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Research Article
Inhibition of DDR1 and DDR2 receptors: The Potential Therapeutic Option to Treat Pancreatic Fibrosis Demonstrated in Experimental Chronic Pancreatitis Model
Chandraiah Godugu
National Institute of Pharmaceutical Education and Research
Corresponding Author
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Discoidin domain receptors (DDR1 and DDR2) are the collagen receptors of the family tyrosine kinases, which play significant role in the diseases like inflammation, fibrosis and cancer. Chronic pancreatitis (CP) is a fibro-inflammatory disease in which recurrent pancreatic inflammation leads to pancreatic fibrosis.
Methods: In the present study for the first time, we have investigated the role of DDR1 and DDR2 in cerulein-induced CP. Pancreatic DDR1 and DDR2 expression was examined by immunoblotting and immunostaining analysis. Subsequently, the protective effects of selective DDR1 and DDR2 inhibitor, imatinib (IMT) was investigated in CP mice as a therapeutic intervention.
Results: Activated pancreatic stellate cells (PSCs) and CP mice showed significant upregulation of DDR1 and DDR2 expression. Pharmacological intervention with IMT effectively downregulated DDR1 and DDR2 expression. Further, we found that pancreatic injury, inflammation, extracellular matrix (ECM) deposition and PSCs activation were significantly inhibited by IMT. Further, we found a significant inhibition of TGF-β1/Smad signaling pathway by IMT and showed its protective effects against CP and associated fibrosis.
Conclusions: Taken together, these results suggest that inhibition of DDR1 and DDR2 controls pancreatic inflammation and fibrosis, which could represent an attractive and promising therapeutic strategy for the treatment of CP.
Keywords
Chronic pancreatitis, Fibrosis, Inflammation, Discoidin domain receptors, Imatinib
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CURRENT STATUS: Under Review
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Received 08 Jan, 2021
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Received 08 Jan, 2021
Reviewer #3 agreed
On 31 Dec, 2020
Reviewer #6 agreed
On 31 Dec, 2020
Reviewer #2 agreed
On 31 Dec, 2020
Reviewer #1 agreed
On 31 Dec, 2020
Reviewer #4 agreed
On 31 Dec, 2020
Reviewer #5 agreed
On 31 Dec, 2020
Reviewers invited
Invitations sent on 29 Dec, 2020
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Editor invited
On 23 Dec, 2020
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This preprint is under consideration at Scientific Reports. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Inhibition of DDR1 and DDR2 receptors: The Potential Therapeutic Option to Treat Pancreatic Fibrosis Demonstrated in Experimental Chronic Pancreatitis Model
Chandraiah Godugu
National Institute of Pharmaceutical Education and Research
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 29 Dec, 2020
No community comments so far
Review #3 received
Received 08 Jan, 2021
Review #1 received
Received 08 Jan, 2021
Review #2 received
Received 08 Jan, 2021
Reviewer #3 agreed
On 31 Dec, 2020
Reviewer #6 agreed
On 31 Dec, 2020
Reviewer #2 agreed
On 31 Dec, 2020
Reviewer #1 agreed
On 31 Dec, 2020
Reviewer #4 agreed
On 31 Dec, 2020
Reviewer #5 agreed
On 31 Dec, 2020
Reviewers invited
Invitations sent on 29 Dec, 2020
Editor assigned
On 23 Dec, 2020
Editor invited
On 23 Dec, 2020
Submission checks complete
On 23 Dec, 2020
First submitted
On 17 Dec, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Discoidin domain receptors (DDR1 and DDR2) are the collagen receptors of the family tyrosine kinases, which play significant role in the diseases like inflammation, fibrosis and cancer. Chronic pancreatitis (CP) is a fibro-inflammatory disease in which recurrent pancreatic inflammation leads to pancreatic fibrosis.
Methods: In the present study for the first time, we have investigated the role of DDR1 and DDR2 in cerulein-induced CP. Pancreatic DDR1 and DDR2 expression was examined by immunoblotting and immunostaining analysis. Subsequently, the protective effects of selective DDR1 and DDR2 inhibitor, imatinib (IMT) was investigated in CP mice as a therapeutic intervention.
Results: Activated pancreatic stellate cells (PSCs) and CP mice showed significant upregulation of DDR1 and DDR2 expression. Pharmacological intervention with IMT effectively downregulated DDR1 and DDR2 expression. Further, we found that pancreatic injury, inflammation, extracellular matrix (ECM) deposition and PSCs activation were significantly inhibited by IMT. Further, we found a significant inhibition of TGF-β1/Smad signaling pathway by IMT and showed its protective effects against CP and associated fibrosis.
Conclusions: Taken together, these results suggest that inhibition of DDR1 and DDR2 controls pancreatic inflammation and fibrosis, which could represent an attractive and promising therapeutic strategy for the treatment of CP.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8