The heparin-binding proteome in normal pancreas and murine experimental acute pancreatitis.

Quentin M Nunes,Robert Sutton,Changye Sun,Wei Huang,Xiaoying Zhang,Daniel J Rigden,Deborah M Simpson,Thao P Bui,Dunhao Su,Yong Li,Philip J Brownridge,David G Fernig,Robert J Beynon,Jon M Jacobs

doi:10.1371/journal.pone.0217633

Quentin M Nunes, Robert Sutton + Show 12 more

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https://doi.org/10.1371/journal.pone.0217633

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Abstract

Acute pancreatitis (AP) is acute inflammation of the pancreas, mainly caused by gallstones and alcohol, driven by changes in communication between cells. Heparin-binding proteins (HBPs) play a central role in health and diseases. Therefore, we used heparin affinity proteomics to identify extracellular HBPs in pancreas and plasma of normal mice and in a caerulein mouse model of AP. Many new extracellular HBPs (360) were discovered in the pancreas, taking the total number of HBPs known to 786. Extracellular pancreas HBPs form highly interconnected protein-protein interaction networks in both normal pancreas (NP) and AP. Thus, HBPs represent an important set of extracellular proteins with significant regulatory potential in the pancreas. HBPs in NP are associated with biological functions such as molecular transport and cellular movement that underlie pancreatic homeostasis. However, in AP HBPs are associated with additional inflammatory processes such as acute phase response signalling, complement activation and mitochondrial dysfunction, which has a central role in the development of AP. Plasma HBPs in AP included known AP biomarkers such as serum amyloid A, as well as emerging targets such as histone H2A. Other HBPs such as alpha 2-HS glycoprotein (AHSG) and histidine-rich glycoprotein (HRG) need further investigation for potential applications in the management of AP. Pancreas HBPs are extracellular and so easily accessible and are potential drug targets in AP, whereas plasma HBPs represent potential biomarkers for AP. Thus, their identification paves the way to determine which HBPs may have potential applications in the management of AP.

Highlights

The pancreas develops from endodermal cells in the foregut and has important exocrine and endocrine functions [1]
Histological analysis of samples of these pancreases demonstrated the classic features of normal pancreas with preserved acinar pattern (Fig 1A) and those associated with acute pancreatitis (AP), namely marked oedema, vacuolisation, neutrophil infiltration in the ductal margins and parenchyma of the pancreas, with focal acinar cell necrosis (Fig 1B)
Heparin-binding proteins (HBPs) are functionally associated with the regulation of cell communication that underlies many physiological and pathological processes

Summary

Introduction

The pancreas develops from endodermal cells in the foregut and has important exocrine and endocrine functions [1]. Acute pancreatitis (AP) is acute inflammation of the pancreas and is mainly caused by gallstones and alcohol [2]. It is a leading gastrointestinal cause of hospitalization and has significant quality of life implications for the patient and cost implications for health systems [3]. The clinical characteristics of AP suggest that an important molecular component is changed in cell communication within the pancreas and, in severe AP, systemically between the pancreas and other organs. The importance of extracellular proteins in mediating communication between cells in multicellular organisms is underscored by the demonstration that the increase in multicellular organism complexity is accompanied by an expansion and increase in the complexity of extracellular proteins [6]. A key non-protein component of the extracellular space is the glycosaminoglycan heparan sulfate (HS), because it binds and regulates the activity of a large number of extracellular proteins involved in cell communication ([7]; reviewed in [8]; [9])

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