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Pediatrics in Review Feb 2021Cystic fibrosis (CF) is one of the most commonly diagnosed genetic disorders. Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine... (Review)
Review
Cystic fibrosis (CF) is one of the most commonly diagnosed genetic disorders. Clinical characteristics include progressive obstructive lung disease, sinusitis, exocrine pancreatic insufficiency leading to malabsorption and malnutrition, liver and pancreatic dysfunction, and male infertility. Although CF is a life-shortening disease, survival has continued to improve to a median age of 46.2 years due to earlier diagnosis through routine newborn screening, promulgation of evidence-based guidelines to optimize nutritional and pulmonary health, and the development of CF-specific interdisciplinary care centers. Future improvements in health and quality of life for individuals with CF are likely with the recent development of mutation-specific modulator therapies. In this review, we will cover the current understanding of the disease manifestations, diagnosis, and management as well as common complications seen in individuals with CF.
Topics: Bone Density; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Humans; Infant; Infant, Newborn; Liver Diseases; Lung; Lung Transplantation; Male; Respiratory Tract Infections; Trypsinogen; Vitamins
PubMed: 33526571
DOI: 10.1542/pir.2019-0212 -
World Journal of Gastroenterology May 2023Acute pancreatitis (AP) is an inflammatory disease of the pancreas, which can progress to severe AP, with a high risk of death. It is one of the most complicated and... (Review)
Review
Acute pancreatitis (AP) is an inflammatory disease of the pancreas, which can progress to severe AP, with a high risk of death. It is one of the most complicated and clinically challenging of all disorders affecting the abdomen. The main causes of AP are gallstone migration and alcohol abuse. Other causes are uncommon, controversial and insufficiently explained. The disease is primarily characterized by inappropriate activation of trypsinogen, infiltration of inflammatory cells, and destruction of secretory cells. According to the revised Atlanta classification, severity of the disease is categorized into three levels: Mild, moderately severe and severe, depending upon organ failure and local as well as systemic complications. Various methods have been used for predicting the severity of AP and its outcome, such as clinical evaluation, imaging evaluation and testing of various biochemical markers. However, AP is a very complex disease and despite the fact that there are of several clinical, biochemical and imaging criteria for assessment of severity of AP, it is not an easy task to predict its subsequent course. Therefore, there are existing controversies regarding diagnostic and therapeutic modalities, their effectiveness and complications in the treatment of AP. The main reason being the fact, that the pathophysiologic mechanisms of AP have not been fully elucidated and need to be studied further. In this editorial article, we discuss the efficacy of the existing diagnostic and therapeutic modalities, complications and treatment failure in the management of AP.
Topics: Humans; Pancreatitis; Acute Disease; Pancreas; Diagnostic Imaging; Biomarkers; Severity of Illness Index
PubMed: 37274068
DOI: 10.3748/wjg.v29.i18.2747 -
Analytical Biochemistry Jul 2022Trypsin has been identified as a pancreatic protease comprising three isoenzymes, trypsin-1, -2, and -3. However, the gene for trypsinogen-3, PRSS3, also gives rise to...
Trypsin has been identified as a pancreatic protease comprising three isoenzymes, trypsin-1, -2, and -3. However, the gene for trypsinogen-3, PRSS3, also gives rise to additional variants, trypsinogen-4A and B, which differ from trypsinogen-3 only with respect to the leader-peptide part, and when activated are identical to trypsin-3. The unique overlapping leader peptides of trypsinogen-4A and B allowed us to develop a specific sandwich-type immunofluorometric assay that detects both these isoforms, but not trypsinogen-3 or activated trypsinogen-4. We measured the concentrations of trypsinogen-4 in various cell line lysates and bile of primary sclerosing cholangitis patients. Lysates of cell lines MDA-MB-231 and PC-3, and astrocytes contained trypsinogen-4, while the conditioned media from these cells did not, suggesting that trypsinogen-4, lacking a classical signal sequence, is not secreted from the cells. Interestingly, 5.7% of the 212 bile samples analyzed contained measurable (>2.4 μg/l) trypsinogen-4. In conclusion, we have established a specific assay for trypsinogen-4 and demonstrated that trypsinogen-4 can be found in biological samples. However, the clinical utility of the assay remains to be established.
Topics: Bile; Humans; Immunoassay; Isoenzymes; Trypsin; Trypsinogen
PubMed: 35417678
DOI: 10.1016/j.ab.2022.114681 -
Genes Apr 2020Discovery of the cystic fibrosis transmembrane conductance regulator ( gene was the long-awaited scientific advance that dramatically improved the diagnosis and... (Review)
Review
Discovery of the cystic fibrosis transmembrane conductance regulator ( gene was the long-awaited scientific advance that dramatically improved the diagnosis and treatment of cystic fibrosis (CF). The combination of a first-tier biomarker, immunoreactive trypsinogen (IRT), and, if high, DNA analysis for CF-causing variants, has enabled regions where CF is prevalent to screen neonates and achieve diagnoses within 1-2 weeks of birth when most patients are asymptomatic. In addition, IRT/DNA () screening protocols simultaneously contribute important genetic data to determine genotype, prognosticate, and plan preventive therapies such as CFTR modulator selection. As the genomics era proceeds with affordable biotechnologies, the potential added value of whole genome sequencing will probably enhance personalized, precision care that can begin during infancy. Issues remain, however, about the optimal size of panels in genetically diverse regions and how best to deal with incidental findings. Because prospects for a primary DNA screening test are on the horizon, the debate about detecting heterozygote carriers will likely intensify, especially as we learn more about this relatively common genotype. Perhaps, at that time, concerns about CF heterozygote carrier detection will subside, and it will become recognized as beneficial. We share new perspectives on that issue in this article.
Topics: Algorithms; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genetic Association Studies; Genetic Counseling; Genetic Predisposition to Disease; Genetic Testing; Genotype; Humans; Infant, Newborn; Neonatal Screening
PubMed: 32276344
DOI: 10.3390/genes11040401 -
Seminars in Immunopathology Jun 2021Eosinophils comprise approximately 1-4% of total blood leukocytes that reside in the intestine, bone marrow, mammary gland, and adipose tissues to maintain innate... (Review)
Review
Eosinophils comprise approximately 1-4% of total blood leukocytes that reside in the intestine, bone marrow, mammary gland, and adipose tissues to maintain innate immunity in healthy individuals. Eosinophils have four toxic granules known as major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN), and upon degranulation, these granules promote pathogenesis of inflammatory diseases like allergy, asthma, dermatitis, and gastrointestinal disorders. Additionally, the role of eosinophils is underscored in exocrine disorders including pancreatitis. Chronic pancreatitis (CP) is an inflammatory disorder that occurs due to the alcohol consumption, blockage of the pancreatic duct, and trypsinogen mutation. Eosinophil levels are detected in higher numbers in both CP and pancreatic cancer patients compared with healthy individuals. The mechanistic understanding of chronic inflammation-induced pancreatic malignancy has not yet been reached and requires further exploration. This review provides a comprehensive summary of the epidemiology, pathophysiology, evaluation, and management of eosinophil-associated pancreatic disorders and further summarizes current evidence regarding risk factors, pathophysiology, clinical features, diagnostic evaluation, treatment, and prognosis of eosinophilic pancreatitis (EP) and pancreatic cancer.
Topics: Blood Proteins; Eosinophil Granule Proteins; Eosinophils; Humans; Neurotoxins; Ribonucleases
PubMed: 33783592
DOI: 10.1007/s00281-021-00853-0 -
Frontiers in Microbiology 2023Acute pancreatitis is caused by trypsinogen activation in acinar cells caused by various injury forms (gallstone, high triglycerides, alcohol, etc.). Viral pancreatitis... (Review)
Review
Acute pancreatitis is caused by trypsinogen activation in acinar cells caused by various injury forms (gallstone, high triglycerides, alcohol, etc.). Viral pancreatitis is a clinically rare disease type, which is easily neglected by clinicians and causes serious adverse consequences. Viral pancreatitis involves the entry of viruses into pancreatic cells, triggering inflammation, immune response activation, and enzymatic autodigestion, leading to tissue damage and potential complications. At present, there are few available reports on viral pancreatitis, most of which are case reports. This review brings attention to clinicians by describing the incidence of viral pancreatitis to enhance clinical understanding and patient care.
PubMed: 38420214
DOI: 10.3389/fmicb.2023.1326837 -
Cells Aug 2022Recent studies have highlighted the importance of autophagy and particularly non-canonical autophagy in the development and progression of acute pancreatitis (a frequent... (Review)
Review
Recent studies have highlighted the importance of autophagy and particularly non-canonical autophagy in the development and progression of acute pancreatitis (a frequent disease with considerable morbidity and significant mortality). An important early event in the development of acute pancreatitis is the intrapancreatic activation of trypsinogen, (i.e., formation of trypsin) leading to the autodigestion of the organ. Another prominent phenomenon associated with the initiation of this disease is vacuolisation and specifically the formation of giant endocytic vacuoles in pancreatic acinar cells. These organelles develop in acinar cells exposed to several inducers of acute pancreatitis (including taurolithocholic acid and high concentrations of secretagogues cholecystokinin and acetylcholine). Notably, early trypsinogen activation occurs in the endocytic vacuoles. These trypsinogen-activating organelles undergo activation, long-distance trafficking, and non-canonical autophagy. In this review, we will discuss the role of autophagy in acute pancreatitis and particularly focus on the recently discovered LAP-like non-canonical autophagy (LNCA) of endocytic vacuoles.
Topics: Acute Disease; Autophagy; Humans; Pancreatitis; Trypsinogen; Vacuoles
PubMed: 36010591
DOI: 10.3390/cells11162514 -
Cell Death & Disease Jun 2021Acinar cell injury and the inflammatory response are critical bioprocesses of acute pancreatitis (AP). We investigated the role and underlying mechanism of...
Acinar cell injury and the inflammatory response are critical bioprocesses of acute pancreatitis (AP). We investigated the role and underlying mechanism of sulfiredoxin-1 (Srxn1) in AP. Mild AP was induced by intraperitoneal injection of cerulein and severe AP was induced by partial duct ligation with cerulein stimulation or intraperitoneal injection of L-arginine in mice. Acinar cells, neutrophils, and macrophages were isolated. The pancreas was analyzed by histology, immunochemistry staining, and TUNEL assays, and the expression of certain proteins and RNAs, cytokine levels, trypsin activity, and reactive oxygen species (ROS) levels were determined. Srxn1 was inhibited by J14 or silenced by siRNA, and overexpression was introduced by a lentiviral vector. Transcriptomic analysis was used to explore the mechanism of Srxn1-mediated effects. We also evaluated the effect of adeno-associated virus (AAV)-mediated overexpression of Srxn1 by intraductal administration and the protection of AP. We found that Srxn1 expression was upregulated in mild AP but decreased in severe AP. Inhibition of Srxn1 increased ROS, histological score, the release of trypsin, and inflammatory responses in mice. Inhibition of Srxn1 expression promoted the production of ROS and induced apoptosis, while overexpression of Srxn1 led to the opposite results in acinar cells. Furthermore, inhibition of Srxn1 expression promoted the inflammatory response by accumulating and activating M1 phenotype macrophages and neutrophils in AP. Mechanistically, ROS-induced ER stress and activation of Cathepsin B, which converts trypsinogen to trypsin, were responsible for the Srxn1 inhibition-mediated effects on AP. Importantly, we demonstrated that AAV-mediated overexpression of Srxn1 attenuated AP in mice. Taken together, these results showed that Srxn1 is a protective target for AP by attenuating acinar injury and inflammation through the ROS/ER stress/Cathepsin B axis.
Topics: Animals; Apoptosis; Cathepsin B; Cells, Cultured; Cytokines; Disease Models, Animal; Endoplasmic Reticulum Stress; Genetic Therapy; Inflammation Mediators; Macrophage Activation; Macrophages; Male; Mice, Inbred C57BL; Neutrophil Activation; Neutrophils; Oxidative Stress; Oxidoreductases Acting on Sulfur Group Donors; Pancreas; Pancreatitis; Reactive Oxygen Species; Signal Transduction; Up-Regulation; Mice
PubMed: 34140464
DOI: 10.1038/s41419-021-03923-1 -
Gastroenterology Mar 2020Mutations in the trypsinogen gene (PRSS1) cause human hereditary pancreatitis. However, it is not clear how mutant forms of PRSS1 contribute to disease development. We...
BACKGROUND & AIMS
Mutations in the trypsinogen gene (PRSS1) cause human hereditary pancreatitis. However, it is not clear how mutant forms of PRSS1 contribute to disease development. We studied the effects of expressing mutant forms of human PRSS1 in mice.
METHODS
We expressed forms of PRSS1 with and without the mutation encoding R122H (PRSS1) specifically in pancreatic acinar cells under control of a full-length pancreatic elastase gene promoter. Mice that did not express these transgenes were used as controls. Mice were given injections of caerulein to induce acute pancreatitis or injections of lipopolysaccharide to induce chronic pancreatitis. Other groups of mice were fed ethanol or placed on a high-fat diet to induce pancreatitis. Pancreata were collected and analyzed by histology, immunoblots, real-time polymerase chain reaction, and immunohistochemistry. Trypsin enzymatic activity and chymotrypsin enzymatic activity were measured in pancreatic homogenates. Blood was collected and serum amylase activity was measured.
RESULTS
Pancreata from mice expressing transgenes encoding PRSS1 or PRSS1 had focal areas of inflammation; these lesions were more prominent in mice that express PRSS1. Pancreata from mice that express PRSS1 or PRSS1 had increased levels of heat shock protein 70 and nuclear factor (erythroid-derived 2)-like 2, and reduced levels of chymotrypsin C compared with control mice. Increased expression of PRSS1 or PRSS1 increased focal damage in pancreatic tissues and increased the severity of acute pancreatitis after caerulein injection. Administration of lipopolysaccharide exacerbated inflammation in mice that express PRSS1 compared to mice that express PRSS1 or control mice. Mice that express PRSS1 developed more severe pancreatitis after ethanol feeding or a high-fat diet than mice that express PRSS1 or control mice. Pancreata from mice that express PRSS1 had more DNA damage, apoptosis, and collagen deposition and increased trypsin activity and infiltration by inflammatory cells than mice that express PRSS1 or control mice.
CONCLUSIONS
Expression of a transgene encoding PRSS1 in mice promoted inflammation and increased the severity of pancreatitis compared with mice that express PRSS1 or control mice. These mice might be used as a model for human hereditary pancreatitis and can be studied to determine mechanisms of induction of pancreatitis by lipopolysaccharide, ethanol, or a high-fat diet.
Topics: Acinar Cells; Adaptive Immunity; Animals; Gene Expression; Humans; Mice; Mice, Transgenic; Mutation; Pancreas; Pancreatitis; Transgenes; Trypsin; Trypsinogen
PubMed: 31419436
DOI: 10.1053/j.gastro.2019.08.016