Fibrosis In Chronic Pancreatitis Research Articles

Nicotine aggravates pancreatic fibrosis in mice with chronic pancreatitis via mitochondrial calcium uniporter.

This study aimed to investigate the effects of nicotine on the activation of pancreatic stellate cells (PSCs) and pancreatic fibrosis in chronic pancreatitis (CP), along with its underlying molecular mechanisms. This was an in vivo and in vitro study. In vitro, PSCs were cultured to study the effects of nicotine on their activation and oxidative stress. Transcriptome sequencing was performed to identify potential signaling pathways involved in nicotine action. And the impact of nicotine on mitochondrial Ca2+ levels and Ca2+ transport-related proteins in PSCs was analyzed. The changes in nicotine effects were observed after the knockdown of the mitochondrial calcium uniporter (MCU) in PSCs. In vivo experiments were conducted using a mouse model of CP to assess the effects of nicotine on pancreatic fibrosis and oxidative stress in mice. The alterations in nicotine effects were observed after treatment with the MCU inhibitor Ru360. In vitro experiments demonstrated that nicotine promoted PSCs activation, characterized by increased cell proliferation, elevated α-SMA and collagen expression. Nicotine also increased the production of reactive oxygen species (ROS) and cellular malondialdehyde (MDA), exacerbating oxidative stress damage. Transcriptome sequencing revealed that nicotine may exert its effects through the calcium signaling pathway, and it was verified that nicotine elevated mitochondrial Ca2+ levels and upregulated MCU expression. Knockdown of MCU reversed the effects of nicotine on mitochondrial calcium homeostasis, improved mitochondrial oxidative stress damage and structural dysfunction, thereby alleviating the activation of PSCs. In vivo validation experiments showed that nicotine significantly aggravated pancreatic fibrosis in CP mice, promoted PSCs activation, exacerbated pancreatic tissue oxidative stress, and increased MCU expression. However, treatment with Ru360 significantly mitigated these effects. This study confirms that nicotine upregulates the expression of MCU, leading to mitochondrial calcium overload and exacerbating oxidative stress in PSCs, and ultimately promoting PSCs activation and exacerbating pancreatic fibrosis in CP.

Chronic organ damage: Understanding fibrosis

Chronic organ damage: Understanding fibrosis Fibrosis was once considered irreversible, resulting from chronic organ damage; Ken-Ichi Kobayashi from Notre Dame Seishin University tells us why the possibility of treatment to reverse the disease is gaining attention. Organ fibrosis is a common phenomenon observed in various organ failure states resulting from disease and aging. The most common examples are renal fibrosis in chronic kidney disease, liver fibrosis in cirrhosis, lung fibrosis in idiopathic pulmonary fibrosis, and pancreatic fibrosis in chronic pancreatitis. The total number of patients with organ fibrosis in Japan is nearly 20 million, and it is no exaggeration to say that it is a ‘national disease.’ Until recently, fibrosis was considered to be the end result of chronic organ damage and an irreversible condition with a poor prognosis. In recent years, however, fibrosis has begun to be recognized as a reversible process, and the possibility of treatment is gaining attention. It is also becoming clear that fibrosis is caused by complex cellular and inter-organic networks rather than by specific organs, and therefore, common pathological mechanisms are thought to exist even in various types of fibrosis. However, the common pathological mechanism of fibrosis, especially fibrosis-attracting factors, is still an enigma.

Activation and Regulation of Pancreatic Stellate Cells in Chronic Pancreatic Fibrosis: A Potential Therapeutic Approach for Chronic Pancreatitis.

In the complex progression of fibrosis in chronic pancreatitis, pancreatic stellate cells (PSCs) emerge as central figures. These cells, initially in a dormant state characterized by the storage of vitamin A lipid droplets within the chronic pancreatitis microenvironment, undergo a profound transformation into an activated state, typified by the secretion of an abundant extracellular matrix, including α-smooth muscle actin (α-SMA). This review delves into the myriad factors that trigger PSC activation within the context of chronic pancreatitis. These factors encompass alcohol, cigarette smoke, hyperglycemia, mechanical stress, acinar cell injury, and inflammatory cells, with a focus on elucidating their underlying mechanisms. Additionally, we explore the regulatory factors that play significant roles during PSC activation, such as TGF-β, CTGF, IL-10, PDGF, among others. The investigation into these regulatory factors and pathways involved in PSC activation holds promise in identifying potential therapeutic targets for ameliorating fibrosis in chronic pancreatitis. We provide a summary of recent research findings pertaining to the modulation of PSC activation, covering essential genes and innovative regulatory mediators designed to counteract PSC activation. We anticipate that this research will stimulate further insights into PSC activation and the mechanisms of pancreatic fibrosis, ultimately leading to the discovery of groundbreaking therapies targeting cellular and molecular responses within these processes.

Ultrasound histography in assessing the degree of pancreatic fibrosis in chronic pancreatitis

Aim: to analyze the clinical and pathogenetic significance of ultrasound histography in pancreatic fibrosis in patients with chronic pancreatitis (CP).
 Materials and methods. One hundred and eighty-six patients with CP were examined. Complete blood count, urinalysis, biochemical blood and urine tests, duodenal intubation test, coproscopy, enzyme immunoassay, and radioimmune assay were performed. The levels of blood transforming growth factor β1 (TGFβ1) and fecal elastase 1 were measured. Ultrasonography and ultrasound histography of the pancreas and liver, Doppler sound study of the abdominal aorta, celiac trunk, and superior mesenteric artery were carried out.
 Results. There were correlations suggesting decreased exocrine pancreatic function as its fibrosis progressed, which was indirectly reflected in the increased L index of an ultrasound histogram. The positive correlation between L index and TGFβ1 also showed increased L index in more severe pancreatic fibrosis. CP exacerbation was accompanied by decreased Kgst and N, which were confirmed by evident hyperenzymemia (the blood enzyme deviation) with the decrease of those indices. The clinical signs of CP, especially the rise in the number of dyspeptic complaints that show decreased pancreatic exocrine secretion, revealed pancreatic fibrosis. This was also shown by the fact that the debit hour of lipase and the activity of fecal elastase 1 decreased as the L index increased. There were signs that decreased blood flow in the pancreas made the fibrosis and insufficiency of the organ worse. Furthermore, ultrasound histographic findings reflected a positive correlation between pancreatic and hepatic fibrosis.
 Conclusion. An examination of pancreatic ultrasound histographic correlations led to the conclusion that this technique could be used to estimate the degree of pancreatic fibrosis and CP exacerbation indirectly.

S1P/S1PR2 promote pancreatic stellate cell activation and pancreatic fibrosis in chronic pancreatitis by regulating autophagy and the NLRP3 inflammasome

Sphingosine-1-phosphate (S1P) is a bioactive lipid molecule that governs various functions by embedding its receptor, S1PR, in different cells. Chronic pancreatitis (CP) is characterized by pancreatic fibrosis via activation of pancreatic stellate cells (PSCs). However, the effect of S1P on CP and PSC activation is still unknown. Here, we conducted a series of experiments to explore the effect of S1P on a CP rat model and primary cultured PSCs. In vivo, CP was induced by intravenous injection of dibutyltin dichloride. S1P was administered at a dosage of 200 μg/kg body weight per day by intraperitoneal injection. After 4 weeks, serum, plasma and pancreas samples were collected for molecular analysis and histological detection. In vitro, PSCs were isolated and cultured for treatment with different doses of S1P. 3MA and MCC950 were used to determine the effect of S1P on PSC activation by regulating autophagy and the NLRP3 inflammasome. JTE013 and Si–S1PR2 were applied to verify that the functions of S1P were realized by combining with S1PR2. Cells were collected for RT‒PCR, western blotting and immunofluorescence. The results showed that S1P was increased in the plasma and pancreatic tissue of CP rats. When S1P was administered to CP rats, the function and histomorphology of the pancreas were severely impaired. In addition, S1P promoted PSC activation, heightened autophagy and enhanced the NLRP3 inflammasome in vivo and in vitro. Moreover, S1PR2 mediated the effect of S1P on PSC activation by regulating autophagy and the NLRP3 inflammasome sequentially. In conclusion, S1P binding to S1PR2 promoted PSC activation and pancreatic fibrosis in CP by regulating autophagy and the NLRP3 inflammasome. These findings provide a theoretical basis for targeting S1P/S1PR2 to treat pancreatic fibrosis and further suggest that considering the role of autophagy and the NLRP3 inflammasome may help with the treatment pancreatic fibrosis.

Psychosomatic disorders in chronic pancreatitis

Diagnosis of pancreatic exocrine insufficiency (PEI) is hindered by methodological difficulties of pancreatic function tests. The probability of PEI in chronic pancreatitis (CP) increases as pancreatic fibrosis develops. Pancreatic fibrosis in CP may be quantified by EUS elastography.To evaluate whether EUS-elastography can predict PEI in patients with CP.Prospective, observational study.Department of Gastroenterology, University Hospital of Santiago de Compostela, Spain.Patients diagnosed with CP based on EUS and magnetic resonance imaging and MRCP findings.Diagnosis of PEI was based on the 13C-mixed triglyceride breath test. EUS-elastography was performed with PENTAX echoendoscopes and Hitachi-Preirus US platform. Two areas were selected for elastographic evaluation: area A corresponds to the pancreatic parenchyma and area B to a soft peripancreatic reference area. The quotient B/A (strain ratio [SR]) was considered the elastographic result.Pancreatic SR in CP patients with and without PEI.A total of 115 patients with CP (mean age, 50.2 years, range, 21-81; 92 male) of different etiologies were included; 35 patients (30.4%) had PEI. Pancreatic SR was higher in patients with PEI (4.89; 95% confidence interval, 4.36-5.41) than in those with a normal breath test result (2.99; 95% confidence interval, 2.82-3.16) (P < .001). A direct relationship was found between the SR and the probability of PEI, which increases from 4.2% in patients with an SR less than 2.5 to 92.8% in those with an SR greater than >5.5.Single-center study.The degree of pancreatic fibrosis as measured by EUS-guided elastography allows quantification of the probability of PEI in patients with CP.

Changes of oral and duodenal microbiota in patients with pancreatic cancer are possible diagnostic and prognostic biomarkers

Diagnosis of pancreatic exocrine insufficiency (PEI) is hindered by methodological difficulties of pancreatic function tests. The probability of PEI in chronic pancreatitis (CP) increases as pancreatic fibrosis develops. Pancreatic fibrosis in CP may be quantified by EUS elastography.To evaluate whether EUS-elastography can predict PEI in patients with CP.Prospective, observational study.Department of Gastroenterology, University Hospital of Santiago de Compostela, Spain.Patients diagnosed with CP based on EUS and magnetic resonance imaging and MRCP findings.Diagnosis of PEI was based on the 13C-mixed triglyceride breath test. EUS-elastography was performed with PENTAX echoendoscopes and Hitachi-Preirus US platform. Two areas were selected for elastographic evaluation: area A corresponds to the pancreatic parenchyma and area B to a soft peripancreatic reference area. The quotient B/A (strain ratio [SR]) was considered the elastographic result.Pancreatic SR in CP patients with and without PEI.A total of 115 patients with CP (mean age, 50.2 years, range, 21-81; 92 male) of different etiologies were included; 35 patients (30.4%) had PEI. Pancreatic SR was higher in patients with PEI (4.89; 95% confidence interval, 4.36-5.41) than in those with a normal breath test result (2.99; 95% confidence interval, 2.82-3.16) (P < .001). A direct relationship was found between the SR and the probability of PEI, which increases from 4.2% in patients with an SR less than 2.5 to 92.8% in those with an SR greater than >5.5.Single-center study.The degree of pancreatic fibrosis as measured by EUS-guided elastography allows quantification of the probability of PEI in patients with CP.

Stopped clock promotes fibrosis in chronic pancreatitis.

Stopped clock promotes fibrosis in chronic pancreatitis.

XCHT alleviates the pancreatic fibrosis via VDR/NLRP3 signaling pathway in a mouse model of CP

Ethnopharmacological relevanceXiao Chai Hu Tang (XCHT) derived from the classic medical book Shang Han Lun (Treatise on Febrile Diseases) in the Eastern Han Dynasty, which has been widely used in China and other Asian countries for the treatment of inflammation and fibrosis of chronic pancreatitis (CP), but the therapeutic mechanism of XCHT in pancreatic fibrosis remains unclear. Aim of the studyThis study aimed to evaluate the intervention effects and explore pharmacological mechanism of XCHT on inflammation and fibrosis in cerulein-induced CP model. Materials and methodsFifty male C57BL/6 mice were randomly divided into five main groups, 10 animals in each: Control, CP model (50 μg/kg cerulein), high dose XCHT-treated CP group (60 g/kg XCHT), medium dose XCHT-treated CP group (30 g/kg XCHT) and low dose XCHT-treated CP group (15 g/kg XCHT). Different doses of XCHT were given to mice by gavage twice a day for 2 weeks after the CP model induction. Pancreatic tissues were harvested and the pancreatic inflammation and fibrosis were evaluated by histological score, Sirius red staining, and alpha-smooth muscle actin (α-SMA) immunohistochemical staining. ELISA, IHC and RT-qPCR were performed to detect the expression of Vitamin D3 (VD3) and Vitamin D receptor (VDR) in serum and pancreatic tissues, respectively. The expressions of NLRP3 inflammasome related genes and molecules were assayed by WB, IHC and RT-qPCR. ResultsThe pathohistological results demonstrated that XCHT markedly inhibited the fibrosis and chronic inflammation of cerulein-induced CP, indicated by reduction of collagen I, collagen III, α-SMA, and NLRP3 expressions. XCHT significantly increased VD3 and VDR expression while reduced the pancreatic NLRP3 expression. Correspondingly, XCHT decreased the levels of NLRP3 downstream targets IL-1β, TNF-α and IL-6. ConclusionsThese results revealed that XCHT suppressed the pancreatic fibrosis and chronic inflammation in cerulein-induced CP model by enhancing the VD3/VDR expression and inhibiting the secretion of NLRP3-assoicated inflammatory factors.

Arecae pericarpium water extract alleviates chronic pancreatitis by deactivating pancreatic stellate cells.

Chronic pancreatitis (CP) is a chronic inflammatory disease of the pancreas with irreversible morphological changes. Arecae pericarpium (ARP), known to improve gastrointestinal disorders, has not yet been reported to inhibit fibrosis in CP. Therefore, we investigated the beneficial effects of ARP on cerulein-induced CP. Cerulein (50 μg/kg) was administered intraperitoneally to mice every hour, six times a day, four times a week for a total of 3 weeks to induce CP. To ascertain the prophylactic effects of ARP, ARP water extract (50, 100, or 200 mg/kg) or saline was administered intraperitoneally 1 h before the onset of CP. To determine the therapeutic effects of ARP, ARP water extract (200 mg/kg) or saline was administered for a total of 1 week or 2 weeks, starting 2 weeks or 1 week after the onset of CP. The pancreas was collected immediately for histological analysis. Additionally, to determine the effectiveness and mechanism of ARP in alleviating pancreatic fibrosis, pancreatic stellate cells (PSCs) were isolated. ARP treatment considerably improved glandular atrophy and inflammation and repressed collagen deposition in the pancreas. Furthermore, ARP water extract inhibited extracellular matrix (ECM) constituents such as alpha-smooth muscle actin (α-SMA), collagen I, and fibronectin 1 (FN1) in pancreatic tissue and PSCs. ARP also suppressed transforming growth factor-β (TGF-β) signaling by inhibiting Smad2 phosphorylation. Our study suggests that ARP exhibits anti-fibrotic effects in cerulein-induced CP by inhibiting TGF-β/Smad signaling.

Quantification of parenchymal fibrosis in chronic pancreatitis: relation to atrophy and pancreatic function.

Non-invasive modalities for assessing chronic pancreatitis (CP) are needed in clinical practice. To investigate the correlation between magnetic resonance elastography (MRE)-derived stiffness and T1 relaxation times (as proxies of fibrosis) and explore their relationships to gland volume and pancreatic functions in patients with CP and healthy controls (HCs). In 49 patients with CP and 35 HCs, pancreatic stiffness, T1 relaxation times, and gland volume were assessed. Fecal elastase and the presence of diabetes were used to evaluate pancreatic exocrine and endocrine functions. Uni- and multivariable linear regression models were used to analyze correlations between imaging parameters. There was a positive correlation between MRE-derived stiffness and T1 relaxation times in patients with CP (R2 = 0.42; P < 0.001) and HCs (R2 = 0.14; P = 0.028). There was no correlation between MRE-derived stiffness and gland volume in patients (R2 = 0.007; P = 0.065) or HCs (R2 = 0.010; P = 0.57). T1 relaxation time was correlated to gland volume (R2 = 0.19; P = 0.002) in patients with CP but not in the HCs (P = 0.056). Severity of pancreatic functional impairment was reflected by increased fibrosis-related parameters in patients without functional impairment, followed by a further increase in fibrosis-related parameters and reduction in gland volume in patients with pancreatic functional impairments. Pancreatic MRE-derived stiffness and T1 relaxation times might reflect early pathophysiological changes in CP. The dynamic correlation with pancreatic function suggests that these parameters may be useful for the non-invasive and early identification of CP.

Immunohistochemical Identification of Pancreatic Stellate Cells in Developing Pancreas of Guinea Pig (Cavia porcellus)

Background: Pancreatic stellate cell (PSC) is now known to play a critical role in pancreatic fibrosis in chronic pancreatitis and pancreatic cancer. In health, quiescent PSCs maintain normal tissue architecture. Methods: The immunohistochemistry of the pancreas of guinea pig six animals each from 0-2 weeks, 2-8 weeks, 8-16 weeks and 16-32 weeks age groups irrespective of sex were conducted by procuring the animals from the Department of Laboratory Animal Medicine. Tissues were normally processed and embedded in paraffin and paraffin sections of three micron thickness were cut and immunohistochemistry staining protocol was followed with using primary antibody markers namely GFAP, alpha SMA and vimentin. Result: In guinea pigs of 0-2 weeks of age, quiescent pancreatic stellate cells surrounding the acini showed mild positive vimentin immunoreaction. Mild alpha SMA immunopositive reaction was noticed in the quiescent pancreatic stellate cells of 2-8 weeks, 8-16 weeks and 16-32 weeks of age groups within the pancreatic acini. The star shaped quiescent pancreatic stellate cells in the pancreas were located in the interacinar spaces or periacinar spaces, with elongated cytoplasmic processes. Strong vimentin positive quiescent pancreatic stellate cells were found in the pancreatic acini of 2-8 weeks, 8-16 weeks and 16-32 weeks of age groups.

St13 protects against disordered acinar cell arachidonic acid pathway in chronic pancreatitis

BackgroundEarly diagnosis and treatment of chronic pancreatitis (CP) are limited. In this study, St13, a co-chaperone protein, was investigated whether it constituted a novel regulatory target in CP. Meanwhile, we evaluated the value of micro-PET/CT in the early diagnosis of CP.MethodsData from healthy control individuals and patients with alcoholic CP (ACP) or non-ACP (nACP) were analysed. PRSS1 transgenic mice (PRSS1Tg) were treated with ethanol or caerulein to mimic the development of ACP or nACP, respectively. Pancreatic lipid metabolite profiling was performed in human and PRSS1Tg model mice. The potential functions of St13 were investigated by crossing PRSS1Tg mice with St13−/− mice via immunoprecipitation and lipid metabolomics. Micro-PET/CT was performed to evaluate pancreatic morphology and fibrosis in CP model.ResultsThe arachidonic acid (AA) pathway ranked the most commonly dysregulated lipid pathway in ACP and nACP in human and mice. Knockout of St13 exacerbated fatty replacement and fibrosis in CP model. Sdf2l1 was identified as a binding partner of St13 as it stabilizes the IRE1α-XBP1s signalling pathway, which regulates COX-2, an important component in AA metabolism. Micro-PET/CT with 68Ga-FAPI-04 was useful for evaluating pancreatic morphology and fibrosis in CP model mice 2 weeks after modelling.ConclusionSt13 is functionally activated in acinar cells and protects against the cellular characteristics of CP by binding Sdf2l1, regulating AA pathway. 68Ga-FAPI-04 PET/CT may be a very valuable approach for the early diagnosis of CP. These findings thus provide novel insights into both diagnosis and treatment of CP.

Imaging of Fibrosis in Chronic Pancreatitis.

Chronic pancreatitis (CP) describes long-standing inflammation of the pancreas, which leads to irreversible and progressive inflammation of the pancreas with fibrosis. CP also leads to abdominal pain, malnutrition, and permanent impairment of exocrine/endocrine functions. However, it is difficult to assess CP pathologically, and imaging modalities therefore play an important role in the diagnosis and assessment of CP. There are four modalities typically used to assess CP. Pancreatic duct features are assessed with magnetic resonance cholangiopancreatography (MRCP) and endoscopic retrograde cholangiopancreatography (ERCP). However, ERCP is a rather invasive diagnostic modality for CP, and can result in adverse events such as post-ERCP pancreatitis. Computed tomography (CT) is often the most appropriate initial imaging modality for patients with suspected CP, and has high diagnostic specificity. However, CT findings typically only appear in advanced stages of CP, and it is difficult to detect early CP. Endoscopic ultrasonography (EUS) provides superior spatial resolution compared with other imaging modalities such as CT and magnetic resonance imaging (MRI), and is considered the most reliable and efficient diagnostic modality for pancreatic diseases. The EUS-based Rosemont classification plays an important role in diagnosing CP in clinical practice. Evaluation of tissue stiffness can be another option to assess the diagnosis and progression of CP, and MRI and EUS can be used to assess CP not only with imaging, but also with elasticity measurement. MR and EUS elastography are expected to provide new alternative diagnostic tools for assessment of fibrosis in CP, which is difficult to evaluate pathologically.

Інвазивна та неінвазивна діагностика фіброзу підшлункової залози у хворих з ускладненими формами хронічного панкреатиту

The purpose of the study was to identify the patterns of changes in the state of the parenchyma of the pancreas in patients with complicated forms of chronic pancreatitis with evaluation of the diagnostic effectiveness of shear wave elastometry (graphy). Materials and methods. For the period from 2006 to 2018 58 patients with complicated forms of chronic pancreatitis were examined. The average age of patients is (47.1±3.2) years old. The medical history ranged from 3 to 15 years. The basis of morphological studies were biopsies of the pancreas obtained during surgery. Ultrasound elastometry and pancreatic parenchymal elastography were performed by transcutaneous shear wave approach in Shear Wave Elastography. Software consistency was assessed by the nature of the color mapping. Results and discussion. The morphometry of the volume parts of the structural components of the pancreas showed that with the development of complicated chronic pancreatitis there is an increase in the area of fibrous tissue and a decrease in the area of acinar components. The proof of this is the strong inverse relationship between the degree of fibrosis and the volume fraction of acinar tissue (r= -0.83; р &lt;0.05), as well as the direct relationship between the degree of fibrosis and the volume fraction of connective tissue (r=0.61; р &lt;0.05). If at a fibrosis of the III degree acinar tissue occupied (25.39±2.01)%, connective – (64.33±3.85)%, fatty – (6.42±4.48)%, at a fibrosis of the IV degree noted the following: the proportion of acinar tissue was only (2.86±0.76)%, connective – (74.11±4.17)%, and (20.14±4.29)% was adipose tissue. Such manifestations indicated severe irreversible changes in the external secretory function of the pancreas. When assessing changes in the stiffness of the pancreatic parenchyma with the deepening of fibrosis processes and data from transcutaneous shear wave elastography, it was found that the degree of fibrosis according to morphological data correlated with the degree of fibrosis according to shear wave elastography, r = 0.71; p &lt;0.05. The following patterns were noted. Grade II pancreatic fibrosis was characterized by intralobular fibrosis, which covered 26-50% of the gland area, which corresponded to the shear wave elastography data in green-blue color (5.98-7.05 kPa). Grade III pancreatic fibrosis corresponded to intralobular fibrosis, which covered 51-75% of the gland area in shear wave elastography in green-yellow color (7.06-9.06 kPa). Grade IV pancreatic fibrosis was characterized by intralobular fibrosis, which covered 76-100% of the gland area, which corresponded to shear wave elastography data in yellow-red color (&gt; 9.07 kPa). Conclusion. Thus, the objectification of shear wave elastography indicators of the pancreas based on the correlation of histological evaluation and morphometric indicators of structural changes in the pathological process allows to consider transcutaneous shear wave elastography as a promising and reliable method of non-invasive diagnosis of fibrosis in chronic pancreatitis

Структурна трансформація протокової системи підшлункової залози у хворих на хронічний панкреатит

Актуальність. Клітини проток становлять до 30 % від маси підшлункової залози (ПЗ) людини, а збільшення кількості бранчів проток відноситься до одних із перших сонологічних ознак хронічного панкреатиту (ХП). Мета дослідження — визначення морфологічних й імуногістохімічних особливостей протокової системи ПЗ хворих на ХП, яким були виконані резекційні та дренуючі операції з приводу ускладнень хронічного панкреатиту. Матеріали та методи. Проведено імуногістохімічне дослідження операційного матеріалу 40 хворих з ускладненим хронічним панкреатитом з використанням реакцій на a-ізоформу гладком’язового актину (a-SMA), десмін, фібронектин й колаген I типу. Результати. Характерна морфологічна картина розвитку ХП є поєднанням фіброзування з деформацією протокової системи за рахунок перидуктального фіброзу з розширенням міждолькових фіброзних септ, потовщенням інтралобулярних сполучно­тканинних тяжів, а також значною звивістістю і розширенням проток з ретенційними кістами. Значна структурна перебудова протокової системи ПЗ у хворих на ХП спостерігалася в 87,5 % випадків, в 17,5 % випадків картина доповнювалася явищами ацинарно-протокової метаплазії з трансформацією ацинарних клітин у протокові і формуванням дрібних дуктулоподібних структур, так званих тубулярних комплексів. У 7,5 % випадків в головній панкреатичній протоці визначалися вогнища атрофії протокового епітелію, які чергувалися з вогнищами папілярної інтраепітеліальної гіперплазії епітелію (PanIN). Розвитку панкреатичного фіброзу при ХП сприяє накопичення a-SMA+-активованих панкреатичних зірчастих клітин, що синтезують надлишок компонентів екстрацелюлярного матриксу, зокрема колагену I типу. Середня площа колагену І типу та інтенсивність його експресії були вірогідно нижче при зниженій експресії a-SMA (p &lt; 0,05) і вірогідно вище у випадках вираженої експресії фібронектину (p &lt; 0,05). Висновки. Вивчення структурних змін протокової системи ПЗ з використанням методів імуногістохімії є одним із способів покращення ранньої діагностики ускладнень ХП.

Milk Fat Globule-EGF Factor 8 Alleviates Pancreatic Fibrosis by Inhibiting ER Stress-Induced Chaperone-Mediated Autophagy in Mice

Pancreatic fibrosis is an important pathophysiological feature of chronic pancreatitis (CP). Our recent study has shown that milk fat globule-EGF factor 8 (MFG-E8) is beneficial in acute pancreatitis. However, its role in CP remained unknown. To study this, CP was induced in male adult Mfge8-knockout (Mfge8-KO) mice and wild type (WT) mice by six intraperitoneal injections of cerulein (50 μg/kg/body weight) twice a week for 10 weeks. The results showed that knockout of mfge8 gene aggravated pancreatic fibrosis after repeated cerulein injection. In WT mice, pancreatic levels of MFG-E8 were reduced after induction of CP and administration of recombinant MFG-E8 alleviated cerulein-induced pancreatic fibrosis. The protective effect of MFG-E8 in CP was associated with reduced autophagy and oxidative stress. In human pancreatic stellate cells (PSCs), MFG-E8 inhibited TGF-β1-induced ER stress and autophagy. MFG-E8 downregulated the expression of lysosomal associated membrane protein 2A (LAMP2A), a key factor in ER stress-induced chaperone-mediated autophagy (CMA). QX77, an activator of CMA, eliminated the effects of MFG-E8 on TGF-β1-induced PSC activation. In conclusion, MFG-E8 appears to mitigate pancreatic fibrosis via inhibiting ER stress-induced chaperone-mediated autophagy. Recombinant MFG-E8 may be developed as a novel treatment for pancreatic fibrosis in CP.

Pancreatic fibrosis in chronic pancreatitis: A new approach of non-invasive diagnosis in clinic

Pancreatic fibrosis in chronic pancreatitis: A new approach of non-invasive diagnosis in clinic

Nicotine facilitates pancreatic fibrosis by promoting activation of pancreatic stellate cells via α7nAChR-mediated JAK2/STAT3 signaling pathway in rats

AimSmoking has been considered as a risk factor of chronic pancreatitis (CP), but the potential mechanism is still unknown. The major pathological feature of CP is pancreatic fibrosis, whose major functional cells are pancreatic stellate cells (PSCs). Nicotine is the major component of cigarette smoke, our recent study suggested that nicotine has the potential to facilitate pancreatic fibrosis in CP. This study was aimed to analyze the function and mechanism of nicotine on PSCs and pancreatic fibrosis in rats. Materials and methodsIn vivo, a rat CP model was induced by intraperitoneal injection of 20 % L-arginine hydrochloride (200 mg/100 g) at 1 h intervals twice per week, nicotine was injected subcutaneously at a dose of 1 mg/kg body weight per day. After four weeks, the pancreatic tissue was collected for H&E, Masson and immunohistochemical staining. In vitro, primary rPSCs were isolated from rats and treated with nicotine (0.1 μM and 1 μM). The proliferation、apoptosis、α-SMA expression、extracellular matrix (ECM) metabolism and α7nAChR-mediated JAK2/STAT3 signaling pathway of rPSCs were detected by CCK-8 assay、flow cytometry、real-time Q-PCR and western blotting analysis. The α7nAChR antagonist α-bungarotoxin (α-BTX) was used to perform inhibition experiments. Key findingsNicotine increased pancreatic damage, collagen deposition and activation of PSCs in the CP rat model. In rPSCs, the proliferation, α-SMA expression and ECM formation were significantly promoted by nicotine in a dose-dependent manner. Meanwhile, the apoptosis of rPSCs was significantly reduced after nicotine treatment. Moreover, nicotine also activated the α7nAChR-mediated JAK2/STAT3 signaling pathway in rPSCs. These effects of nicotine on rPSCs were blocked by α-BTX. SignificanceOur finding in this research suggests that nicotine facilitates pancreatic fibrosis by promoting activation of pancreatic stellate cells via α7nAChR-mediated JAK2/STAT3 signaling pathway in rats, partly revealing the mechanism of smoking on chronic pancreatitis.

New approaches to non-invasive diagnosis of pancreatic fibrosis in chronic pancreatitis

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