally administered dabigatran etexilate (with anticoagu-
lant and trypsin-inhibiting activities) could reduce trypsin activ-
ity and had therapeutic efcacy in a cerulein pancreatitis mouse
model (T7K24R), but not in a more aggressive AP model.[111]
This work demonstrates that benzamidine derivatives like dab-
igatran can be potent trypsin inhibitors. However, their efcacy
may be limited by the severity of the pathology and drug con-
centrations in the pancreas.[111] Clinically, a retrospective study
of 190,474 AP patients found that those on anticoagulation
therapy before onset had lower risks of ICU admission, acute
kidney injury, organ failure, and inpatient mortality, suggesting
a therapeutic role in AP.[112] These results suggest that heparin,
non-heparin anticoagulants, and non-anticoagulant heparin
derivatives may be future options for AP treatment.
Hormones
Hormonal regulation plays a critical role in the body’s response
to various forms of stress, including AP. In this context, hor-
mones like ghrelin, leptin, and melatonin are metabolic
regulators and are found to be protective roles in AP. By inter-
acting with immune factors, these hormones may support innate
defense mechanisms that reduce the severity of pancreatitis.
Ghrelin has been shown to exert a protective effect in AP mod-
els by modulating inammatory pathways.[113,114] Specically,
ghrelin decreases the expression of nuclear factor kappa B
(NFκB) and the inammatory signal transduction pathway,[115]
leading to lower levels of inammatory cytokines such as IL-1β
and tumor necrosis factor-α (TNFα).[116] Furthermore, ghrelin’s
protective inuence extends to reducing pancreatitis-associated
lung injury and neutrophil sequestration, showcasing its sys-
temic anti-inammatory potential.[116,117]
When given intraperitoneal or intracerebroventricular,
leptin, another hormone modulating immune response, can
reduce experimental AP severity.[116] The underlying mechanism
involves the engagement of sensory nerves and the neuropeptide
calcitonin gene–related peptide (CGRP), essential for leptin’s
protective action.[118] Leptin enhances pancreatic tissue repair
and decreases lung injuries, similar to ghrelin.[119] Its therapeutic
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Zaman and Gorelick • Journal of Pancreatology (2024) 7:1 www.jpancreatology.com
effects include the activation of the nitric oxide (NO) system,
improvement in pancreatic microcirculation, and the potential
release of glucocorticoids that attenuate inammation.[120,121]
Melatonin, commonly known for regulating circadian
rhythms, also confers protection against acute pancreatic inam-
mation.[114,122] Its administration to animal models before induc-
ing pancreatitis results in a marked reduction of inammation
markers, such as edema and leukocyte inltration. It decreases
proinammatory cytokines while increasing anti-inammatory
IL-10 levels.[114,123] It also diminishes apoptosis and necrosis in
pancreatic tissues and improves pancreatic blood ow, which
aids in the clearance of inammatory mediators.[113,124,125]
These ndings support that ghrelin, leptin, and melatonin
could be integral components of the natural defense system
against pancreatic inammation. Their increased blood levels
during the initial phase of pancreatic inammation represent a
physiological response to suppress or mitigate the inammatory
process within the pancreas, offering a promising avenue for
therapeutic intervention in AP.
An emerging interest in examining the utility of corticoste-
roids for severe AP treatment is reected by a favorable meta-
analysis.[126] The benets of corticosteroids when used in selective
coronavirus disease 2019 (COVID-19) patients may also be a
factor. A 5-year prospective clinical trial based on the Beth Israel
Deaconess Medical Center on corticosteroid use in severe AP is
underway (completion date: 2027; gov ID: NCT05160506) in
the United States.
Gut microbiome
Recent research has underscored the gut microbiome’s inuence
on AP using experimental models.[127] Antibiotic therapy can
improve the course of AP in rodents by reducing innate immune
system activation.[128,129] However, we are unaware of ndings
that show similar benets of antibiotics in clinical AP.
A recent study has also shown how microbial imbalances
may relate to the severity of necrotizing pancreatitis. In a study
comparing the gut bacteria of healthy individuals with AP
patients, marked differences were found in microbial diversity
and composition. Specically, patients with necrotizing pan-
creatitis demonstrated microbial species with altered ketone
body and benzoate metabolism.[130] Enterococcus faecium and
Finegoldia magna were identied as potential biomarkers for
necrotizing pancreatitis and infected necrotizing pancreatitis,
respectively.[130] These ndings suggest that gut microbiota pro-
les could inform early necrotizing pancreatitis diagnosis and
treatment, highlighting the microbiome’s potential as a target
for AP management and intervention. However, probiotics’
role in treating AP remains controversial. A meta-analysis of
13 randomized controlled trials with 950 patients reveals that
supplementing pre-, pro-, and synbiotics to standard enteral
nutrition may reduce hospital stays for severe AP in Chinese
cohorts. However, other clinical outcomes showed no signif-
icant improvement.[131] The Probiotics in Pancreatitis Trial
(PROPATRIA), a multicenter, randomized, double-blind, placebo-
controlled trial of 298 patients with severe AP, demonstrated
that enteral probiotic prophylaxis did not decrease infectious
complications in patients with severe AP and was linked to sig-
nicantly increased mortality and gut ischemia in the probiotic
arm of the trial. This has caused broad caution about their use
in this patient population, though this may change with time
and more information.[132–134] Notably, the authors cautioned
against considering probiotics universally harmless, especially
in critically ill patients.[135] The contrasting results from the prior
studies and debate regarding the results of the PROPATRIA trial
advocate for further large-scale, rigorously designed, and con-
trolled studies to conrm the efcacy and safety of probiotic
supplementation in AP treatment and whether any specic spe-
cies of bacteria may have specic benets in AP patients.
Conclusions
AP remains a disease with signicant morbidity and mortality
despite improvements in supportive care. Pathologic calcium
signaling, mitochondrial dysfunction, organelle stress, zymo-
gen activation, lipotoxicity, and uncontrolled inammation are
key mechanisms that drive acinar cell injury and systemic AP
complications. This review summarizes promising pharmaco-
logic approaches that target these underlying disease processes,
including inhibitors of calcium inux, boosters of calcium
efux, anti-inammatory therapies, antioxidants, and strategies
to lower circulating lipotoxic factors (Table 1).
Table 1
Summary of potential therapeutic targets and agents for AP based on current preclinical studies and early clinical trials
General target Specific target Inhibitor or agonist References
Calcium Orai1 (SOCE) CM4620, GSK-7975A, CM_128 [35, 36]
Calcium TRPV1, TRPV4 [38, 39]
Calcium Piezo1 GsMTx4 [40]
Calcium IP3R Caffeine [45]
Calcium RYR Dantrolene [43, 44]
Calcium PMCA (calcium efflux) Insulin, renalase [47, 49–51]
Calcium Calcineurin Tacrolimus, cyclosporine A [48, 52, 53, 55]
Mitochondria MPTP Cyclophilin D inhibitors [65]
Inflammation TNF-αAnti–TNF-α antibodies, infliximab [86–89]
Inflammation MLKL CXCL10 neutralizing antibody [85]
Inflammation NLRP3 inflammasome Lactate [90, 91]
Triglyceride hydrolysis PNLIP Orlistat [98]
Triglyceride hydrolysis PNLIPRP2 [99]
Triglycerides Circulating Triglycerides Plasmapheresis, insulin [105–107]
SARAF SARAF SARAF stabilizers [108]
MicroRNAs miR-26a miR-26a mimic [109]
HMGB-1 HMGB-1 Heparin derivatives [110]
Trypsin Trypsin Dabigatran [111]
The table lists general target categories, specific molecular targets or pathways within each category, and examples of pharmacological inhibitors, agonists, or other interventions that have shown potential
benefits in experimental models or early human studies of AP.
AP = acute pancreatitis, CXCL = chemokine (C-X-C) ligand, HMGB-1 = high mobility group box 1, IP3R = inositol 1,4,5-tris-phosphate receptor, MLKL = mixed lineage kinase domain-like protein, MPTP
= mitochondrial permeability transition pore, NLRP3 = PMCA = plasma membrane calcium ATPase, PNLIP = pancreatic triacylglycerol lipase, PNLIPRP2 = pancreatic triacylglycerol lipase and pancreatic
lipase-related protein 2, RYR = ryanodine receptor, SARAF = Store-Operated Calcium Entry Associated Regulatory Factor, SOCE = store-operated calcium entry, TNF = tumor necrosis factor, TRPV =
transient receptor potential cation channel subfamily V.
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Zaman and Gorelick • Journal of Pancreatology (2024) 7:1 Journal of Pancreatology
Early clinical trials demonstrate the safety and potential ef-
cacy of interventions like TNF-α inhibition, reducing calcium
entry with Orai1-inhibition, and tacrolimus in reducing the inci-
dence and severity of pancreatitis. Further studies are needed to
show denitively improved clinical outcomes. While additional
basic research is still required to elucidate mechanisms fully,
the translation of novel treatments from preclinical studies to
human trials appears to be accelerating.
Multifunctional therapies that simultaneously address sev-
eral pathologic mechanisms may provide the greatest benet.
Further characterization of pathologic pathways and crosstalk
between organelles and cell types will aid in developing combina-
torial treatments. Improved early diagnosis and risk stratication
will enable therapies to be administered quickly and targeted to
patients most likely to benet. With continued progress in under-
standing disease mechanisms and applying this knowledge to
human trials, the management of AP is poised for major advances
in the coming years. Ultimately, the goal is to move beyond sup-
portive care toward therapeutic interventions interrupting the
underlying disease process and improving short- and long-term
patient outcomes.
Acknowledgments
None.
Author contributions
SZ: Project administration; writing - review & editing. FG:
Project administration; resources; supervision; writing - review
& editing.
Financial support
FG’s research is supported by a Veterans Administration Senior
Clinical Scientist Merit Award (BX003250), a Department of
Defense Investigator Initiated Award (PR220457), and the
Henry and Joan Binder Endowment.
Conflicts of interest
The authors declare no conicts of interest.
Ethics approval
Our review did not involve any clinical or animal experiments
and was analyzed only using published open-source stud-
ies, therefore did not involve the approval of the Institutional
Review Board.
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How to cite this article: Zaman S, Gorelick F. Acute pancreatitis: pathogenesis
and emerging therapies. J Pancreatol 2024;7:10–20. doi: 10.1097/
JP9.0000000000000168
