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The Role ofthe Intestine andMesenteric Lymph inthe Development ofOrgan Dysfunction inSevere Acute Pancreatitis

Alistair B.J. Escott1, Anthony R.J. Phillips2, and John A. Windsor

Department of Surgery, University of Auckland, Auckland, New Zealand

Applied Surgery and Metabolism Laboratory, School of Biological Sciences and Department of Surgery, University of Auckland, Auckland, NewZealand

Surgical and Translational Research Centre, University of Auckland, Auckland, New Zealand

Introduction

Acute pancreatitis (AP) is a complex and challenging disease with an unpredictable course[1]. The severity and outcome of AP are primarily determined by local and systemic factors; the presence of infected (peri)pancreatic necrosis (e.g., “acute necrotic collections” and/or “walled off necrosis”) and persistent end- organ dysfunction (e.g., cardiovascular, pulmonary and/or renal failure) [2]. Recent improvements in the management and outcomes of infected pancreatic necrosis means that it is less important in driving organ dysfunction/failure and impacting clinical outcome. This is evidenced by the marked diminution of the second (late) peak in the bimodal mortality profile of severe acute pancreatitis[3]. Organ failure is the leading cause of death from AP. The pattern of this organ failure is broadly similar across acute and critical diseases, suggesting common drivers for the “multiple organ dysfunction syndrome” (MODS)[4]. This pattern appears to be no different for severe acute pancreatitis[5,6].

The aim of this chapter is to review the role of the intestine in the development of MODS, the evidence for the gut–lymph concept in promoting MODS in acute pancreatitis and to discuss the potential to translate this to effective clinical treatments.

Role ofthe Intestine andMesenteric Lymph inMultiple Organ Dysfunction Syndrome

The concept that the intestine drives critical illness was developed in the 1960s when bacterial endotoxin was demonstrated in the systemic circulation of patients with

infective and noninfective severe diseases[7]. This gave rise to the bacterial translocation hypothesis where gut organisms were proposed to cross the intestinal barrier to create a “septic-

like state” [8]. In the 1980s, the gut motor hypothesis expanded this concept to acknowledge the contribution of changes in the intestinal flora and the increased permeability of the gut barrier, postulating that bacterial pathogens and endotoxins enter the systemic circulation via the portal venous system[9]. This was largely discredited when it was not possible to prospectively demonstrate bacteria in the portal vein or systemic circulation in patients with major trauma[10]. A further concept was advanced where neutrophil priming occurred in the mesenteric circulation and that this contributed to both local gut injury and distant organ injury [11–13]. This was the basis of the second- hit hypothesis, which implicates the intestine but does not rely on a direct bacterial role.

Using experimental models of hemorrhagic shock and trauma Deitch and colleagues introduced the concept that organ failure might be promoted by gut- derived mesenteric lymph. They suggested that primed neutrophils and other intestine-

derived toxic factors were the mediators of MODS, and that this occurred in association with increased gut permeability but independent of bacterial translocation [14]. Deitch went on to demonstrate that these intestine- derived factors were transported by thoracic duct lymph to reach the systemic circulation to promote systemic inflammation and organ dysfunction [14,15]. He termed this the “gut–lymph hypothesis” [16]. Demonstrating that lung injury mediated by hemorrhagic shock altered mesenteric lymph was key to validating this concept in the experimental

The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler, RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/beger/thepancreas4e

Intestinal Injury andDysfunction Is Associated withSevere Acute Pancreatitis 139

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setting. Ligation of the mesenteric lymph duct before hemorrhagic shock prevented lung injury in a rodent model, while done after shock but before resuscitation only partially prevented lung injury[17]. It was found that mesenteric lymph from these rats was cytotoxic to endothelial cells and caused increased permeability to both a monolayer of endothelial cells and lung tissue while portal vein plasma did not[17,18]. The early failure of lung function[4–6] has also been demonstrated in experimental models of burns[19], shock [20], and sepsis[21] and AP[22]. Furthermore, ligation of the mesenteric or thoracic duct ligation in these different models has been shown to prevent neutrophil priming [23], reduce red blood cell deformity [24,25], reduce cardiac dysfunction[26–28], protect against renal injury[29], and increa se ATP and ATPase renal activity[30].

The plausibility of the gut–lymph concept is enhanced by considering the anatomy of the mesenteric/thoracic duct lymphatics[31]. Gut and mesenteric lymph drains from the intestine and mesentery to the cisterna chyli and then ascends through the mediastinum in the thoracic duct. Almost 75% of thoracic duct lymph arises from the abdomen and pelvis [32]. The thoracic duct lymph drains into the internal jugular or subclavian veins on the left side of the neck, immediately upstream of the heart, lungs, and kidneys, the organs most often involved in MODS. It is noteworthy that this lymph bypasses the liver and its detoxification processes (Fig.14.1).

While there has been considerable interest in how intestinal injury contributes to the severity of AP, the gut–lymph concept has only recently been considered of potential clinical relevance[33].

Intestinal Injury andDysfunction Is Associated withSevere Acute Pancreatitis

There are several mechanisms of intestinal injury during acute pancreatitis. Splanchnic vasoconstriction is a key, but not sole, mechanism (Fig. 14.1), and is the reflex response to redistribute blood from the splanchnic region to vital organs. This splanchnic vasoconstriction can cause ischemic injury to the mucosa and wall of the intestine, as well as the pancreas. In the intestine the microanatomy of the intestinal mucosa makes it particularly prone to ischemic injury. The villus tip is most susceptible to ischemia due to the countercurrent flow of oxygen via the rich capillary network between the parallel artery and vein[34]. This ischemic injury can be compounded by the use of nonselective inotropes in persistently hypotensive patients[35]. Intestinal injury is also increased with fluid resuscitation and reperfusion injury[36]. Intestinal ischemia is related to the severity of AP[37] with a lower gastric intramucosal pH (pHi) in

Figure14.1 Schematic of the gut–lymph concept

emphasizing that in acute pancreatitis (and other acute and critical diseases) the vasoconstriction (*) of the intestinal arterial supply to redistribute blood to vital organs results in intestinal ischemia. Drainage of lymph from the intestine via the thoracic duct, bypasses the liver, to enter the circulation proximal to heart, lungs, and kidneys, organs that fail most often.

Thoracic duct

Portal vein

Hepatic vein

The Role ofthe Intestine andMesenteric Lymph inthe Development ofOrgan Dysfunction inSevere Acute Pancreatitis

INTESTINE

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140

patients admitted to intensive care than those that remain on the ward, and a low pHi is correlated with an increased risk of mortality[38,39]. Ischemic injury to the intestine is also known to contribute to the breakdown of protective mucus [40], which is compounded by the action of pancreatic proteases [41,42]. The ischemic environment also induces mucosal atrophy, mitochondrial dysfunction [43], oxidative stress, and cell death. Interestingly the mitochondrial dysfunction found early in AP appears to occur in the pancreas, lung, and jejunum with relative sparing of the liver, heart, and kidneys[43].

There is strong evidence for intestinal dysfunction in AP (Fig. 14.2), and it is estimated to occur in 60% of patients[44]. Clinically this dysfunction can be evident as an ileus (dysmotility) [45], feeding intolerance [46], and at the severe end of the spectrum, nonocclusive intestinal ischemia[47,48]. Although suspected, there is still no clear clinical evidence that increased intestinal permeability, as detected by enterally administered polyethylene glycol, is associated with an increased risk of MODS in AP[49]. Increased urinary intestinal fatty acid binding protein, a marker of intestinal mucosal injury, has been correlated with the severity of AP[37,50]. The depletion of IgG anti-

endotoxin antibodies, indicative of exposure to endotoxin and “gut barrier failure,” is strongly associated with the development of organ failure and death in severe AP [51]. The administration of enteral

nutrition (rather than starvation or parenteral nutrition) has been associated with a reduction in infectious complications and mortality in patients with AP[52], giving rise to the concept of “gut rousing” and “gut protection” to maintain and improve intestine function[53] during AP and other acute and critical diseases.

Altered Gut–Lymph Composition inAcute Pancreatitis

There is a significant body of experimental evidence that mesenteric lymph undergoes significant compositional change during acute and critical diseases, such as hemorrhagic shock, sepsis, trauma, and burns[14]. Comparable experimental evidence is only now emerging for AP. A canine model of AP with thoracic duct cannulation demonstrated that a significant proportion of pancreatic amylase and lipase is transported via thoracic duct lymph compared with peritoneal absorption from pancreatic ascites[54]. A rodent model of acute pancreatitis revealed a profound change in the proteome of mesenteric lymph[55]. Of the eight proteins exhibiting a significant increase in mesenteric lymph seven were pancreatic proteases, and the increase was up to 40flooding of mesenteric lymph with pancreatic proteases there was no commensurate increase in the abundance of antiproteases. Lipase is also markedly elevated in

fold. Despite this

Autodigestion/NFκB

Inflammation/edema

Hypoperfusion

Necrosis

Infected necrosis

Initiating event(s)

Hypovolemia

Reflex vasoconstriction

Activated

inflammatory pathways

SIRS/MODS

Altered mesenteric lymph

Hypoperfusion

Ischemia

± Reperfusion

Ileus

Barrier failure

PANCREAS

Dysbiosis

Figure14.2 A summary of the complex interactions between the pancreas and the intestine in the development of systemic

inflammation (SIRS) and multiple organ dysfunction (MODS) in the pathogenesis of severe acute pancreatitis. Source: Adams DB (2017)/ John Wiley & Sons.

Gut–Lymph Toxicity inAcute Pancreatitis 141

(a) (b)

Cardiac output (mL/min)

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mesenteric lymph during AP and generates free and unsaturated fatty acids in mesenteric lymph that are directly toxic to umbilical vein cells[56], exhibit systemic toxicity, and are associated with ARDS and MODS[57]. The gut lymph profile of noncoding microRNA is also altered in AP, in both the experimental and clinical settings [58]. Interestingly, there were seven miRNAs that were increased in intestinal lymph during experimental AP and their log abundance correlated with AP severity [58]. The clinical significance of these microRNA changes has yet to be determined, but these molecules can regulate gene expression, influence cell function in remote organs, and offer potential therapeutic strategies with designer antisense sequences. Other groups have demonstrated changes in mesenteric lymph composition in AP. For example, it has been found that the tryptophan metabolites kynurenine and 3- hydroxykynurenine are elevated in rodent mesenteric lymph and plasma during AP and this elevation correlated with disease severity[59].

One of the challenges in studying the role of mesenteric lymph in patients with severe AP is the difficulty in gaining access to thoracic duct lymph in the clinical setting. A pilot nontherapeutic study was conducted in postesophagectomy patients which allowed serial sampling of thoracic duct lymph for several days following surgery[60]. While not in AP patients it did allow confirmation of compositional changes in human lymph similar to the rodent studies of AP. The effect of enteral feeding on TD lymph composition, and in particular on the markers of intestinal ischemia and injury, suggested that intestinal injury occurs with enteral feeding in these patients.

Gut–Lymph Toxicity inAcute Pancreatitis

The pathophysiologic and clinical significance of the profound compositional changes in mesenteric lymph in AP is still to be fully elucidated. Some progress has been made by testing the toxicity of the altered mesenteric lymph. In our own studies we have tested toxicity on four levels: organelle (e.g., mitochondrial function), cell (e.g., endothelial, cardiac), organ (e.g., isolated perfused heart and lung), and organism (e.g., rodent AP model). Mesenteric lymph from experimental AP incubated with either endothelial cells or cardiac fibers was toxic, causing increased cell death. In the case of cardiac fibers there was lymph- induced toxicity that induced mitochondrial complex dysfunction[61]. Experimental AP is associated with a reduction in cardiac output, contractility, and impaired relaxation, which can be replicated by infusion of mesenteric lymph collected from an experimental model of AP and then infused into an isolated and paced heart model [28]. Significantly, as further evidence of lymphatic toxicity, experimental work has shown that cardiac dysfunction can be prevented by thoracic duct ligation[28] (Fig.14.3). In another critical study mesenteric lymph from a rodent model of ischemiainjury was intravenously infused into other rats with AP [62] causing an increase in AP severity, augmented microcirculatory collapse and produced evidence of lung injury[62]. Other studies have shown that thoracic duct ligation[22] and lymph diversion[63] have been shown to ameliorate lung injury in AP.

reperfusion

Figure14.3 (a) Cardiac output is reduced in exvivo

working hearts by acute pancreatitis- conditioned gut–lymph when compared to saline or sham lymph. (b) Cardiac output is maintained in rats with acute pancreatitis when compared to sham rats or rats with acute pancreatitis in which the thoracic duct is ligated. *P < 0.05, **P < 0.02.

Saline infusion

40 20

Sham lymph infusion

AP lymph infusion

10 15

Preload (cmH

100

Cardiac output (mL/min)

20 7.5 12.5 17.5 22.5

O) Preload (cmH2O)

Sham AP AP + lymph diversion

The Role ofthe Intestine andMesenteric Lymph inthe Development ofOrgan Dysfunction inSevere Acute Pancreatitis

2500

Sham ML + FU

LDH (IU/L)

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142

Translating theGut–Lymph Concept toClinical Treatments forAcute Pancreatitis

2000

Open surgical drainage of thoracic duct lymph has previously been explored as a treatment for a number of diseases. There have been over 70 publications[64] in the English literature, but none since 2004. There is an even more extensive non- English literature from Eastern European countries[65]. The reasons for the discontinuation of this treatment is likely a combination of the invasive nature of the thoracic duct cannulation and the lack of compelling evidence due to the predominance of underpowered, nonrandomized and uncontrolled study designs. Within this seemingly forgotten literature there were four studies [66–69] in which external lymph drainage was used for the treatment of acute pancreatitis. One uncontrolled study of 10 patients reported an improvement in abdominal pain, peritonism, and shock in a “dose-

dependent” manner related to the volume of lymph drained[66]. Three of these studies investigated the effect of thoracic duct lymph drainage on pulmonary function in the setting of AP- associated acute respiratory distress syndrome. One study noted that arterial oxygenation improved once drainage was instituted [67]. Another case series demonstrated elevated levels of pancreatic enzymes and cytokines in lymph and plasma but no clinical improvement[69].

With the evidence that proteases contribute to lung injury in acute pancreatitis[70] and the evidence that thoracic duct lymph is flooded by pancreatic proteases in AP[55] suggests that external drainage is a treatment strategy warranting more careful evaluation. A canine model of thoracic duct external drainage has shown that this is effective in reducing plasma amylase and lipase in AP[54].

One of the major barriers to advancement in this area has been the lack of a reliable, safe, and minimally invasive technique for sampling, monitoring, and draining thoracic duct lymph in patients with severe AP. Theadvent of innovative retrograde percutaneous radiological techniques for cannulating and externally draining the thoracic duct[71] is stimulating the conduct of more studies to evaluate external drainage of thoracic duct lymph to mitigate an important driver of MODS[72].

Another potential treatment strategy based on the gut– lymph concept is the design and delivery of treatments that target known toxic factors in mesenteric lymph[73]. In an experimental rodent model it was demonstrated that inhibition of tryptophan metabolites kynurenine and 3- hydroxykynurenine, which are elevated in mesenteric lymph of rats with AP, is protective against MODS[74].

1500

1000

500

Control

Control + FUT

Figure14.4 Cell death (LDH level) of endothelial cells (HMEC) was

increased on treatment with hemorrhagic shock (HS) or APconditioned gut–lymph (ML) when compared to control media or mesenteric lymph (ML) from sham- treated rats (*P < 0.05). Cotreatment with the antiprotease nafamostat (FUT) reduced cell death (**P < 0.05) (unpublished).

Sham ML

HS ML

HS ML + FUT

AP ML

AP ML + FUT

In another experiment it was found that antiprotease treatment with nafamostat significantly reduced endothelial cell death when combined with mesenteric lymph from experimental hemorrhagic shock and AP (Fig.14.4). This raises the possibility of delivering antiprotease treatment to mesenteric lymph by supplementing enteral nutrition with lipophilic transporters. In a similar manner it is possible to deliver anti- lipase treatment (i.e., orlistat) to mesenteric lymph to reduce the generation of toxic fatty acids, which are known to exacerbate organdysfunction[75]. Enhanced delivery of oral orlistat to mesenteric lymph has been achieved in rodent models[76].

In order to translate the gut–lymph concept into effective clinical treatments, a more complete understanding the role of mesenteric lymph in the pathogenesis of the systemic inflammatory response and organ dysfunction will be required. These experimental studies are examples of potential new treatment strategies.

Conclusion

There is now compelling experimental evidence that altered mesenteric lymph contributes to the systemic inflammation and MODS that characterizes severe AP. The “gut–lymph” concept provides a new disease paradigm, a new field of research, and a long- awaited opportunity to develop new and specific treatments for MODS in severe AP.

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The Role ofNeurogenic Inflammation inPancreatitis

Metrah Mohammad Nader1 and Jami L. Saloman

University of Pittsburgh, School of Medicine Class of 2023, University of Pittsburgh, Pittsburgh, PA, USA

Department of Medicine/Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA

Department of Neurobiology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA

Pittsburgh Center for Pain Research, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA

2,3,4

Introduction

Pancreatitis is a clinical condition in which the main pathology is inflammation of the pancreatic tissue. It has multiple etiologies that include both genetic and environmental components. It also can be classified as acute or chronic pancreatitis. Acute pancreatitis typically resolves, but it is associated with acinar cell death and activation of subsequent inflammatory cascades [1,2]. Chronic pancreatitis, conversely, is a progressive destruction of the pancreas by repetitive insults. This leads to replacement of viable tissue by fibrotic tissue and subsequently alters pancreatic nerves around the area of inflammation [3–5]. Pathological activation of sensory neurons and the inflammatory sequelae are known as neurogenic inflammation. Neurogenic inflammation is the process by which substances released from sensory nerve terminals promote inflammation in their target tissue. The inciting factors that lead to pancreatic inflammation can be varied; however, the resulting pathology has a common histologic presentation, including edema, vasodilation, invasion of immune cells, and varying degrees of breakdown in the barriers between different tissue compartments within the pancreas.

The central and peripheral nervous systems (CNS and PNS, respectively) can adapt to an ongoing disease process in the gastrointestinal tract. A major role has been recognized for the PNS as a driver of inflammatory pancreatic responses, such that it is being investigated as both a prognostic biomarker as well as a therapeutic target. Experiments in animal models indicate that manipulation of the PNS can alter the course of the disease. Specifically, these manipulations have targeted sensory

innervation of the pancreas in studies that go back to the early twentieth century, which found that activation of the primary sensory neurons produced vasodilation[6]. The studies by Bayliss[6] were the beginning of the recognition that sensory neurons have an “efferent” function through the peripheral release of small molecules that can act on blood vessels and immune cells to establish “neurogenic inflammation.” Here we review the current state of our understanding of the role of neurogenic inflammation in pancreatitis and how this information might be translated into new treatments for human disease.

Innervation ofPancreas

The pancreas is innervated by two distinct neural pathways, vagal and spinal. Historically, they have been further divided into two distinct types of nerve fibers: afferent fibers conducting sensory information from the pancreas to CNS and efferent autonomic fibers (parasympathetic and sympathetic) conveying motor commands from the CNS to the pancreas (Fig. 15.1). The vagus nerve comprises both parasympathetic and sensory fibers. Pancreatic sensory afferents originate from the nodose ganglia (NG)[7]. They transmit information to the nucleus tractus solitarii (NTS) in the brainstem. Preganglionic parasympathetic neurons originate from the dorsal motor nucleus of the vagus (DMV) located in the brainstem and medulla [8]. These fibers activate parasympathetic postganglionic neurons located in the intrapancreatic ganglia[8,9]. The sympathetic efferent fibers of the pancreas consist of preganglionic and postganglionic neurons. Preganglionic

sensory neuron

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Neuroimmune Signaling 147

SMG, respectively). Preganglionic sympathetic neurons synapse on postganglionic sympathetic neurons in the CG and SMG [8,11]. The postganglionic sympathetic fibers subsequently project to intrapancreatic ganglia, islets, ducts, and blood vessels, and release neurotransmitters[12]. Parasympathetic and sympathetic efferent fibers release various neurotransmitters that directly affect blood pressure, pH, temperature, and metabolism of pancreatic tissues[9,12]. Spinal sensory afferent fibers originate from dorsal root ganglia (DRG) at (T6- L2) segments of the spinal cord. These afferent fibers, located in the splanchnic nerves pass through the celiac plexus and transmit information from the pancreas to the spinal cord[8,10].

DRG

CG/IMG

preganglionic parasympathetic neuron preganglionic sympathetic neuron postganglionic sympathetic neuron

Figure15.1 The pancreas receives sensory input from primary

afferents whose cell bodies are located in the nodose ganglion (NG) and run in the vagus nerve (VN). Sensory innervation from dorsal root ganglia (DRG; also known as spinal ganglia) to the pancreas travels with sympathetic preganglionic axons in the greater splanchnic nerve (SN) and passes through the celiac ganglia (CG), which together with the IMG form the celiac plexus. The VN also contains axons from parasympathetic preganglionic neurons whose cell bodies are located in the brainstem (in the dorsal motor nucleus of the vagus, not shown). These axons synapse on parasympathetic postganglionic neurons (not shown) that are in the organ. Sympathetic innervation arises from sympathetic preganglionic neurons whose cell bodies are located in the spinal cord intermediolateral cell column (not shown) at T5–9 vertebral levels. Axons from these neurons innervate sympathetic postganglionic neurons in prevertebral ganglia found near the organ. The prevertebral ganglia include the CG, whose neurons innervate pancreas. Anatomy shown for human, but rodents are organized in a similar fashion, varying only in the details. Figure created with BioRender.com.

efferent sympathetic fibers project from cell bodies in the lateral horn of the spinal cord called the intermediolateral cell column (C8- L3). Information is transmitted to paravertebral and prevertebral sympathetic ganglia in the celiac plexus (celiac and superior mesenteric ganglia; CG and

Neuroimmune Signaling

Under healthy conditions, neurohormonal signaling pathways involving both autonomic (parasympathetic, sympathetic) and sensory nerves regulate the exocrine and endocrine functions of the pancreas [9]. However, given that the primary function of the exocrine pancreas is production of digestive enzymes (proteases), the pancreas is always on the edge of activating inflammatory cascades. Sensory fibers transduce chemical and mechanical stimuli to the CNS, but they also release neurotransmitters and neuropeptides into the parenchyma, which can recruit and activate immune cells, thereby promoting inflammation.

Twenty years ago, patients with AP were reported to have increased levels of circulating inflammatory cytokines[13]. Studies of models of AP established that in response to the initial insult, acinar cells produce and release a variety of inflammatory mediators that initiate the inflammatory response. More specifically, a feedback loop begins when damaged acinar cells release TNF- α, IL- 6, IL- 8, IL- 10, and chemokines into the cir- culatory system. These mediators subsequently recruit neutrophils, and then macrophages, monocytes, and lymphocytes, to the pancreas. The recruited white cells cause the release of more proinflammatory cytokines, which leads to more edema and local inflammation suggesting that the initial inflammatory responses and signals that recruit leukocytes originate in injured pancreatic acinar cells[14]. It is not exactly clear how acinar cell injury leads to the induction of inflammatory mediators, but the process involves activation of specific transcription factors. NF- κB, in particular, is acti- vated in experimental and human AP, and genetic and pharmacologic approaches have shown its important role in the cytokine storm[15].

In addition, interleukins and TNF- alpha cytokines released by innate immune cells during inflammation are directly sensed by nociceptors, which lead to increased membrane excitability. Nerve growth

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