Severe Pancreatic Injury Research Articles

Targeting extracellular CIRP with an X-aptamer shows therapeutic potential in acute pancreatitis

Severe acute pancreatitis (AP) is associated with a high mortality rate. Cold-inducible RNA binding protein (CIRP) can be released from cells in inflammatory conditions and extracellular CIRP acts as a damage-associated molecular pattern. This study aims to explore the role of CIRP in the pathogenesis of AP and evaluate the therapeutic potential of targeting extracellular CIRP with X-aptamers. Our results showed that serum CIRP concentrations were significantly increased in AP mice. Recombinant CIRP triggered mitochondrial injury and ER stress in pancreatic acinar cells. CIRP-/- mice suffered less severepancreatic injury and inflammatory responses. Using a bead-based X-aptamer library, we identified an X-aptamer that specifically binds to CIRP (XA-CIRP).Structurally, XA-CIRP blocked the interaction between CIRP and TLR4. Functionally, it reduced CIRP-induced pancreatic acinar cell injury invitro andL-arginine-induced pancreatic injury and inflammation invivo. Thus, targeting extracellular CIRP with X-aptamers may be a promising strategy to treat AP.

Unity is Strenght: Multidisciplinary Approach to a Severe Liver and Pancreatic Injury

Unity is Strenght: Multidisciplinary Approach to a Severe Liver and Pancreatic Injury

S1675 Blame It on the Bamboo Stump: A Pancreatic Ductal Disruption Successfully Managed With Two-Step Endoscopic Therapy

Introduction: Non-penetrating, isolated pancreatic injuries are rare, and the management is not well-established and challenging. Most injuries are managed by surgery, but recently several case reports discuss endoscopic therapy for treatment of main pancreatic duct disruption. We report a case of pancreatic injury from falling on a bamboo stump with complete pancreatic ductal disruption and complete pancreas divisum with a dominant dorsal duct that was successfully nonoperatively managed through endoscopic therapy. Case Description/Methods: An 18-year-old male transferred for worsening abdominal pain from a grade IV pancreatic injury complicated by pancreatic ascites and massive pancreatic fluid collections (PFCs) sustained a month prior after a non-penetrating fall onto a bamboo rod in the Caribbean. He had failed conservative therapy and 2 attempts with ERCP for pancreatic duct (PD) stent placement. CT A/P and MRCP showed a 13cm cyst consistent with hemorrhagic pancreatic pseudocyst (Figure A-B). Labs showed leukocytosis, elevated lipase and LFTs, but he was hemodynamically stable. US-guided paracentesis drained 250mL of fluid consistent with pancreatic ascites. To allow for pancreatic edema reduction, we elected for a 2-step procedure with separate EUS and ERCP. EUS showed multiple PFCs s/P endoscopic cyst-gastrostomy with Axios stent (Figure C-D). Repeat CT A/P showed decrease in size of the PFCs (Figure E). He was discharged and returned in one week for ERCP that revealed a surprising complete pancreas divisum and total disrupted main dorsal PD, which was endoscopically treated with sphincterotomy of the minor papilla and a long PD stent across the disruption (Figure F-H). The Axios stent was removed a week later, and 4 weeks later we successfully removed the PD stents from both the major and minor papillae. He made an uneventful recovery and remains well. Discussion: Pancreatic disruption syndrome or Disconnected Pancreatic Duct Syndrome (DPDS) is an interruption of pancreatic duct continuity, usually from necrotizing pancreatitis, but can occur with blunt or penetrating abdominal injury, as in our patient. Endoscopic management is a minimally invasive option for DPDS and pancreatic ascites. Our patient had severe pancreatic injury managed using 2-stage endoscopic therapy, demonstrating a successful treatment strategy for pancreatic injury with total main DPDS. Further studies are required regarding the selection of patients, safety, and long-term outcomes.Figure 1.: Image A: CT A/P (coronal) demonstrating edematous pancreas with significant peripancreatic fat stranding, with a peripherally enhancing hypodense fluid collection near the body and tail of the pancreas measuring approximately 4.0 x 4.8 x 13 cm in the maximum AP, RL and SI dimensions (red arrow). Image B: MRCP (coronal) Abutting the pancreatic body is a multilobulated rim-enhancing complex fluid collection that extends from the level of the diaphragmatic hiatus to just above the level of the aortoiliac bifurcation and measures 6.8 x 9.7 x 19.1 cm (AP by TR by SI, red arrow). Image C-D: EUS demonstrating large pancreatic fluid collection (PFC, left) and s/P Axios cyst-gastrostomy (right). Image E: CT A/P (coronal) demonstrating cyst-gastrostomy placement with interval decrease in PFC. Image F-H: Pancreatogram showed extravastion of contrast material at the junction of proximal 2/3 and distal1/3 of the dorsal PD c/w disrupted dorsal PD (Complete Pancreas divisum, left). Placement of a 5 Fr 9 cm Zimmon PD stent with pigtail crossing the disruption at the minor papilla (center). Pancreatogram showing no extravasation of contrast material s/P PD stent placement.

S1933 Acute Pancreatitis Attributed to COVID-19: An Unusual Infectious Etiology

Introduction: COVID-19 can affect multiple organs and has various presentations, including respiratory symptoms and fever being the most common. Gastrointestinal symptoms can be reported in up to 25% of patients, with diarrhea, nausea, and emesis the usual presentation. However, abdominal pain is less than 6.8% of cases, and of those, only 27% presented with Acute Pancreatitis (AP). Here we present a case of severe AP with multiorgan involvement as the initial presentation of COVID19. Case Description/Methods: Case of a 19 y/o Female with a medical history of Obesity class I arrived at the ED with recurrent emesis and altered mental status. Symptoms began around four days prior with 6-7 episodes of non-bloody, non-bilious emesis, fatigue, subjective fever, and decreased oral intake, followed by acute onset of diffuse abdominal pain. Upon arrival, the patient was found encephalopathic with dry oral mucosa, tachycardic and tachypneic. Laboratories were remarkable for lipase 2483, amylase 382, LDH 315, ALP 219 U/L, sodium 155 mEq/L, creatinine 1.33 mg/dL, bicarbonate < 9 mmol/L, pH 7.0, pO2Sat 96%, hematocrit 51.8%, WBC 14.9 cells/L, glucose 774 mg/dL, and COVID 19 PCR positive. Abdominal US and CT with no findings suggestive of gallstones or intraabdominal pathology. Aggressive intravenous fluid, insulin, broad-spectrum antibiotics, bicarbonate replacement, analgesia, and antiemetics were implemented. Hospitalization was complicated as the patient did not tolerate PO intake, and the high anion gap metabolic acidosis was difficult to close for several days. After almost two weeks in the ICU, the patient was discharged home without apparent pancreatitis or COVID-19 repercussions. Discussion: Our case did not have any risk factors for AP, and extensive investigations did not reveal a clear etiology. Viral, bacterial, fungal, and parasitic infections are less common causes of AP. There are limited data on COVID-19 and pancreatitis; however, recent studies suggest a higher mortality rate with a 20% increased chance of dying and worse clinical outcomes. The mechanism of pancreatic injury is not well understood, but there is a link between COVID-19 and the precipitation of autoimmune and systemic diseases. Our case is an example of severe pancreatic injury with multiorgan involvement in mild symptomatic COVID 19.

Case report of an isolated pancreatic transection from low impact blunt abdominal trauma necessitating resective surgery

Introduction and importanceIsolated pancreatic injury from blunt force trauma is an extremely rare entity accounting for less than 1 % of trauma presentations. This case highlights the diagnostic difficulties of identifying a ductal injury and presents a rare instance of an isolated pancreatic transection from a relatively low-impact blunt abdominal trauma.Case presentationA 30 year old lady presented to the emergency department 24 h following a low impact abdominal trauma. CT scan showed a complete pancreatic transection with significant peripancreatic free fluid. MRCP showed the main pancreatic duct to be in alignment on either side of the transection plane, however given the significant surrounding free fluid she was taken to the operating theatre for exploration and resective surgery. Intraoperative findings were that of a complete pancreatic transection involving the main pancreatic duct.DiscussionCurrent management guidelines focus on the correct evaluation of main pancreatic duct integrity. Timely intervention is essential for improving mortality and morbidity outcomes. Reported sensitivity and specificity for imaging modalities vary between studies, likely reflecting inherent challenges in accurately identifying pancreatic duct injuries. Multi-modal assessment is recommended to reach a timely diagnosis and hence, institute the appropriate therapy.ConclusionLow-energy trauma can result in isolated injuries of the pancreas. Multi-modal imaging should be encouraged for evaluation of main pancreatic duct integrity. This will facilitate timely decision making regarding the need for definitive surgery.

Clinical Analysis of Acute Organophosphorus Pesticide Poisoning and Successful Cardiopulmonary Resuscitation: A Case Series.

Acute organophosphorus pesticide poisoning (AOPP) with cardiac arrest has an extremely high mortality rate, and corresponding therapeutic strategies have rarely been reported. Therefore, this study aimed to explore the prognostic factors and effective treatments of AOPP-related cardiac arrest. This retrospective study was conducted in our department in the years 2018–2021. We conducted a descriptive analysis of the clinical manifestations, rescue strategies, and prognosis of patients with AOPP who had experienced cardiac arrest and successful cardiopulmonary resuscitation. This study included six cases of patients with AOPP in addition to cardiac arrest; in four cases, cardiac arrest occurred <12 h after ingestion, and in two, cardiac arrest occurred more than 48 h after ingestion. Five patients had not undergone hemoperfusion therapy before cardiac arrest, and all six were treated with atropine during cardiopulmonary resuscitation and subsequent pralidoxine. Four patients recovered and were discharged from the hospital, one died in our department, and one was transferred to a local hospital and died there 2 h later. The last two patients had severe pancreatic injuries and disseminated intravascular coagulation. This, along with their death, might have been related to their prognosis. Cardiac arrest can occur in patients with severe AOPP for whom antidote administration was insufficient or not timely. Application of atropine and pralidoxine in a timely manner after cardiac arrest following AOPP is the key to successful treatment. This study provides useful guidelines for the treatment of similar cases in the future.

Efficacy of damage control surgery and staged endoscopic pancreatic ductal double stenting therapy for severe pancreatic head injury: a case report

BackgroundA high-grade pancreatic injury is a life-threatening injury that is associated with high mortality and morbidity. It is currently unclear which treatment strategy results in good clinical outcomes.Case presentationA 23-year-old Japanese woman sustained severe injury in a motor vehicle accident. Abdominal computed tomography revealed severe pancreatic head injury with extravasation of contrast media. Since it was not possible to insert an endoscopic pancreatic stenting tube into the main pancreatic duct, damage control surgery was performed. On day 3, we could insert the endoscopic pancreatic stenting tube from the ampulla of Vater and an endoscopic nasopancreatic drainage tube in the distal pancreatic duct from the accessory ampulla before the second operation. Drainage tubes were placed around the pancreatic head in the second operation. The endoscopic nasopancreatic drainage tube tube was converted to endoscopic pancreatic stenting tube on day 9. On day 51, the patient was discharged on foot from our hospital without serious complications.ConclusionEarly and effective hemostasis, staged pancreatic duct drainage with stenting, and surgical external drainage around the pancreas in combination with an endoscopic procedure and damage control surgery were considered appropriate therapeutic strategy for high-grade pancreatic injury.

Analysis of Later Stage Morbidity and Mortality after Pancreatic Surgery Because of Abdominal Trauma

Background: Pancreatic trauma surgery is a complicated surgical procedure for severe pancreatic injuries, accompanied by a high incidence of complications and mortality. This study was designed to explore the long-term prognosis of pancreatic surgery because of abdominal trauma. Patients and Methods: The clinical data of 103 patients who were admitted to Jinling Hospital between August 2012 and August 2019 who had pancreatic trauma surgery were analyzed retrospectively. Results: All admissions involved pancreatic trauma surgery performed at an outside hospital network, which later transferred patients to our institution because of post-operative later-stage complications. Eight patients received American Association for the Surgery of Trauma (AAST) grade 1 or 2 pancreatic injuries and 95 received AAST grade 3, 4, or 5 pancreatic injuries. The primary surgical management of pancreatic injuries included drainage of the pancreatic injury (n = 28), repair of the pancreas (n = 35), partial pancreatectomy (n = 15), pancreaticojejunostomy (n = 6), and pancreaticoduodenectomy (n = 19). The most common mechanism of trauma was motor vehicle collision (n = 72), crush injury (n = 26), and stab wound (n = 5). Of 103 patients suffered varying degrees of gastrointestinal fistulae and intra-abdominal infections, there were 66 cases of pancreatic fistulae (64.1%), 49 cases of enteric fistulae (47.6%), 26 cases of colonic fistulae (25.2%), 14 cases of gastric or gastrointestinal anastomotic fistulae (13.6%), and 13 cases of biliary fistulae (12.6%). Ninety-five patients survived and eight patients died after therapy; the mean length of intensive care unit stay was 33 days. The number of patients who underwent emergency pancreaticoduodenectomy (EPD), the incidence of blood transfusion, the number of fistulae per patient, and the duration of mechanical ventilation and bacteremia in the mortality group were substantially higher than in the survival group (p < 0.05 each). The patients who underwent EPD had more grade 5 pancreatic injuries, more blood transfusions, higher peak total bilirubin, greater numbers of fistulae and open abdomen, and longer duration of mechanical ventilation and mortality than other patients (p < 0.05 each). Conclusions: The grade of pancreatic injury was associated with mortality and post-operative complications. The post-operative mortality and occurrence of complications of EPD because of abdominal trauma were significant; use of damage control surgery could potentially reduce the morbidity and mortality related to this procedure.

PD-1/PDL1 Blockade Exacerbates Pancreatic Damage and Immune Response in a Mouse Model of Acute Pancreatitis.

Programmed necrosis factor 1 (PD-1) is significantly overexpressed in lymphocytes, neutrophils, and macrophages and has been studied in depth in tumors. As a member of the negative costimulatory family of immune regulatory molecules, expression of PD-1 and its primary regulatory pathway are related to immune cells. Recently, PD-1 was demonstrated to be clinically important in inflammatory diseases, such as multiple sclerosis, glomerulonephritis, and inflammatory bowel disease. PD-1, a negative regulator molecule, was recently found to protect tissues from the inflammatory response and inflammatory cell infiltration. Conversely, PD-1 deficiency may contribute to the occurrence of a diverse array of inflammatory diseases. However, whether PD-1 regulates the pathogenesis of acute pancreatitis (AP) is unclear. AP is a noninfectious inflammatory disease with primary pathological manifestations that include edema, inflammatory cell infiltration, and acinar cell necrosis. Among these features, costimulatory molecules including PD-1/PDL1 play a critical role in the regulation of immune response and immune activation. Here, we first found that PD-1 is notably upregulated in neutrophils and macrophages in peripheral blood and pancreatic injury tissue in AP mice. PD-1 gene deficiency exacerbated pancreatic injury in an experimental mouse model of AP. We observed more severe pancreatic injury in PD-1-deficient mice than in control mice, including increased pancreatic edema, inflammatory cells, infiltration, and acinar cell necrosis. We also found that PD-1-deficient mice exhibited higher levels of serum enzymology and inflammatory factors in AP. Furthermore, PD-1/PDL1 neutralizing antibodies significantly aggravated pancreatic and lung injury and increased serum inflammatory cytokine levels. These findings were consistent with those in PD-1-deficient mice. In summary, PD-1 may protect against AP in mice and act as a potential target for the prevention of AP in the future.

Milk fat globule EGF factor 8 restores mitochondrial function via integrin-medicated activation of the FAK-STAT3 signaling pathway in acute pancreatitis.

Acute pancreatitis (AP) remains a significant clinical challenge. Mitochondrial dysfunction contributes significantly to the pathogenesis of AP. Milk fat globule EGF factor 8 (MFG‐E8) is an opsonizing protein, which has many biological functions via binding to αvβ3/5 integrins. Ligand‐dependent integrin‐FAK activation of STAT3 was reported to be of great importance for maintaining a normal mitochondrial function. However, MFG‐E8's role in AP has not been evaluated.MethodsBlood samples were acquired from 69 healthy controls and 134 AP patients. Serum MFG‐E8 levels were measured by ELISA. The relationship between serum concentrations of MFG‐E8 and disease severity were analyzed. The role of MFG‐E8 was evaluated in experimental models of AP.ResultsSerum concentrations of MFG‐E8 were lower in AP patients than healthy controls. And serum MFG‐E8 concentrations were negatively correlated with disease severity in AP patients. In mice, MFG‐E8 administration decreased L‐arginine‐induced pancreatic injury and mortality. MFG‐E8's protective effects in experimental AP were associated with improvement in mitochondrial function and reduction in oxidative stress. MFG‐E8 knockout mice suffered more severe pancreatic injury and greater mitochondrial damage after l‐arginine administration. Mechanistically, MFG‐E8 activated the FAK‐STAT3 pathway in AP mice. Cilengitide, a specific αvβ3/5 integrin inhibitor, abolished MFG‐E8's beneficial effects in AP. PF00562271, a specific FAK inhibitor, blocked MFG‐E8‐induced STAT3 phosphorylation. APTSTAT3‐9R, a specific STAT3 antagonist, also eliminated MFG‐E8's beneficial effects under such a condition.ConclusionsMFG‐E8 acts as an endogenous protective mediator in the pathogenesis of AP. MFG‐E8 administration protects against AP possibly by restoring mitochondrial function via activation of the integrin‐FAK‐STAT3 signaling pathway. Targeting the action of MFG‐E8 may present a potential therapeutic option for AP.

Hyperlipasemia and Potential Pancreatic Injury Patterns in COVID-19: A Marker of Severity or Innocent Bystander?

Hyperlipasemia and Potential Pancreatic Injury Patterns in COVID-19: A Marker of Severity or Innocent Bystander?

The modern trauma pancreaticoduodenectomy for penetrating trauma: a propensity-matched analysis.

Trauma pancreaticoduodenectomy (TP) remains a challenging operation with morbidity and mortality rates as high as 80% and 50%. Many trauma surgeons consider it surgical dogma to avoid performing a TP during the index operation for patients with severe pancreatic or duodenal injuries. However, there is no modern analysis evaluating this belief. Therefore, we hypothesized no difference in risk of mortality between patients with severe pancreatic or duodenal injury undergoing a TP for penetrating trauma to propensity-matched controls undergoing laparotomy without TP. The Trauma Quality Improvement Program (2010–2016) was queried for adults with severe penetrating pancreatic or duodenal injuries undergoing laparotomy. A 1:2 propensity-matching including demographics/comorbidities, injury severity score, vitals on admission, Glasgow Coma Scale and concomitant injuries for laparotomy with or without TP was performed. Risk of mortality was reported using a univariable logistic regression model. Of 2182 patients with severe pancreatic or duodenal injuries undergoing laparotomy, 54 (2.5%) underwent TP and 2128 (97.5%) underwent laparotomy without TP. There were no differences in propensity-matching characteristics. Patients undergoing TP had a similar mortality rate (20.0% vs. 28.7%, p = 0.302) but a longer length of stay (LOS) (27.5 vs. 16.5 days, p = 0.017). The TP group had a similar associated risk of mortality (OR = 0.62, p = 0.302) but higher risk of major complications (OR 3.44, CI 1.35–17.47, p = 0.015). In appropriately selected penetrating trauma patients with severe pancreatic/duodenal injuries, TP is associated with a similar risk of mortality compared to laparotomy without TP. However, TP patients did have an increased associated risk of major complications and longer LOS.

Rapamycin Alleviates Hypertriglyceridemia-Related Acute Pancreatitis via Restoring Autophagy Flux and Inhibiting Endoplasmic Reticulum Stress.

Hypertriglyceridemia (HTG) can aggravate acute pancreatitis (AP), but its pathogenesis remains unclear. As autophagic activity is closely related to lipid metabolism and AP, we investigated the autophagic response in models of AP aggravated by HTG and explored whether rapamycin has a protective effect against HTG-related pancreatitis. HTG-associated AP models were established in vivo in rats and in vitro. The degree of inflammation, pancreatic injury, the expression of endoplasmic reticulum (ER) stress, and autophagy markers (P62, LC3) were compared. Autophagic flux were assessed using immunostaining, electron microscopy, and immunoblotting. Compared with the normal diet group, the high-fat diet (HFD) AP group exhibited more severe pancreatic injury, apoptosis, and blocked autophagic flux. In addition, the three branches (PERK-eIF2α, ATF-6-GRP78, and IRE1-sXBP1) of the unfolded protein response and mTORC1/S6K1 pathway were activated in HFD AP models. Moreover, the same phenomena were confirmed in vitro in palmitic acid-stimulated pancreatic acinar cells. Preincubation with the mTOR inhibitor rapamycin restored the autophagic flux and markedly reduced the adverse effects of HTG. In conclusion, the autophagic flux is impaired in HFD-induced AP models and is strongly associated with ER stress. Rapamycin could prevent the aggravation of HTG-associated AP via inhibiting mTORC1/S6K1 pathway.

Identification of irisin as a therapeutic agent that inhibits oxidative stress and fibrosis in a murine model of chronic pancreatitis

BackgroundAbnormal activation of pancreatic stellate cells (PSCs) plays a crucial role in the pathogenesis of chronic pancreatitis (CP). Irisin, an exercise-induced hormone, has been shown to mitigate liver fibrosis by inhibiting the activation of hepatic stellate cells. However, the effect of irisin in CP has not been evaluated. MethodsThis study aimed to determine whether irisin is protective in CP. CP was induced by 6 IP injections of cerulein (50 μg/kg/body weight). HPSCs were treated with 5 ng/ml TGF-β1 as in vitro experiment. ResultsOur results showed that repeated cerulein injection induced severe pancreatic injury and fibrosis in mice and the serum irisin level in cerulein-treated mice decreased as in CP patients. Excessive oxidative and ER stress was also present in the pancreas of cerulein-treated mice. Irisin treatment significantly alleviated pancreatic injury and fibrosis, which was associated with reduced oxidative and ER stress. In cultured PSCs, irisin directly inhibited TGF-β-induced α-SMA and collagen I expression. This effect appears to be mediated through downregulation of kindlin-2 and inhibition of the SMAD2/3 pathway. ConclusionsIrisin alleviated pancreatic injury and fibrosis, which was associated with reduced oxidative and ER stress. Thus, irisin may offer therapeutic potential for patients with CP.

Grade IV traumatic pancreatic injury with primary duodenum malignant lymphoma following pancreatoduodenectomy: a case report

BackgroundTraumatic pancreatic injury with a main pancreatic duct injury has a high incidence of mortality and requires a prompt and appropriate treatment. However, the best approach, and treatment options, which may be limited, remains controversial especially for the elderly patients. Herein, we present a case of traumatic pancreatic injury in an elderly patient for whom pancreatoduodenectomy was safe and effective.Case presentationAn 87-year-old man was diagnosed with a traumatic pancreatic injury with a main pancreatic duct injury. In addition, the horizontal segment of the duodenum was largely eradicated. There were no comorbidities, and his vital signs were stable. A pancreatoduodenectomy was performed. The postoperative course was uneventful, and he was discharged. Pathological examination revealed a primary follicular lymphoma of the duodenum.ConclusionsThis case demonstrated that pancreatoduodenectomy could be performed safely for a severe pancreatic injury in an elderly patient. However, special attention should be paid to select the optimal surgical procedure. Further, this was a rare case, as initially a primary follicular lymphoma of the duodenum was suspected as a duodenal injury coexisting with a traumatic pancreatic injury because of the increased duodenal thickness.

The relationship between serum triglyceride levels and acute pancreatitis in an animal model and a 14-year retrospective clinical study

ObjectivesThe aim of the current study was to evaluate influence of serum triglyceride levels on the course of acute pancreatitis (AP).MethodsRats models of hypertriglyceridemic were used in animal experiments. Following induction of acute pancreatitis, amylase, and pancreas histological scores were all compared. In addition, in a clinical study, clinical data were collected from 1681 AP patients admitted from 2003 to 2016 who were divided into 4 groups based on their serum triglyceride (TG) levels. The clinical features among these 4 groups were compared, and a receiver operating characteristic (ROC) curve analysis was also performed on TG values to estimate their relationship with severity.ResultsIn animal experiments, the hypertriglyceridemic pancreatitis (HTGP) group had markedly higher serum amylase, and histological scores relative to the other animal groups. In the clinical study, we identified significant differences in gender, age, body mass index (BMI), cost, and incidence of partial complications among the 4 TG-based groups. Importantly, the TG levels on day 3–4 after admission could be used to accurately predict disease severity.ConclusionsHypertriglyceridemia (HTG) can aggravate pancreatic injury, and hypertriglyceridemia patients are more likely to suffer from severe pancreatic injury with a higher possibility of complications. In addition, triglyceride levels are correlated with the severity of AP positively.

Bone marrow-derived mesenchymal stem cells repair severe acute pancreatitis by secreting miR-181a-5p to target PTEN/Akt/TGF-β1 signaling

BackgroundSevere acute pancreatitis (SAP) is associated with high morbidity and mortality. Bone marrow mesenchymal stem cells (BMSCs) have shown obvious protective effect on SAP. However, little is known about the underlying mechanism. The objective of this study is to unravel the role and regulatory mechanism of miR-181a-5p in BMSCs-mediated pancreatic repair. MethodsBMSCs were isolated from Sprague-Dawley rats and characterized by flow cytometry and Oil Red O staining. Sodium taurocholate- and caerulein-induced models were used as SAP models in vivo and in vitro, respectively. Pancreatic injury were evaluated by H&E and histopathological analysis, as well as by measuring levels of amylase, lipase and cytokines. qRT-PCR and western blotting were performed to detect the level of miR-181a-5p and the protein levels of PTEN/Akt, respectively. ELISA was conducted to detect the levels of TNF-α, IL-1β, IL-6, angiopoietin, IL-4, IL-10 and TGF-β1. The apoptotic rate of AR42J cells was quantitated by concurrent staining with Annexin-V-FITC and PI. ResultsBMSCs significantly attenuated pancreatic injury in SAP rats by reducing inflammatory infiltration and necrosis, and this effect was abolished by CXCR4 agonist AMD3100. ADM3100 exhibited more severe pancreatic injury and decreased miR-181a-5p levels in the pancreas and serum compared to SAP group. Overexpression of miR-181a-5p in BMSCs (BMSCs-miR-181a-5p) markedly potentiated the protective effect of BMSCs by reducing histological damage and levels of amylase and lipase. Moreover, BMSCs-miR-181a-5p dramatically reduced levels of angiopoietin, TNF-α, IL-1β and IL-6, but induced the levels of IL-4 and IL-10. In caerulein-treated AR42J cells, co-culturing of BMSCs-miR-181a-5p alleviated caerulein-induced increase of amylase and lipase, and apoptosis via PTEN/Akt/TGF-β1 signaling. ConclusionBMSCs alleviate SAP and reduce inflammatory responses and apoptosis by secreting miR-181a-5p to target PTEN/Akt/TGF-β1 signaling. Hence, BMSCs-miR-181a-5p could serve as potential therapeutic target for SAP.

Large triglyceride-rich lipoproteins in hypertriglyceridemia are associated with the severity of acute pancreatitis in experimental mice

Hypertriglyceridemia severity is linked to acute pancreatitis prognosis, but it remains unknown why a portion of severe hypertriglyceridemia patients do not develop severe acute pancreatitis. To investigate whether hypertriglyceridemia subtypes affect acute pancreatitis progression, we analyzed two genetically modified hypertriglyceridemia mouse models—namely, glycosylphosphatidylinositol high-density lipoprotein binding protein 1 knockout (Gpihbp1−/−) and apolipoprotein C3 transgenic (ApoC3-tg) mice. Acute pancreatitis was induced by 10 intraperitoneal caerulein injections. Biochemical assays and pathological analysis were performed for the severity evaluation of acute pancreatitis. Plasma triglyceride-rich lipoproteins (TRLs), including chylomicrons and very low-density lipoprotein (VLDL), were collected via ultracentrifugation to evaluate their cytotoxic effects on primary pancreatic acinar cells (PACs). We found that the particle sizes of Gpihbp1−/− TRLs were larger than ApoC3-tg TRLs. Severe pancreatic injury with large areas of pancreatic necrosis in the entire lobule was induced in Gpihbp1−/− mice when plasma triglyceride levels were greater than 2000 mg/dL. However, ApoC3-tg mice with the same triglyceride levels did not develop large areas of pancreatic necrosis, even upon the administration of poloxamer 407 to further increase triglyceride levels. Meanwhile, in the acute pancreatitis model, free fatty acids (FFAs) in the pancreas of Gpihbp1−/− mice were greater than in ApoC3-tg mice. TRLs from Gpihbp1−/− mice released more FFAs and were more toxic to PACs than those from ApoC3-tg mice. Chylomicrons from patients showed the same effects on PACs as TRLs from Gpihbp1−/− mice. Gpihbp1−/− mice with triglyceride levels below 2000 mg/dL had milder pancreatic injury and less incidence of pancreatic necrosis than those with triglyceride levels above 2000 mg/dL, similar to Gpihbp1−/−mice with triglyceride levels above 2000 mg/dL but with fenofibrate administration. These findings demonstrated that hypertriglyceridemia subtypes with large TRL particles could affect acute pancreatitis progression and that chylomicrons showed more cytotoxicity than VLDL by releasing more FFAs.

Surfactant Protein D Dampens Lung Injury by Suppressing NLRP3 Inflammasome Activation and NF-κB Signaling in Acute Pancreatitis.

Wild-type C57BL/6 (WT), SP-D knockout (KO), and humanized transgenic SP-D (hTG) mice were used in this study. SAP was induced by administration of one-dose lipopolysaccharide (10 mg/kg) and 6 hourly intraperitoneal injections of cerulein (Cn) (100 μg/kg). Animals were killed 6 and 24 h after first Cn treatment. Histopathologic changes in pancreas and lung were assessed by light and electron microscopes. Serum amylase, IL-1β, IL-6, and MCP-1 levels were determined by kit/ELISA. NLRP3 inflammasome, NF-κB, and MPO activations were analyzed by western blotting and immunofluorescence. KO mice showed more severe pancreatic and lung injury than WT mice in SAP. hTG mice exhibited similar degree in lung injury as WT mice. Mitochondrial and rough endoplasmic reticulum damages, autophagosome formation were observed in the alveolar type II and acinar cells of SAP mice. SAP KO mice had increased bronchoalveolar lavage fluid inflammatory cells, higher levels of serum IL-1β, IL-6, and MCP-1 than SAP WT and hTG mice. Levels of NLRP3 inflammasome (NLRP3, ASC, and Caspase-1) and NF-κB activation in SAP KO mice were higher than SAP WT and hTG mice. SP-D exerts protective effects against ALI via suppressing NLRP3 inflammasome and NF-κB activation in experimental SAP.

A Case of Severe Traumatic Pancreatic Injury Treated with Pancreaticoduodectomy

A Case of Severe Traumatic Pancreatic Injury Treated with Pancreaticoduodectomy