Blood leucocyte signaling profiles and trypsinogen-3 in severe acute pancreatitis

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

Acute pancreatitis (AP) is common disease with a wide range of clinical manifestations. In most cases it is a self-limiting local inflammation. However, about 20-30% of the patients develop a more severe form of the disease (moderately severe or severe AP), which is complicated by systemic inflammation, organ dysfunction (OD) and possibly pancreatic necrosis. To prevent mortality, it would be crucial to identify at admission the patients at risk to develop a more severe form of AP, and to provide them with maximal supportive care. The present studies were designed to delineate the blood leucocyte signaling profiles in patients with AP and OD, and to investigate whether circulating trypsinogen-3 is associated with AP. The study consisted of four parts, in all of which the patients were admitted to hospital because of AP, and treated in the Intensive Care Unit for AP complicated by OD and immunosuppression. Studies I-III consisted of a cohort of 13 patients (with additional three patients in study II) and study IV of 82 patients. Phosphorylation of nuclear factor-κB (NFκB), mitogen-activated protein kinases (MAPK) p38 and extracellular signal-regulated kinases 1/2 (ERK1/2), and signal transducers and activators of transcription (STATs) 1,3,5,6 were studied from appropriately stimulated and non-stimulated blood samples using phospho-specific whole blood flow cytometry. In addition, transmigration of monocytes and polymorphonuclear leucocytes (PMNLs) were investigated using cells of an endothelial cell line. Trypsinogen-3 was measured with a new specific sandwich-type immunoassay to investigate it s clinical utility as a diagnostic and predictive tool in AP. We found that in AP patients monocytes have impaired NFκB and STAT1 activation, which may increase susceptibility to secondary infections. p38 activation is normal and STAT3 activation is depressed, which may contribute to the maintenance of systemic inflammation. ERK1/2 activation is impaired which may depress monocytes transmigration and may increase the risk for infection. The lymphocytes showed impaired NFκB activation, which may increase the risk for secondary infection. p38 activation was enhanced, which may sustain inflammation. Constitutive STAT3 activation may favour Th17 lineage of CD4+ lymphocyte differentiation. STAT1 activation is impaired and STAT6 activation enhanced, which denotes a shift from Th1 towards Th2 differentiation. The PMNLs showed depressed NFκB activation, normal p38 activation and decreased ERK1/2 activation. STAT3 was constitutively activated in five patients. Transmigration of the PMNLs was increased, which may sustain end organ dysfunction. Trypsinogen-3 distinguished AP patients from controls with high accuracy. However, it did not predict the severity of AP. In conclusion, these studies show that AP patients with OD and immunosuppression have multiple aberrations in blood leucocyte signalling pathways. These results may offer a potential predictive marker for the development of OD or secondary infections. Trypsinogen-3 can detect patients with AP but does not predict the severity of the disease.
Original languageEnglish
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-3186-7
Electronic ISBNs978-951-51-3187-4
Publication statusPublished - 2017
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • 3121 Internal medicine

Cite this

@phdthesis{ccf8129af23a4a4fa8216bb3a6c8d4c7,
title = "Blood leucocyte signaling profiles and trypsinogen-3 in severe acute pancreatitis",
abstract = "Acute pancreatitis (AP) is common disease with a wide range of clinical manifestations. In most cases it is a self-limiting local inflammation. However, about 20-30{\%} of the patients develop a more severe form of the disease (moderately severe or severe AP), which is complicated by systemic inflammation, organ dysfunction (OD) and possibly pancreatic necrosis. To prevent mortality, it would be crucial to identify at admission the patients at risk to develop a more severe form of AP, and to provide them with maximal supportive care. The present studies were designed to delineate the blood leucocyte signaling profiles in patients with AP and OD, and to investigate whether circulating trypsinogen-3 is associated with AP. The study consisted of four parts, in all of which the patients were admitted to hospital because of AP, and treated in the Intensive Care Unit for AP complicated by OD and immunosuppression. Studies I-III consisted of a cohort of 13 patients (with additional three patients in study II) and study IV of 82 patients. Phosphorylation of nuclear factor-κB (NFκB), mitogen-activated protein kinases (MAPK) p38 and extracellular signal-regulated kinases 1/2 (ERK1/2), and signal transducers and activators of transcription (STATs) 1,3,5,6 were studied from appropriately stimulated and non-stimulated blood samples using phospho-specific whole blood flow cytometry. In addition, transmigration of monocytes and polymorphonuclear leucocytes (PMNLs) were investigated using cells of an endothelial cell line. Trypsinogen-3 was measured with a new specific sandwich-type immunoassay to investigate it s clinical utility as a diagnostic and predictive tool in AP. We found that in AP patients monocytes have impaired NFκB and STAT1 activation, which may increase susceptibility to secondary infections. p38 activation is normal and STAT3 activation is depressed, which may contribute to the maintenance of systemic inflammation. ERK1/2 activation is impaired which may depress monocytes transmigration and may increase the risk for infection. The lymphocytes showed impaired NFκB activation, which may increase the risk for secondary infection. p38 activation was enhanced, which may sustain inflammation. Constitutive STAT3 activation may favour Th17 lineage of CD4+ lymphocyte differentiation. STAT1 activation is impaired and STAT6 activation enhanced, which denotes a shift from Th1 towards Th2 differentiation. The PMNLs showed depressed NFκB activation, normal p38 activation and decreased ERK1/2 activation. STAT3 was constitutively activated in five patients. Transmigration of the PMNLs was increased, which may sustain end organ dysfunction. Trypsinogen-3 distinguished AP patients from controls with high accuracy. However, it did not predict the severity of AP. In conclusion, these studies show that AP patients with OD and immunosuppression have multiple aberrations in blood leucocyte signalling pathways. These results may offer a potential predictive marker for the development of OD or secondary infections. Trypsinogen-3 can detect patients with AP but does not predict the severity of the disease.",
keywords = "Biomarkers, +blood, Critical Care, Critical Illness, Extracellular Signal-Regulated MAP Kinases, Leukocytes, +immunology, Lymphocyte Subsets, Monocytes, +physiology, Multiple Organ Failure, +diagnosis, +pathology, NF-kappa B, Neutrophils, Pancreatitis, +complications, Pancreatitis, Acute Necrotizing, Risk Assessment, Sensitivity and Specificity, STAT Transcription Factors, Signal Transduction, Trypsin, p38 Mitogen-Activated Protein Kinases, 3121 Internal medicine",
author = "Jani Oiva",
note = "M1 - 106 s. + liitteet Volume: Proceeding volume:",
year = "2017",
language = "English",
isbn = "978-951-51-3186-7",
publisher = "[J. Oiva]",
address = "Finland",

}

Blood leucocyte signaling profiles and trypsinogen-3 in severe acute pancreatitis. / Oiva, Jani.

Helsinki : [J. Oiva], 2017. 106 p.

Research output: ThesisDoctoral ThesisCollection of Articles

TY - THES

T1 - Blood leucocyte signaling profiles and trypsinogen-3 in severe acute pancreatitis

AU - Oiva, Jani

N1 - M1 - 106 s. + liitteet Volume: Proceeding volume:

PY - 2017

Y1 - 2017

N2 - Acute pancreatitis (AP) is common disease with a wide range of clinical manifestations. In most cases it is a self-limiting local inflammation. However, about 20-30% of the patients develop a more severe form of the disease (moderately severe or severe AP), which is complicated by systemic inflammation, organ dysfunction (OD) and possibly pancreatic necrosis. To prevent mortality, it would be crucial to identify at admission the patients at risk to develop a more severe form of AP, and to provide them with maximal supportive care. The present studies were designed to delineate the blood leucocyte signaling profiles in patients with AP and OD, and to investigate whether circulating trypsinogen-3 is associated with AP. The study consisted of four parts, in all of which the patients were admitted to hospital because of AP, and treated in the Intensive Care Unit for AP complicated by OD and immunosuppression. Studies I-III consisted of a cohort of 13 patients (with additional three patients in study II) and study IV of 82 patients. Phosphorylation of nuclear factor-κB (NFκB), mitogen-activated protein kinases (MAPK) p38 and extracellular signal-regulated kinases 1/2 (ERK1/2), and signal transducers and activators of transcription (STATs) 1,3,5,6 were studied from appropriately stimulated and non-stimulated blood samples using phospho-specific whole blood flow cytometry. In addition, transmigration of monocytes and polymorphonuclear leucocytes (PMNLs) were investigated using cells of an endothelial cell line. Trypsinogen-3 was measured with a new specific sandwich-type immunoassay to investigate it s clinical utility as a diagnostic and predictive tool in AP. We found that in AP patients monocytes have impaired NFκB and STAT1 activation, which may increase susceptibility to secondary infections. p38 activation is normal and STAT3 activation is depressed, which may contribute to the maintenance of systemic inflammation. ERK1/2 activation is impaired which may depress monocytes transmigration and may increase the risk for infection. The lymphocytes showed impaired NFκB activation, which may increase the risk for secondary infection. p38 activation was enhanced, which may sustain inflammation. Constitutive STAT3 activation may favour Th17 lineage of CD4+ lymphocyte differentiation. STAT1 activation is impaired and STAT6 activation enhanced, which denotes a shift from Th1 towards Th2 differentiation. The PMNLs showed depressed NFκB activation, normal p38 activation and decreased ERK1/2 activation. STAT3 was constitutively activated in five patients. Transmigration of the PMNLs was increased, which may sustain end organ dysfunction. Trypsinogen-3 distinguished AP patients from controls with high accuracy. However, it did not predict the severity of AP. In conclusion, these studies show that AP patients with OD and immunosuppression have multiple aberrations in blood leucocyte signalling pathways. These results may offer a potential predictive marker for the development of OD or secondary infections. Trypsinogen-3 can detect patients with AP but does not predict the severity of the disease.

AB - Acute pancreatitis (AP) is common disease with a wide range of clinical manifestations. In most cases it is a self-limiting local inflammation. However, about 20-30% of the patients develop a more severe form of the disease (moderately severe or severe AP), which is complicated by systemic inflammation, organ dysfunction (OD) and possibly pancreatic necrosis. To prevent mortality, it would be crucial to identify at admission the patients at risk to develop a more severe form of AP, and to provide them with maximal supportive care. The present studies were designed to delineate the blood leucocyte signaling profiles in patients with AP and OD, and to investigate whether circulating trypsinogen-3 is associated with AP. The study consisted of four parts, in all of which the patients were admitted to hospital because of AP, and treated in the Intensive Care Unit for AP complicated by OD and immunosuppression. Studies I-III consisted of a cohort of 13 patients (with additional three patients in study II) and study IV of 82 patients. Phosphorylation of nuclear factor-κB (NFκB), mitogen-activated protein kinases (MAPK) p38 and extracellular signal-regulated kinases 1/2 (ERK1/2), and signal transducers and activators of transcription (STATs) 1,3,5,6 were studied from appropriately stimulated and non-stimulated blood samples using phospho-specific whole blood flow cytometry. In addition, transmigration of monocytes and polymorphonuclear leucocytes (PMNLs) were investigated using cells of an endothelial cell line. Trypsinogen-3 was measured with a new specific sandwich-type immunoassay to investigate it s clinical utility as a diagnostic and predictive tool in AP. We found that in AP patients monocytes have impaired NFκB and STAT1 activation, which may increase susceptibility to secondary infections. p38 activation is normal and STAT3 activation is depressed, which may contribute to the maintenance of systemic inflammation. ERK1/2 activation is impaired which may depress monocytes transmigration and may increase the risk for infection. The lymphocytes showed impaired NFκB activation, which may increase the risk for secondary infection. p38 activation was enhanced, which may sustain inflammation. Constitutive STAT3 activation may favour Th17 lineage of CD4+ lymphocyte differentiation. STAT1 activation is impaired and STAT6 activation enhanced, which denotes a shift from Th1 towards Th2 differentiation. The PMNLs showed depressed NFκB activation, normal p38 activation and decreased ERK1/2 activation. STAT3 was constitutively activated in five patients. Transmigration of the PMNLs was increased, which may sustain end organ dysfunction. Trypsinogen-3 distinguished AP patients from controls with high accuracy. However, it did not predict the severity of AP. In conclusion, these studies show that AP patients with OD and immunosuppression have multiple aberrations in blood leucocyte signalling pathways. These results may offer a potential predictive marker for the development of OD or secondary infections. Trypsinogen-3 can detect patients with AP but does not predict the severity of the disease.

KW - Biomarkers

KW - +blood

KW - Critical Care

KW - Critical Illness

KW - Extracellular Signal-Regulated MAP Kinases

KW - Leukocytes

KW - +immunology

KW - Lymphocyte Subsets

KW - Monocytes

KW - +physiology

KW - Multiple Organ Failure

KW - +diagnosis

KW - +pathology

KW - NF-kappa B

KW - Neutrophils

KW - Pancreatitis

KW - +complications

KW - Pancreatitis, Acute Necrotizing

KW - Risk Assessment

KW - Sensitivity and Specificity

KW - STAT Transcription Factors

KW - Signal Transduction

KW - Trypsin

KW - p38 Mitogen-Activated Protein Kinases

KW - 3121 Internal medicine

M3 - Doctoral Thesis

SN - 978-951-51-3186-7

PB - [J. Oiva]

CY - Helsinki

ER -