Recombinant human hepatocyte growth factor provides protective effects in cerulein‐induced acute pancreatitis in mice

Domínguez, Mayrel Palestino; Peláez-Luna, Mario; Lazzarini‐Lechuga, Roberto; Rodriguez‐Ochoa, Ignacio; Souza, Verónica; Miranda, Roxana U.; Pérez-Aguilar, Benjamín; Bucio, Leticia; Marquardt, Jens U.; Gómez–Quiroz, Luis E.; Gutiérrez‐Ruiz, María Concepción

doi:10.1002/jcp.26444

Cited by 18 publications

(28 citation statements)

References 41 publications

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“…AP is the outcome of inopportune activation of proenzymes within acinar cells and following this process, the levels of digestive enzymes immediately increase in patient serum. We administered experimental AP by cerulein injection, which is a typical animal model of AP that induces pancreatitis signs similar to AP disease in human 3,35 . Data collected for this study demonstrate that hBM-MSCs treatment results in a reduction of serum amylase and decrease of lipase levels, as well as pathological alternations of AP, indicating that hBM-MSCs have beneficial effects on experimental models.…”

Section: Discussionmentioning

confidence: 99%

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Human Bone Marrow Mesenchymal Stromal Cells Attenuate Tissue Injury and Reduce Inflammation in Experimental Acute Pancreatitis

et al. 2021

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Purpose: Acute pancreatitis (AP) which is distinguished by local pancreatic necrosis, following by systemic organ failure is known as an inflammatory disease. Up to now, there are only a few treatment options accessible for patients suffering from AP. In this study, we aimed to examine the anti-inflammatory capacities of human bone marrow-derived mesenchymal stromal cells (hBM-MSC) in a detailed AP model experiment. Methods: AP was induced in C57BL/6 mice by intraperitoneal administration of cerulein (100 µg/kg/h × 7 doses) at intervals of 1 hour (h). Then, 2×105 MSCs were infused in the AP mice by tail vein 6 h after the last cerulein injection. Mice were sacrificed 12 h following the injection of hBM-MSC, and blood samples and pancreas tissues were obtained. Results: We first determined the presence of transplanted hBM-MSC in the pancreas of mice with AP, but not the control mice. Our data indicate that administration of hBM-MSCs to mice with AP lead to (i) decreased serum levels of amylase, lipase and myeloperoxidase activities, (ii) downregulation of proinflammatory cytokine, macrophage inflammatory protein 2 (MIP-2), and (iii) upregulation of the anti-inflammatory cytokine, interleukin 10 (IL-10). Moreover, hBM-MSC administration results in notably attenuated cerulein-induced histopathological alternations and edema. Conclusion: we demonstrate that hBM-MSC attenuates AP signs and indicating that hMB-MSC therapy could be a suitable approach for the treatment of inflammatory disease such as AP.

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Section: Discussionmentioning

confidence: 99%

“…Acute pancreatitis (AP), as an important inflammatory illness, presents clinically from mild and self-limiting to severe and necrotizing disease [1][2][3] . Severe AP is a major challenge for clinicians, and the mortality in this group of patients is 25-30% 4 .…”

Section: Introductionmentioning

confidence: 99%

Human Bone Marrow Mesenchymal Stromal Cells Attenuate Tissue Injury and Reduce Inflammation in Experimental Acute Pancreatitis

et al. 2021

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“…A major limitation of chemotherapeutic regimens is the onset of collateral effects inducing damages to a plethora of organs and tissues [31]. It is well known that wild type MET signaling has a protective role in lung fibrosis [32], liver cirrhosis [33], acute pancreatitis [34], and acute kidney injury [35]. Moreover, MET activation protects cardiomyocytes from apoptosis through inhibition of the mitochondrial pathway [12,36,37].…”

Section: Discussionmentioning

confidence: 99%

Molecular Engineering Strategies Tailoring the Apoptotic Response to a MET Therapeutic Antibody

Modica

Gallo

Chiriaco

et al. 2020

Cancers

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The MET oncogene encodes a tyrosine kinase receptor involved in the control of a complex network of biological responses that include protection from apoptosis and stimulation of cell growth during embryogenesis, tissue regeneration, and cancer progression. We previously developed an antagonist antibody (DN30) inducing the physical removal of the receptor from the cell surface and resulting in suppression of the biological responses to MET. In its bivalent form, the antibody displayed a residual agonist activity, due to dimerization of the lingering receptors, and partial activation of the downstream signaling cascade. The balance between the two opposing activities is variable in different biological systems and is hardly predictable. In this study, we generated and characterized two single-chain antibody fragments derived from DN30, sharing the same variable regions but including linkers different in length and composition. The two engineered molecules bind MET with high affinity but induce different biological responses. One behaves as a MET-antagonist, promoting programmed cell death in MET "addicted" cancer cells. The other acts as a hepatocyte growth factor (HGF)-mimetic, protecting normal cells from doxorubicin-induced apoptosis. Thus, by engineering the same receptor antibody, it is possible to generate molecules enhancing or inhibiting apoptosis either to kill cancer cells or to protect healthy tissues from the injuries of chemotherapy.

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“…A large number of experiments in different inflammatory diseases show controversial effects of the activation of the HGF/c-Met axis. In atherosclerosis, HGF was found to be associated with disease progression [ 42 ], whereas in a pancreatitis model in mice and in drug-induced oxidative liver damage [ 43 ], results displayed protective effects of the administration of recombinant human HGF.…”

Section: Discussionmentioning

confidence: 99%

c‐Met Signaling Protects from Nonalcoholic Steatohepatitis‐ (NASH‐) Induced Fibrosis in Different Liver Cell Types

Drescher

Schumacher

Schenker

et al. 2018

Oxidative Medicine and Cellular Longevity

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Nonalcoholic steatohepatitis (NASH) is the most common chronic, progressive liver disease in Western countries. The significance of cellular interactions of the HGF/c-Met axis in different liver cell subtypes and its relation to the oxidative stress response remains unclear so far. Hence, the present study is aimed at investigating the role of c-Met and the interaction with the oxidative stress response during NASH development in mice and humans. Conditional c-Met knockout (KO) lines (LysCre for Kupffer cells/macrophages, GFAPCre for α-SMA+ and CK19+ cells and MxCre for bone marrow-derived immune cells) were fed chow and either methionine-choline-deficient diet (MCD) for 4 weeks or high-fat diet (HFD) for 24 weeks. Mice lacking c-Met either in Kupffer cells, α-SMA+ and CK19+ cells, or bone marrow-derived immune cells displayed earlier and faster progressing steatohepatitis during dietary treatments. Severe fatty liver degeneration and histomorphological changes were accompanied by an increased infiltration of immune cells and a significant upregulation of inflammatory cytokine expression reflecting an earlier initiation of steatohepatitis development. In addition, animals with a cell-type-specific deletion of c-Met exhibited a strong generation of reactive oxygen species (ROS) by dihydroethidium (hydroethidine) (DHE) staining showing a significant increase in the oxidative stress response especially in LysCre/c-Metmut and MxCre/c-Metmut animals. All these changes finally lead to earlier and stronger fibrosis progression with strong accumulation of collagen within liver tissue of mice deficient for c-Met in different liver cell types. The HGF/c-Met signaling pathway prevents from steatosis development and has a protective function in the progression to steatohepatitis and fibrosis. It conveys an antifibrotic role independent on which cell type c-Met is missing (Kupffer cells/macrophages, α-SMA+ and CK19+ cells, or bone marrow-derived immune cells). These results highlight a global protective capacity of c-Met in NASH development and progression.

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Recombinant human hepatocyte growth factor provides protective effects in cerulein‐induced acute pancreatitis in mice

Cited by 18 publications

References 41 publications

Human Bone Marrow Mesenchymal Stromal Cells Attenuate Tissue Injury and Reduce Inflammation in Experimental Acute Pancreatitis

Human Bone Marrow Mesenchymal Stromal Cells Attenuate Tissue Injury and Reduce Inflammation in Experimental Acute Pancreatitis

Molecular Engineering Strategies Tailoring the Apoptotic Response to a MET Therapeutic Antibody

c‐Met Signaling Protects from Nonalcoholic Steatohepatitis‐ (NASH‐) Induced Fibrosis in Different Liver Cell Types

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