Acute pancreatitis (AP) is a common gastrointestinal disease of varying severity. While mild AP is a local inflammation of the pancreas that resolves within days, in severe AP (SAP) systemic inflammatory response, complicated by persistent organ dysfunction (OD), is comparable to that seen in bacterial sepsis and associated with substantial morbidity and mortality. In half of the SAP patients the clinical signs of OD are not yet present on admission to hospital, potentially delaying the diagnosis of SAP and the initiation of maximal supportive care, thus worsening the prognosis. The aims of this study were (i) to identify early predictive markers of SAP among patients with no OD on admission to hospital and (ii) to elucidate the aberrations in blood leukocyte signaling pathways in the early phase of AP and sepsis, which could reveal novel predictive markers of OD. This clinical study consists of four prospective studies. All AP patients investigated were admitted to Helsinki University Hospital within 72 or 96 hours of onset of symptoms during the years 2003-2008 (Studies I and III), 2011-2014 (Study II), and 2010-2012 (Study IV). The levels of circulating 48 cytokines in 163 patients (Study I), interleukin (IL)-8 and hepatocyte growth factor (HGF) in 176 patients (Study II), and nucleosomes in 74 patients (Study III) were determined on hospital admission to identify predictors of SAP, especially in AP patients presenting without OD. In the fourth study, the phosphorylation of nuclear factor kappa B (NF-ĸB), signal transducers and activators of transcription (STATs) 1 and 3, and extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinases (MAPK) were examined in appropriately stimulated or non-stimulated circulating leukocytes in 18 patients with AP, 14 patients with sepsis, and 28 healthy controls. Our results show that IL-8, HGF, granulocyte colony-stimulating factor (G-CSF), and nucleosomes are associated with the severity of AP and predict development of SAP among AP patients without OD on admission. The result concerning IL-8 and HGF was confirmed in a second study, which also shows that among patients with OD on admission IL-8 may predict persistent OD, i.e. SAP. The discovered signaling aberrations in NF-ĸB, STAT1, STAT3, and ERK1/2 MAPK pathways are largely similar in sepsis and SAP. However, only the results concerning STAT1 and STAT3 are associated with the severity of AP. Additionally, STAT3 distinguishes patients with persistent OD (i.e. sepsis and SAP) from those without OD (i.e. mild and moderately severe AP). In conclusion, circulating levels of IL-8 and HGF may serve as useful predictors of SAP in AP patients without OD on admission. Additionally, G-CSF and nucleosomes may predict development of SAP. Among patients with OD on admission, IL-8 may predict persistent OD. Signaling aberrations of circulating leukocytes in sepsis resemble those discovered in SAP. Aberrations in STAT1 and STAT3 pathways associate with the severity of AP and those in STAT3 with the presence of OD. Possibility that aberrations in STAT1 and STAT3 pathways provide novel markers for predicting development of OD warrants further studies. Early and accurate identification of patients at risk for SAP or OD may improve their prognosis. Additionally, such early markers may help to identify individual patients that will potentially benefit from immunomodulatory treatment modalities in the future.
|Myöntöpäivämäärä||18 toukokuuta 2018|
|Tila||Julkaistu - 2018|
|OKM-julkaisutyyppi||G5 Tohtorinväitöskirja (artikkeli)|
LisätietojaM1 - 114 s. + liitteet
- 3126 Kirurgia, anestesiologia, tehohoito, radiologia
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